Nasal drug delivery is ideally suited to the topical treatment of local nasal conditions, such as the common cold, allergic and nonallergic rhinitis, nasal polyps, and chronic nasal and sinus inflammations. Drugs for topical delivery include antihistamines (e.g., azelastine), anti-inflammatory corticosteroids (e.g., budesonide and fluticasone), and topical nasal decongestants (e.g., oxymetazoline and xylometazoline). The idea is that delivered locally, these drugs are effectively targeted to their site of action, which should maximize their therapeutic effect while minimizing unwanted side effects. However, as described in this chapter, current delivery devices are in fact not very effective at targeting to the posterior nasal cavity; drug delivery to this region requires optimization.

The nasal route is also increasingly used as a noninvasive route for systemic delivery, particularly when rapid systemic absorption and clinical effect are desired, for example, in the rapid relief of a migraine attack. Marketed nasal antimigraine drugs include sumatriptan (Imitrex^® nasal spray), zolmitriptan (Zomig^® nasal spray), and dihydroergotamine mesylate (Migranal^® nasal spray). A further example is the intranasal (IN) delivery of opiates, such as fentanyl (Lazanda^® and Instanyl^®), when rapid pain relief is required. In addition, nasal delivery has become a useful alternative for systemic drug absorption in situations where the gastrointestinal (GI) route is unfeasible, such as for patients with nausea, vomiting, and gastric stasis (frequent in migraine patients); or patients with swallowing difficulties, such as children and elderly; or those who suffer from dry mouth.

The nasal route is suitable for drugs with poor oral bioavailability, due to, for example, GI instability, poor and delayed oral absorption, and drugs that undergo extensive first-pass effects in the gut wall or liver. A variety of peptide and protein drugs that demonstrate poor oral bioavailability are capable of systemic absorption via the nasal route, and a number of commercially available preparations are on the market, including for nafarelin (Synarel^®), salmon calcitonin (Miacalcin^®, Roritcal^®), oxytocin (Syntocinon^®), desmopressin (Desmospray^®), and buserelin (Suprecur^®). Similarly, “biologic” drugs such as monoclonal antibodies and antisense DNA demonstrate poor oral bioavailability and currently must be given by injection. These molecules are unlikely to realize their full clinical potential unless the patient can easily and conveniently self-administer the drug. The nasal route has emerged as a highly promising alternative epithelial route for the systemic delivery of these drugs.

The nasal route may also be used as an alternative to injections for the administration of vaccines, potentially including immunotherapeutics. For example, FluMist^®, a nasal vaccine to protect against influenza, has been commercially available since 2003. A further possibility of the nasal route is as a portal of entry for drugs into the central nervous system (CNS). The barrier between the blood and the brain (the blood–brain barrier [BBB]) plays a vital role in protecting the delicate milieu of the brain, but also prevents CNS therapeutics from gaining access. Exploitation of a direct “nose-to-brain” (N2B) pathway, which bypasses the BBB, could therefore facilitate the treatment of numerous disabling psychiatric and neurodegenerative disorders, as well as brain cancers.

The complex anatomical features of the nose are designed to facilitate its role in protecting the lower airways by filtering, warming, and humidifying the inhaled air. When air enters the nostrils, it passes first through the nasal vestibule, which is lined by the skin containing vibrissae (short, coarse hairs) that filter out large dust particles. The nasal valve is the narrowest portion of the nasal passage, with a mean cross-sectional area of only about 0.6 cm² on each side. It is the primary regulator of airflow and resistance, accounting for up to 80% of nasal resistance, and almost half of the total resistance of the entire respiratory system. With increasing inspiratory flow rate, the action of Bernoulli forces progressively narrow the valve. The valve can even close completely with vigorous sniffing. Beyond the valve, the nasal cavity comprises a set of narrow, warrenlike passageways, the meatuses. The turbinates introduce turbulence to the airflow, forcing it through the narrow meatuses and ensuring maximal contact between the incoming air and the mucosal surface. The dense vascular capillary bed directly beneath the mucosal surface, in addition to the mucus layer and nasal secretions, ensures that the incoming air is warmed and humidified. The arrangement of conchae and meatuses also increases the available surface area of the internal nose and prevents dehydration by trapping water droplets during exhalation.

Goblet cells in the mucosa secrete mucus, a complex, thick, viscoelastic gel, containing specific glycoproteins known as mucins, which give the secretions their characteristic viscosity and elasticity. Mucos also contains proteins, lipids, and antibacterial enzymes (such as lysozyme and immunoglobulins). The secreted mucosal blanket lies over the nasal epithelium and functions as a protective barrier against the entry of pathogens. The underlying epithelial cells are ciliated, and the mucus works in tandem with the ciliated cells, in an extremely efficient self-cleansing mechanism known as the “mucociliary escalator.” In this process, inhaled particulates (dust, pollutants, microbes, etc.) become trapped in the sticky mucus layer. The underlying cilia beat in unison, via an ATP energy–dependent process, propelling the mucus layer toward the throat. The ciliary movement can be considered a form of rhythmic waving, which enables hooklike structures at the ciliary tips to propel mucus along. The ciliary beat frequency is in the range of about 100 strokes per minute. At the throat, entrapped particles are removed, either by being swallowed or expectorated.

The same anatomical and physiological features that enable the many vital functions of the nose also impose substantial hurdles for efficient nasal drug delivery (Djupesland 2013; Djupesland et al. 2014). These barriers are considered here.

The small size of the nasal cavity limits the volume of a liquid formulation that can be administered. Typically, volumes about 100–200 μL in each nostril are possible. A larger volume can drip back out of the nostril, which can cause discomfort and embarrassment. Drip-out also reduces the actual fraction of dose retained in the cavity, thereby introducing variability in the administered dose. Throat run-off is a further problem: high liquid volumes can “flood” the nasal cavity so that the dose runs off to the throat and is swallowed, resulting in drug loss and a bitter aftertaste, which can adversely affect patient compliance. Drugs with low aqueous solubility and/or requiring high doses can therefore present a problem for IN delivery.

The complex geometry of the nose and the associated turbulent airflow present multiple barriers to the access and penetration of drug molecules. Initial entry is limited by the small size of the nasal vestibule. Beyond the vestibule, the narrow, slit-like, nasal valve constitutes a major, and often ignored, challenge to successful nasal drug delivery and targeting. As described earlier, the narrow valve becomes even narrower during inhalation, and it can close entirely during sniffing. Beyond the valve, the posterior nasal cavity comprises a complex labyrinthine series of tunnels and passageways, with turbulent airflow, which makes deep penetration further into the cavity very difficult.

Drug delivery from conventional nasal delivery devices (sprays, drops, pressurized metered-dose inhalers [pMDIs], nebulizers, and powder sprayers) is described in detail in the following texts, but it should be pointed out here at the outset that drug delivery from all the currently available conventional devices is suboptimal. A common feature of all these devices is their limited ability to deliver drug past the nasal valve, resulting in a large fraction of the dose being deposited in the anterior region of the nose (Aggarwal et al. 2004; Djupesland et al. 2014). Drug deposited in the anterior cavity is subject to loss via drip out and run off to the throat; further elimination occurs via sneezing, mechanical wiping, and ingestion. Anterior deposition also causes patient annoyance and discomfort or, more seriously, irritation and crusting of the tissue (Waddell et al. 2003). From a drug delivery perspective, deposition in the anterior cavity means that the drug is delivered to a limited, restricted portion of the nose, but fails to reach the much larger, highly vascular, expanded surface area of the posterior cavity.

Drug molecules that do succeed in penetrating the valve tend to enter the posterior cavity via the wider, lower part of the triangular-shaped valve, thereby gaining access to the floor of the nasal cavity. As such, the formulation tends to run off along the cavity floor to the throat but has limited exposure to the rest of the posterior cavity (Djupesland 2013).

The mucus layer and the process of mucociliary clearance present a number of obstacles for nasal drug delivery. For systemically acting drugs, the mucus layer presents a diffusional barrier for a drug in transit to the epithelial surface. The rate of diffusion of a drug through mucus depends on a number of factors, including the thickness and viscosity of the mucus layer, as well as the physicochemical properties of the drug. However, nasal mucus is only a few microns thick (in contrast, for example, to the GI tract, which has a mucus thickness of about 500 μm) and so does not present as substantial diffusional barrier here as compared to the GI tract and other mucosal sites.

Mucociliary clearance may limit the contact time of a drug molecule with the epithelial surface. The drug, instead of settling locally, can instead be removed to the throat, to be swallowed or expectorated. The mucociliary escalator moves the mucus blanket toward the nasopharynx at an average speed of 6 mm/minute, so that a particle deposited in the valve region of the nose is cleared to the nasopharynx within 15–20 minutes. Limited contact time with the absorbing surface may compromise drug absorption for a systemically active drug, or shorten drug–receptor interaction time for a locally acting drug.

The nasal cycle is an alternating cycle of congestion and decongestion that occurs every 1–4 hours and is observed in at least 80% of healthy humans. This reciprocal autonomic cycling of mucosal swelling means that at any given time, even though the total combined resistance remains fairly constant, one of the nostrils is generally considerably more congested than the other, with most of the airflow passing through the passage of lesser congestion. This may be a challenge to efficient drug delivery. Therefore, for most indications, it would seem prudent to deliver the drug to both nasal passages, when administering a given dose (Djupesland 2013).