Intranasal Drug Delivery to the Brain
Drug delivery into the central nervous system (CNS) compartment is often restricted by the blood–brain barrier (BBB) and blood–cerebrospinal fluid barriers (BCSFB) that separate the blood from brain interstitial and cerebrospinal fluids, respectively. New
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Intranasal Drug Delivery to the Brain Jeffrey J. Lochhead and Robert G. Thorne
Abstract Drug delivery into the central nervous system (CNS) compartment is often restricted by the blood–brain barrier (BBB) and blood–cerebrospinal fluid barriers (BCSFB) that separate the blood from brain interstitial and cerebrospinal fluids, respectively. New strategies to circumvent the BBB are greatly needed to utilize polar pharmaceuticals and large biotherapeutics for CNS disease treatment because the BBB is typically impermeable to such compounds. Intranasal administration is a noninvasive method of drug delivery that potentially allows even large biotherapeutics access to the CNS along extracellular pathways associated with the olfactory and trigeminal nerves. Rapid effects, ease of self-administration, and the potential for frequent, chronic dosing are among the potential advantages of the intranasal route. 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 the preclinical and clinical literature related to intranasal targeting of biotherapeutics to the CNS and speculate on future directions.
J.J. Lochhead Pharmaceutical Sciences Division, University of Wisconsin—Madison School of Pharmacy, Madison, WI, USA R.G. Thorne (*) Pharmaceutical Sciences Division, University of Wisconsin—Madison School of Pharmacy, Madison, WI, USA Center for Neuroscience & Neuroscience Training Program, University of Wisconsin—Madison, Madison, WI, USA Cellular and Molecular Pathology Graduate Training Program, University of Wisconsin—Madison, Madison, WI, USA Clinical Neuroengineering Training Program, University of Wisconsin—Madison, Madison, WI, USA e-mail: [email protected] M. Hammarlund-Udenaes et al. (eds.), Drug Delivery to the Brain, AAPS Advances in the Pharmaceutical Sciences Series 10, DOI 10.1007/978-1-4614-9105-7_14, © American Association of Pharmaceutical Scientists 2014
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J.J. Lochhead and R.G. Thorne
Introduction
The blood–brain barrier (BBB) and blood–cerebrospinal fluid barriers (BCSFB) are critical for maintenance of central nervous system (CNS) homeostasis. Although these barriers restrict neurotoxic substances from entering the brain, they also restrict many potential therapeutics from reaching the CNS. The BBB, formed by brain endothelial cells lining microvessels, exhibits a low rate of pinocytosis and possesses tight junction (TJ) protein complexes on neighboring cells that limit paracellular permeability (Reese and Karnovsky 1967). These TJ create a high transendothelial electrical resistance of 1,500–2,000 Ω cm2 compared to 3–30 Ω cm2 across most peripheral microvessels (Crone and Olesen 1982; Butt et al. 1990). This high resistance is associated with very low paracellular permeability, and typically, only small (
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