Intranasal Drug Delivery to the Brain

Jeffrey J. Lochhead, Niyanta N. Kumar, Geetika Nehra, Mallory J. Stenslik, Luke H. Bradley, Robert G. Thorne

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

Abstract

The barriers that separate the blood from brain interstitial and cerebrospinal fluids present a significant challenge to efficient and practical drug delivery into the central nervous system (CNS). New strategies to circumvent the blood-brain barrier (BBB) have long been needed to utilize polar pharmaceuticals and large biotherapeutics for CNS disease treatment because the BBB is typically impermeable to such compounds. The increasing application of biologics as therapeutics over the past several decades has brought much new interest in routes of drug delivery that may be more easily utilized for chronic dosing of large molecules, e.g., oral, subcutaneous, transdermal, pulmonary, and intranasal administration. The intranasal route in particular offers a number of advantages for chronic dosing including its noninvasiveness, efficient uptake and absorption into a highly vascular submucosa, avoidance of hepatic first-pass elimination, rapid pharmacokinetic profiles, and ease of administration. Importantly, the intranasal route has also been demonstrated to potentially allow a variety of drugs direct access to the brain and/or cerebrospinal fluid. Studies over the past few decades have shown that even large biotherapeutics may have access to the CNS along extracellular pathways associated with the olfactory and trigeminal nerves. This chapter provides an overview of the unique anatomic and physiologic attributes of the nasal mucosa and its associated cranial nerves that allow small but significant fractions of certain intranasally applied drugs to transfer across the nasal epithelia and subsequently be transported directly into the CNS. We also review some of the preclinical and clinical literature related to intranasal targeting of biologics to the CNS and comment on future directions for the further clinical translation of this route of administration.

Original languageEnglish
Title of host publicationAAPS Advances in the Pharmaceutical Sciences Series
Pages461-500
Number of pages40
DOIs
StatePublished - 2022

Publication series

NameAAPS Advances in the Pharmaceutical Sciences Series
Volume33
ISSN (Print)2210-7371
ISSN (Electronic)2210-738X

Bibliographical note

Funding Information:
Acknowledgments Portions of this work were supported by the University of Wisconsin-Madison School of Pharmacy, the Graduate School at the University of Wisconsin, the Michael J. Fox Foundation for Parkinson’s Research, the Wisconsin Alzheimer’s Disease Research Center (NIH P50-AG033514), and the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS; grant UL1TR000427). Additional funding was provided by the NIA (T32-AG000242: M.J.S.). All content is solely the responsibility of the authors and does not necessarily represent the off ial views of the NIH. Robert Thorne is currently a full-time employee of Denali Therapeutics, and both Niyanta Kumar and Mallory Stenslik are currently full-time employees of Merck. Additionally, Robert Thorne acknowledges service on the scientic advisory boards for Alcyone Lifesciences and for a Lundbeck Foundation-funded Research Initiative on Brain Barriers and Drug Delivery. Jeffrey Lochhead and Robert Thorne also acknowledge being inventors on patents and/or patent applications related to intranasal drug delivery. Luke Bradley acknowledges being an inventor on patents and/or patent applications related to DNSP-11.

Funding Information:
Portions of this work were supported by the University of Wisconsin-Madison School of Pharmacy, the Graduate School at the University of Wisconsin, the Michael J. Fox Foundation for Parkinson’s Research, the Wisconsin Alzheimer’s Disease Research Center (NIH P50-AG033514), and the Clinical and Translational Science Award (CTSA) program, through the NIH National Center for Advancing Translational Sciences (NCATS; grant UL1TR000427). Additional funding was provided by the NIA (T32-AG000242: M.J.S.). All content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Robert Thorne is currently a full-time employee of Denali Therapeutics, and both Niyanta Kumar and Mallory Stenslik are currently full-time employees of Merck. Additionally, Robert Thorne acknowledges service on the scientific advisory boards for Alcyone Lifesciences and for a Lundbeck Foundation-funded Research Initiative on Brain Barriers and Drug Delivery. Jeffrey Lochhead and Robert Thorne also acknowledge being inventors on patents and/or patent applications related to intranasal drug delivery. Luke Bradley acknowledges being an inventor on patents and/or patent applications related to DNSP-11.

Publisher Copyright:
© 2022, American Association of Pharmaceutical Scientists.

Keywords

  • Drug delivery
  • Gene vectors
  • Nasal passage
  • Olfactory
  • Proteins
  • Stem cells
  • Trigeminal

ASJC Scopus subject areas

  • Pharmaceutical Science

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