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Review
. 2018 Aug 3;10(3):116.
doi: 10.3390/pharmaceutics10030116.

Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa

Stella Gänger  1   2 , Katharina Schindowski  3
Affiliations
Review

Tailoring Formulations for Intranasal Nose-to-Brain Delivery: A Review on Architecture, Physico-Chemical Characteristics and Mucociliary Clearance of the Nasal Olfactory Mucosa

Stella Gänger et al. Pharmaceutics. .

Abstract

The blood-brain barrier and the blood-cerebrospinal fluid barrier are major obstacles in central nervous system (CNS) drug delivery, since they block most molecules from entering the brain. Alternative drug delivery routes like intraparenchymal or intrathecal are invasive methods with a remaining risk of infections. In contrast, nose-to-brain delivery is a minimally invasive drug administration pathway, which bypasses the blood-brain barrier as the drug is directed from the nasal cavity to the brain. In particular, the skull base located at the roof of the nasal cavity is in close vicinity to the CNS. This area is covered with olfactory mucosa. To design and tailor suitable formulations for nose-to-brain drug delivery, the architecture, structure and physico-chemical characteristics of the mucosa are important criteria. Hence, here we review the state-of-the-art knowledge about the characteristics of the nasal and, in particular, the olfactory mucosa needed for a rational design of intranasal formulations and dosage forms. Also, the information is suitable for the development of systemic or local intranasal drug delivery as well as for intranasal vaccinations.

Keywords: CNS drug delivery; NALT; biopharmaceuticals; dosage form; medical device; nanoparticles; olfactory epithelium; respiratory epithelium; semisolid.

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Conflict of interest statement

The authors declare no commercial or financial conflict of interest.

Figures

Figure 1
Figure 1
Nose-to-brain (N2B) delivery allows application of drugs at the roof of the nasal cavity, which are transported to the central nervous system (CNS) of humans (A) and rodents (B). N2B transport can either be mediated via the olfactory or the trigeminal pathway. Drugs passing along the olfactory pathway target the olfactory bulb, whereas drugs transported via the trigeminal pathway are delivered predominantly to the brain stem. Abbreviations: OE: olfactory epithelium/mucosa; RE: respiratory epithelium/mucosa.
Figure 2
Figure 2
Anatomy of the human nasal cavity. Squamous mucosa (green) is located at the frontal parts of the nasal vestibules. The three turbinates (inferior, middle and superior) humidify and warm the inhaled air. The area covered predominantly with respiratory mucosa is labelled in blue. The olfactory mucosa (yellow) is located next to the cribriform plate at the skull base down to the superior turbinate. Nasally transmitted substances can cross the cribriform plate via different pathways to enter the brain. Nasopharynx-associated lymphatic tissue (NALT) is located in close proximity to the tonsils at the nasopharynx.
Figure 3
Figure 3
Structure of the olfactory mucosa: the olfactory sensory neurons (OSN) and the trigeminal nerve are embedded in a layer of supporting cells (sustentacular cells) and Bowman’s glands. Horizontal and globose basal stem cells are embedded in the lamina propria. The OSN axons are surrounded by olfactory ensheathing cells and form neuronal bundles. The neuronal bundles penetrate the cribriform plate and extend into the olfactory bulb.
Figure 4
Figure 4
Structure of motile and non-motile cilia. Motile cilia show a cartwheel like structure with nine microtubule pairs surrounding a central pair. The outer microtubule pairs are connected via radial spokes to the central one. Motility of the cilium is provided by the nexin-dynein motor complex. Non-motile cilia lack the central microtubule pair as well as the nexin-dynein motor complex.
Figure 5
Figure 5
Secreted mucin fibres have a common scaffold consisting of a recurring PTS backbone (proline-threonine-serine) with intermitting cysteine rich domains. These domains are coiled due to their disulphide bond interactions. PTS backbones contain different amino sugar glycosylation such as N-Acetylgalactosamine (GalNac), N-Acetylgalactosamine-Galactose (GalNac-Gal) glycosylation, N-Acetylgalactosamine-Galactose-N-Acetylglucosamine (GalNac-Gal-GlcNac) glycosylation, or N-Acetylgalactosamine-Galactose-N-Acetylglucosamine-Sialic acid (GalNac-Gal-GlcNac-Sa) glycosylation. The degree of glycosylation influences mucus permeability and viscosity.
Figure 6
Figure 6
Physicochemical properties of mucus. The viscoelasticity and permeability of mucus is dependent of the degree of glycosylation and fibre interaction, as well as of the pore size, ion concentration and pH.
Figure 7
Figure 7
Four different routes have been described for N2B drug delivery. The extracellular pathway ① directs the drug to the CNS along the OSN (or trigeminal nerve which is not shown here) via bulk flow processes. For the intracellular route ② the drug is endocytosed and then shuttled to the CNS where it is finally exocytosed. ③ and ④ describe drug transport through or along supporting cells. The drug molecule can either be endocytosed by supporting cells or travel through the intercellular space. By travelling through the intercellular space ④ the drug has to pass tight junctions like zonula occludens (ZO), claudin (CL) and occludin (OC). It should be noted that intranasal drug delivery is rather a mixture of these different pathways than being limited to one only. Abbreviations: SUS: sustentacular cells; OSN: olfactory sensory neuron; OEC: olfactory ensheathing cell; GOB: globose basal cells; HBC: horizontal basal cells; BG: Bowman’s gland; CP: cribriform plate; OB: olfactory bulb.
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