CONTENTS
10.2 Anatomy and Physiology of the Nasal Cavity: Implications for Drug Delivery
10.2.2 Mucus and the Mucociliary Escalator
10.3 Overview of Nasal Drug Delivery
10.3.1 Limiting Factors for Nasal Drug Delivery
10.3.1.1 Small Size of the Nasal Cavity
10.3.1.2 Constraints of Nasal Geometry: Access and Penetration Difficulties
10.3.1.3 Mucus and Mucociliary Clearance
10.3.1.8 Patient Acceptability and Compliance
10.3.2 Nasal Deposition and Clearance
10.4 Nasal Drug Delivery Devices
10.4.2 Pressurized Metered-Dose Inhalers
10.4.6 Breath Powered™ Bi-Directional™ Nasal Device: A Case Study
10.5 Nasal Formulation Factors
10.5.3 Mucoadhesives and Ciliastatics
10.5.4 Other Formulation Excipients
10.5.5 Micro- and Nanoparticulate Drug Delivery Systems
10.6 Nose-to-Brain Drug Delivery
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.
10.2 ANATOMY AND PHYSIOLOGY OF THE NASAL CAVITY: IMPLICATIONS FOR DRUG DELIVERY
The anatomy of the nose is shown in Figure 10.1. It extends 6–9 cm from the nostrils to the nasopharynx (throat) and is subdivided into left and right sides by a vertical partition, the nasal septum. The anterior portion of the nasal cavity, the nasal vestibule, then narrows into a triangular-shaped slit, the nasal valve, located approximately 1.5–2.5 cm from the nostril. Beyond the valve region, the posterior cavity is characterized by groove-like air passages (meatuses), formed by the scrolllike projections of the superior, middle, and inferior turbinates (conchae), which extend out from the lateral walls, almost reaching the septum.
Specific anatomical and physiological features of the nasal cavity have important implications for nasal drug delivery and targeting, and are discussed in more detail here.
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.
FIGURE 10.1 The complex anatomy of the nasal airways and paranasal sinuses. (With kind permission from Springer Science+Business Media: Drug Deliv. Transl. Res., Nasal drug delivery devices: Characteristics and performance in a clinical perspective—A review, 3, 2013, 42, Djupesland, P.G., Copyright 2012.)
10.2.2 MUCUS AND THE MUCOCILIARY ESCALATOR
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 nasal vestibule is lined by nonciliated, stratified squamous epithelium, which gradually transitions in the valve region into a ciliated, pseudostratified, columnar epithelium with goblet cells (see also Chapter 4, Figure 4.9). Mucus secreted by the goblet cells lies over the epithelium as a protective layer, and the mucociliary escalator filters the incoming air. In addition to cilia, the epithelial cells contain microvilli, which increase the available surface area.
Another important function of the nose is olfaction and, as such, the nasal cavity also contains a specialized olfactory epithelium, located in the roof of the nasal cavity. The olfactory epithelium and a direct olfactory pathway to the brain are described further in Section 10.6, in the context of N2B delivery (Figure 10.4).
10.3 OVERVIEW OF NASAL DRUG DELIVERY
As outlined in Section 10.1, nasal drug delivery is highly versatile and can be used for a variety of delivery options, including (1) for local delivery to the nose and (2) as a noninvasive route for systemic delivery, (3) for nasal immunization and vaccine delivery, and (4) for delivery of drugs to the CNS, via N2B delivery. The nasal route offers a number of advantages for these various delivery options, outlined here.
1. An expanded surface area: The area available for absorption is enhanced by the labyrinthine passages of the nasal cavity, as well as the microvilli present on the apical surface of the epithelial cells. The total surface area of the nasal cavity is about 160 cm2 (although the effective surface area for absorption is influenced by the type of dosage form used to deliver the drug, and other factors).
2. Permeable epithelium: The epithelium of the nose is described in Chapter 4 (Figure 4.9). It is more permeable than that of the GI tract. For example, molecules larger than 500 Da are too large to permeate the GI tract via transcellular passive diffusion, whereas the cutoff molecular weight for nasal transcellular diffusion seems to be about 1000 Da. This enhanced permeability, coupled with reduced metabolic activity, accounts for the number of commercially available preparations for the systemic delivery of peptide drugs via the IN route, as listed in Section 10.1.
3. Rich blood supply: The nasal mucosa is highly vascularized, with specialized capacitance vessels that facilitate heat exchange and other physiological roles. The rich blood supply promotes the rapid absorption of drug molecules and is especially useful when rapid onset is desirable, for example, in the treatment of migraine attacks or breakthrough pain (BTP) in cancer.
4. Relatively low enzymatic activity: Nasal secretions possess a wide range of enzymes, including proteases such as neutral endopeptidase, aminopeptidase peroxidase, and caboxypeptidase N. Furthermore, intracellular enzymes are found in the epithelial cells lining the cavity. Nevertheless, the metabolic activity of the nose is relatively low, in particular in comparison with other epithelial sites such as the GI tract, so that enzymatic activity is not considered a substantial obstacle to nasal drug delivery. Hepatic first-pass metabolism is also avoided via this route.
5. Accessibility and compliance: The nasal route is easily accessible and nasal delivery devices (sprays, drops, etc.) tend to be unobtrusive and relatively easy to use. The route is noninvasive, with all the associated advantages over parenteral delivery, e.g., no needles/sharps and associated biohazard/disposal issues, less need for specialized medical personnel to administer the dose, nasal formulations do not normally require cold storage or have to be sterile.
6. Suitability for controlled release: Various types of nasal drug delivery systems (DDS) and formulation additives can allow for a sustained release of drug over time. Although in general, it should be noted that the nose is not particularly suited for sustained-release purposes.
7. Delivery to the CNS: The specialized olfactory epithelium of the nose offers a potential route for direct N2B drug delivery.
8. Delivery to the lymphoid tissue: As described in Section 10.7, the nasal-associated lymphoid tissue (NALT) makes the nose a highly effective immunological site, making the route an attractive one for the delivery of vaccines.
10.3.1 LIMITING FACTORS FOR NASAL DRUG DELIVERY
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.
10.3.1.1 Small Size of the Nasal Cavity
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.
10.3.1.2 Constraints of Nasal Geometry: Access and Penetration Difficulties
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).
Access and penetration difficulties are compounded in those pathological states that are associated with a hypersecretion of mucus, such as in inflammatory conditions and allergies. As described in Section 10.6, the specialized olfactory region of the nose associated with N2B delivery is located far beyond the valve, up in the roof of the nasal cavity (Figure 10.4). Accessing this area for the delivery of CNS therapeutics is also a formidable challenge.
10.3.1.3 Mucus and Mucociliary Clearance
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.
If systemic absorption is the aim of therapy, the epithelial barrier must also be considered. Transport across epithelial barriers is described in detail in Chapter 4. To summarize here with respect to the nasal route, drug permeation via the paracellular route (i.e., between epithelial cells) is limited because of the tight junctional complexes that are present between cells. The predominant transport pathway across nasal epithelium is usually via the transcellular route, by means of transcellular passive diffusion. The rate of absorption is governed by Fick’s law (Chapter 4, Equation 4.1). The most important physicochemical drug factors affecting nasal absorption are as follows: (1) molecular weight (nasal absorption drops off sharply for drugs with a molecular weight > 1000 Da) and (2) lipophilicity (polar, hydrophilic, or ionized molecules exhibit poor permeability).
Thus, drugs currently administered nasally for systemic action generally comprise low molecular weight, lipophilic compounds. Although some peptides do show some systemic absorption (calcitonin, oxytocin, etc., see Section 10.1), the absolute bioavailability of peptide drugs via the nasal route is still relatively low. For example, the IN bioavailability of salmon calcitonin (MW 3432 Da) is only about 3%. Low bioavailability is compensated for by the extremely high potency of these drugs, which can produce therapeutic effects even at low plasma concentrations.
Mucosal sensitivity is a natural component of the nasal defense mechanism, but it also complicates nasal drug delivery, by making this area highly susceptible to irritation and injury. Exposure to chemicals, gases, particles, temperature, and pressure changes, as well as direct tactile stimuli, may cause nasal irritation, secretion, tearing, itching, sneezing, and severe pain. Nosebleeds, crusting, and potentially erosions or perforations may arise because of factors such as direct contact of the tip of a nasal spray nozzle during actuation and/or localized concentrated drug deposition on the septum. Formulation additives such as absorption enhancers (AEs) may also cause mucosal irritation or damage (see Section 10.5.1).
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).
As described further in Section 10.3.2, nasal deposition and clearance are dependent on a number of complex, interrelated factors, including the type of nasal delivery device, drug physicochemical factors, formulation factors, and physiological, anatomical and pathological factors. These factors combine to introduce considerable variability with respect to the emitted dose, the site of deposition, the resulting clearance, and ultimately, the clinical response. The variability is particularly serious for drugs with a narrow therapeutic index (e.g., opiates and hormonal drugs), and represents a limitation of the route.
10.3.1.8 Patient Acceptability and Compliance
Nasal delivery devices can be difficult and uncomfortable to use, which can compromise patient acceptability and compliance. These problems are described further in Section 10.4, with respect to each type of device. To summarize briefly here, compliance issues include drip-out and run-off problems for nasal drops and high volume nasal sprays; discomfort when using aqueous sprays; cold shock sensations associated with pMDIs; nebulizers that can be difficult and cumbersome to use; and nasal drops that require extreme head positions for their correct administration.
10.3.2 NASAL DEPOSITION AND CLEARANCE
For IN administered drugs, the site of drug deposition and the resulting clearance from that site are important determinants of the clinical response. Drug deposition and clearance, in turn, are dependent on a number of other interrelated factors, outlined here and discussed further in the following sections.
The device: A wide variety of devices (including sprays, pMDIs, nebulizers, and drops) can be used to effect nasal drug delivery. The type of device used profoundly affects characteristics such as the velocity and size of the emitted particles, the plume characteristics, the volume emitted, and the angle of entry.
The drug: The physicochemical properties of the drug, such as molecular weight and volume, lipophilicity, solubility, and susceptibility to enzyme degradation, affect its deposition and clearance in vivo.
The formulation: A liquid formulation will result in different deposition and clearance patterns to a solid formulation; other factors affecting deposition and clearance include the formulation viscosity and the effects of formulation excipients such as AEs, enzyme inhibitors, mucoadhesives, and gel formers.
The patient: Patient factors that influence nasal deposition and clearance include the patient’s skill at using the device, and whether the instructions for administration are followed correctly. Further factors include inter-individual anatomical and physiological variability, as well as the impact of airflow and breathing patterns and the presence of any pathologies (e.g., mucus hypersecretion).
A careful consideration of these interrelated factors is necessary to optimize the route. Nasal deposition and clearance patterns can be studied in vitro using nasal casts made of silicone or other materials. It is essential for interpretation that the nasal cast geometry and dimensions are realistic and validated, which unfortunately is not always the case. Furthermore, caution is necessary because such casts do not characterize physiological factors such as nasal valve dynamics, or mucociliary clearance. The field of computational fluid dynamics is a further important in vitro tool, which will play an increasingly important role as the quality and capabilities of the simulations increases.
Colored dyes offer a quick and inexpensive semiquantitative assessment of nasal deposition and clearance in vivo. More detailed information is achieved using gamma-deposition studies, where the fate of a radiolabel can be tracked in vivo. In particular, recent studies have carefully assessed regional differences in tissue attenuation in different nasal segments and also between the nose and lungs (Djupesland and Skretting 2012). These sophisticated studies have provided greater insight into regional nasal deposition and clearance, showing more precisely where drug deposits from different types of delivery devices. These and similar studies are helping to elucidate how drug delivery via the nasal route can be optimized.
10.4 NASAL DRUG DELIVERY DEVICES
A summary of the most widely used nasal devices is given here. Further information on a wide variety of nasal drug delivery devices is given in a recent extensive review (Djupesland 2013).
Metered-dose spray pumps are the most widely used nasal delivery devices and have been for several decades. Their popularity is attributed mainly to their ease of use. They comprise a container, a pump with a valve, and an actuator. Actuating the pump creates a force that drives the liquid through a swirl chamber at the tip of the applicator and out through the circular nozzle orifice (Figure 10.2). The pumps typically deliver volumes of 100 μL (range 25–200 μL) per spray, and they offer high reproducibility with respect to the emitted dose, particle size, and plume geometry.
FIGURE 10.2 Nasal spray pump. (Markus Gann/Shutterstock.com.)
Traditional spray pumps replace the emitted liquid with air, and preservatives are therefore required to prevent contamination. Driven by early concerns that preservatives may impair mucociliary function, various preservative-free spray pumps have been developed. For example, Aptar Pharma has developed a pump that incorporates an aseptic microfilter membrane and a ball valve at the tip. Single-dose spray devices offer the advantages of being preservative free, as well as being easily portable and offering high accuracy of dosing. A Pfeiffer/Aptar single-dose device is used for the nasal delivery of the antimigraine drugs sumatriptan and zolmitriptan. However, initial fears about possible adverse effects of preservatives have proven unwarranted and many long-term studies have concluded that preservatives do not represent a safety concern (Marple et al. 2004). Their safety is evidenced, for example, by the fact that preservatives are found in all of the current top-selling formulations for topical steroids, i.e., in preparations which are intended for chronic use.
Future directions in pump technology include the development of pumps that incorporate pressure-point features, to improve dose reproducibility. This is because mechanical pumps rely on hand actuation, which inevitably provides a variable force that can influence particle size distribution and plume characteristics. Other optimization approaches involve the development of pumps that need less priming (which causes drug wastage), and which feature dose counters.
As introduced in Section 10.3.1.2, a major limitation associated with nasal sprays is their suboptimal delivery efficiency. Nasal sprays generate an expanding conical-shaped plume, with the majority of the particles at the periphery (Figure 10.2). Even if the spray pump is inserted as deep as 10–15 mm into the nostril, there is an obvious mismatch between the dimensions and shape of the expanding circular plume (diameter ≈ 2 cm), compared to the constricting dimension of the nasal vestibule, and the confined nasal geometry beyond. The mechanical action of inhalation further narrows the nasal valve, making plume penetration even more difficult. Sniffing, either intentionally or reflexively to avoid drip-out, will further narrow the nasal valve and limit access. Thus, the majority of the drug particles, particularly those traveling at high speed, will impinge on the walls of the anterior nasal cavity and deposit there.
The sensation of high-speed particles impacting on the nasal walls can be unpleasant and uncomfortable for the patient. Drug formulation deposited in the anterior cavity may drip out of the nostril or run off to the throat. The small fraction of drug that actually penetrates the valve gains access predominantly to the floor of the nasal cavity, but fails to reach the majority of the rest of the nasal cavity, the ideal target site.
Nasal sprays can also be generated using squeeze bottles. The patient squeezes a plastic bottle partly filled with air, and the drug is atomized when delivered from a jet outlet. However, delivery efficacy is poor: in addition to the access and penetration issues common to all nasal sprays, the dose and particle size will vary considerably according to the squeezing force applied, causing dose reproducibility issues. Furthermore, nasal secretions and microorganisms may be sucked back into the bottle when the pressure is released.
10.4.2 PRESSURIZED METERED-DOSE INHALERS
pMDIs are used widely in pulmonary drug delivery and the reader is referred to Chapter 11 (Section 11.7) for a detailed description of this type of device. For the nasal route, conventional pMDIs based on the use of chlorofluorocarbon (CFC) propellants were associated with a number of disadvantages, including (1) very high particle speeds, which caused discomfort on impaction with the walls of the nasal cavity, (2) the unpleasant “cold freon effect” (the cold blast of propellant hitting the walls of the nose), and (3) nasal irritation and dryness. Following the ban on ozone-depleting CFC propellants, the number of pMDI products for both pulmonary and nasal delivery diminished rapidly, and they were removed from the U.S. market in 2003.
3M has pioneered the development of environmentally friendly hydrofluoroalkanes (HFA) as an alternative to the CFC propellants. HFA is now used as the propellant in pMDIs for the nasal delivery of a variety of drugs, including triamcinolone acetonide (Nasacort HFA®), ciclesonide (Omnaris HFA®), and beclomethasone (Qnasl®). These new-generation devices are associated with many advantages. HFA-based pMDIs do not cause as much drip-out or run-off as traditional liquid spray pumps, which aids patient acceptance and compliance, and reduces drug loss. Also known as “slow-mist” devices, HFA-based pMDIs produce much slower particle speeds than the old CFC versions. The slower speeds reduce particle impaction against the nasal walls, thereby enhancing nasal drug delivery, as well as patient comfort.
However, the speed of the emitted particles with the new HFA pMDIs is still the same, or even higher, than the speed of particles emitted for spray pumps: patients still describe the cold shock feeling on impact, and how they have to steel themselves prior to dosing. Furthermore, although the aerosol-generating mechanism is different, a similar mismatch exists between the expanding conical-shaped plume produced by a pMDI and the dimensions of the narrow nasal valve. Therefore, access and penetration difficulties remain an important issue. Gamma-deposition studies with these devices confirm this pattern of limited posterior disposition, with a very distinct anterior “hotspot” (Djupesland 2013).
It has been claimed that anterior deposition provides enhanced efficacy for the IN delivery of topical anti-inflammatory steroids using HFA pMDIs (Righton 2011). We question the validity of this idea. Drug deposited in the anterior cavity is subject to all the disadvantages outlined earlier (e.g., drip-out and elimination). Furthermore, nasal inflammatory diseases (e.g., rhinitis and sinusitis) are not associated with the anterior cavity but are localized instead in the posterior cavity, so that topical steroid therapy would be optimized by targeting this region instead (Djupesland 2013).
Dry powder formulations may also be administered intranasally. Nasal powder sprayers utilize a pressure gradient to force out a fine plume of powder particles, similar to that of a liquid spray. The Becton Dickinson and Aptar group both offer powder sprayers that utilize a plunger technology: pressing the plunger ruptures a membrane to expel the powder. In the Fit-lizer™ multidose system, a capsule is first inserted into a holding chamber, which slices off the capsule ends. The patient then compresses the plastic bottle: the compressed air passes up through the sliced-open capsule, forcing out a fine spray of powder particles. In common with liquid sprays, there remains a mismatch between an expanding powder plume and the constricted nasal geometry, so that most of the dose is deposited in the anterior cavity.
Rhinocort Turbuhaler® is a newer breath-actuated nasal inhaler, based on a modification of the Turbuhaler® device for pulmonary delivery. To use, the patient is required to sniff quickly and forcefully through an adaptor: the resulting negative pressure pulls the powder formulation into the nose. However, as described earlier, sniffing causes constriction (and even possible closing) of the nasal valve, resulting in unwanted deposition in the anterior cavity. Furthermore, many rhinitis patients have nasal congestion, which can impede the flow rates required for efficient delivery. Nasal inhalation for the Turbuhaler® was also shown to produce significant drug deposition in the lungs (Thorsson et al. 1993).
Nebulizers use compressed gases (air, oxygen, nitrogen), or ultrasonic or mechanical power, to break up medical solutions and suspensions into small aerosol droplets that can be directly inhaled into the mouth or nose over a period of minutes. The aerosol can be administered passively or assisted by active nasal inhalation, or even assisted by suction from the contralateral nostril. Nebulizers are primarily used to delivery topically acting drugs such as antibiotics or steroids, in patients with chronic rhinosinusitis (CRS).
Compared to other nasal delivery devices, nebulizers produce aerosols with a smaller particle size (<10 μm), traveling at slower speeds. These features are associated with less impaction against the nasal walls and greater drug deposition in the posterior nasal cavity. However, particles less than 5–10 μm can evade the normal filtration and cleaning mechanisms of the nose and may be inhaled into the lungs. For example, studies have shown that using a nebulizer resulted in as much as 33%–58% of the administered dose resulting in unwanted lung deposition (Suman et al. 1999; Djupesland et al. 2004). Lung deposition results in drug waste, as well as possible pulmonary irritation and unwanted systemic absorption. Unwanted lung deposition is an area of increasing concern, reflected by the most recent Food and Drug Administration (FDA) guidelines for nasal devices, which recommend minimizing the fraction of respirable particles below 9 μm. A further disadvantage of traditional nebulizers is that they cannot provide the dose reproducibility required for most active drugs.
A new generation of nasal nebulizers is under development, in order to achieve improved delivery profiles. ViaNase® is a handheld, battery-driven device that atomizes liquids by a process of Controlled Particle Dispersion™ and produces a vortical flow on the droplets as they exit the device. Flow characteristics (circular velocity and direction) can be altered to achieve different droplet trajectories and customized delivery. The ViaNase® device has been used to deliver nasal insulin in patients with early Alzheimer’s disease, and clinical benefit has been demonstrated (Craft et al. 2012). However, unwanted lung deposition of up to 9% of the delivered dose was also reported for this device (Reger et al. 2008).
The Vibrent® pulsation nebulizer generates a fine aerosol mist of an aqueous liquid via a perforated pulsating membrane. Breath holding during delivery is recommended, in order to reduce the risk of lung inhalation. A further device is the Aeroneb Solo® (Aerogen), which uses a vibrating mesh technology to produce a low-velocity aerosol. The aerosol is delivered into one nostril, while a pump simultaneously aspirates at the same flow rate from the other nostril; meanwhile, the subject is instructed to avoid nasal breathing.
Although the new generation of nebulizers (ViaNase®, Vibrent®, Aeroneb Solo®) improves nasal deposition into the posterior cavity and sinuses, and reduces unwanted lung deposition, gamma-deposition studies have demonstrated that deposition still occurs mainly at the nasal valve, with a substantial fraction of the drugs delivered outside the target regions (Vecellio et al. 2011). Furthermore, these new devices are relatively complex in operation; the recommended delivery procedures require patient cooperation and take several minutes. The special breathing patterns may be challenging for some patients, especially when they are sick.
Nasal drops are administered by drawing liquid into a glass/plastic dropper, inserting the dropper into the nostril with an extended neck, and then squeezing the rubber top to emit the drops. Nasal drops are commercially available, for example, for the topical delivery of decongestants. A variant of nasal drops is the rhinyle catheter, where drops are filled by the patient into a thin flexible tube. One end of the tube is inserted in the mouth and the other is placed at the entrance of the nostril. Drops are delivered to the nose by blowing through the tube. The rhinyle catheter is used in some countries for the IN delivery of desmopressin.
Nasal drops, when delivered correctly, can increase penetration beyond the nasal valve—this facilitates deposition in the upper posterior nasal segments. This improved deposition is associated with improved clinical outcome. For example, a study showed significant benefits of fluticasone drops, compared with nasal spray, in avoiding surgery in patients with CRS and polyps (Aukema et al. 2005). Improved deposition was attributed to the gravitational forces in operation when the drops were administered using the requisite head maneuvers.
However these requisite head maneuvers constitute a major limitation of nasal drops: for their correct administration, they require the patient to assume an extreme head extension or adopt the “Mekka position,” or similar. In this way, gravity helps to get the drops to the middle part of the nose and reduce complications of run-off and drip-out. But most patients do not want, or are unable, to perform the necessary head extensions required, as they are cumbersome and can be very uncomfortable, especially for patients with sinusitis and headaches. When nasal drops are administered without assuming a correct position, drip-out and run-off problems arise.
10.4.6 BREATH POWERED™ BI-DIRECTIONAL™ NASAL DEVICE: A CASE STUDY
The Breath Powered™ Bi-Directional™ device by OptiNose is designed to optimize nasal drug delivery by exploiting functional aspects of the nasal anatomy. The device has a mouthpiece, connected to a delivery unit and a sealing nosepiece (Figure 10.3a). The user slides the nosepiece into one nostril until it forms a seal at the nostril opening—at which point it also mechanically expands the narrow slit-shaped part of the nasal valve. The user exhales into the mouthpiece, and the exhaled breath carries medication through the nosepiece into one side of the nose (Figure 10.3b). The pressure of the patient’s exhaled breath automatically elevates the soft palate, sealing off the nasal cavity completely, thereby preventing unwanted lung deposition (Figure 10.3b). The breath pressure also gently expands the narrow nasal passages. Due to the sealing nosepiece, the force of the air exhaled into the mouthpiece balances the pressure across the closed soft palate so that an open flow path between the two nostrils is maintained. Thus, liquid or powder drug particles are released into an airstream that enters one nostril, passes entirely around the nasal septum posteriorly, and exits through the opposite nostril, following a “Bi-Directional” flow path (Figure 10.3c). The OptiNose technology can be combined with a variety of dispersion technologies (sprays, pMDIs, nebulizers) for the delivery of both powders and liquids.
In operation, the device ensures a mechanical expansion of the narrow nasal valve and also gently expands the narrow nasal passageways, thereby improving nasal deposition in the posterior cavity. Human studies of deposition patterns using gamma scintigraphy have shown that the OptiNose device achieves less deposition in the vestibule and significantly greater deposition to the upper posterior target regions beyond the nasal valve, when compared to conventional nasal spray devices, for both liquid and powder formulations (Djupesland et al. 2006; Djupesland and Skretting 2012; Djupesland 2013). Comparisons using nebulized formulations with the OptiNose devices have shown that unwanted lung inhalation is prevented, even when small respirable particles are delivered.
FIGURE 10.3 (a) The OptiNose Breath Powered™ Bi-Directional™ devices. Multi-use powder device (blue) with disposable nosepiece on the left and the multi-dose liquid device (white) on the right. (b) Using the OptiNose devices automatically causes soft palate closure, thereby sealing off the nasal cavity and avoiding unwanted lung deposition. (c) Bidirectional flow: drug particles enter one nostril, pass posteriorly around the nasal septum, and exit via the opposite nostril. (Courtesy of OptiNose, Inc.)
Furthermore, the OptiNose device is simple to use, which enhances patient compliance. It does not require extreme head positions, and reduces problems of drip-out and run-off. The system uses warm, moist air to carry the particles, which enhances comfort and avoids cold shock sensations. Nebulizers can be adapted to the device with a breath-triggered mechanism, thereby avoiding the breath coordination issues and suction mechanisms required for the new-generation nasal nebulizers recently developed. The OptiNose powder device delivering sumatriptan has recently received US marketing approval for the treatment of acute migraine in adults (OnzetraTM, XsailTM). A multidose liquid device version delivering fluticasone propionate has recently completed Phase 3 trials in patients with CRS with nasal polyps.
10.5 NASAL FORMULATION FACTORS
Liquid formulations, including solutions, suspensions, and emulsions, currently dominate the nasal drug market. Liquid formulations provide a humidifying effect, which is useful as many allergic and chronic diseases are associated with crusting and drying out of mucous membranes. Disadvantages of liquid formulations include (1) their susceptibility to microbial contamination, (2) potentially reduced chemical stability of the active, and (3) potentially short residence time in the nasal cavity, unless countermeasures are taken. Powder formulations can offer the advantage of greater stability than liquid formulations and the possibility of avoiding the use of preservatives. Powder formulations may also offer an increased residence time in the nasal cavity and also possibly sustained-release effects, as the drug must initially dissolve in the nasal fluids, prior to being absorbed.
A variety of different formulation excipients can be included in a formulation, and many different agents are being investigated, in order to optimize nasal delivery and targeting (Illum 2003, 2012). For optimal results, the formulation should be tailored to the specific drug, therapeutic indication (i.e., for local, systemic, immunologic, or N2B delivery), and type of delivery (spray, nebulizer, dry powder, etc.) required.
AEs can be included in formulations intended for systemic delivery in order to increase nasal bioavailability. They can potentially facilitate the systemic absorption of a wide range of drugs, including large biologics such as polypeptides, proteins, and antisense molecules (Merkus et al. 1993). As described in detail in Chapter 7 (Section 7.6.1.1), AEs generally act via a combination of complementary mechanisms. Many AEs are amphipathic in nature and thus associate with the amphipathic bilayers of the plasma membranes, increasing the fluidity and permeability of membranes and promoting transcellular transport. Some also interact with the junctional complexes between epithelial cells, facilitating paracellular transport. These agents may also promote nasal absorption via other effects, including increasing drug solubility, enzyme inhibition, and mucoadhesion.
However, AEs are also associated with safety and toxicity concerns. AEs can directly damage the delicate nasal epithelium. Early AEs, including surfactants such as laureth-9, bile salts, and their derivatives such as sodium taurodihydrofusidate and fatty acids, were associated with mucosal damage and are now used less frequently. The nasal epithelium provides a protective barrier defense mechanism against the entry of harmful agents. Interfering with this protective barrier could potentially facilitate the bystander absorption of harmful, irritating, and infectious agents. These safety concerns are reflected in the difficulties in getting regulatory approval for a new AE—which is almost as difficult as getting approval for a new therapeutic agent. Due to the regulatory hurdles, what may have originally been intended as an inexpensive formulation additive can actually become a very expensive, time-consuming approach, which may even require a completely new set of clinical trials. Therefore, the focus in this field is on investigating “generally regarded as safe” (GRAS) agents, rather than discovering new types of AEs.
Chitosan is being investigated as an AE for the nasal delivery of a number of drugs (its use in mucoadhesion is discussed in the following texts), including peptides and proteins (including leuprolide, salmon calcitonin, and parathyroid hormone), and most successfully for the IN delivery of morphine in BTP for cancer (Casettari and Illum 2014). The IN administration of morphine with a chitosan formulation facilitated up to sixfold increase in bioavailability compared to controls, with maximum plasma levels reached within minutes, and is currently showing promise in clinical trials.
Intravail® comprises a class of alkylsaccharides that have demonstrated impressive absorption enhancement for a range of peptides in a selection of animal models (Maggio and Pillion 2013). Surfactant in nature (the molecules contain a polar sugar head group, such as maltose or sucrose, esterified with a hydrophobic alkyl chain; the lead compound is tetradecyl maltoside), they are thought to interact with the amphipathic membranes of the nasal epithelial cells, inducing membrane-permeabilizing effects.
It should also be remembered, however, that although many AEs have demonstrated pronounced enhancement effects in animal studies, these effects can be a significant overestimation of what can realistically be achieved in humans, given the very distinct architectures and morphologies of the nasal cavity in different species.
A drug for IN delivery may be administered as a nasal gel (typically a high-viscosity thickened solution or suspension), or an in situ gel-forming agent may be included in the formulation. The high viscosity of the formulation can facilitate a longer residence time in the nasal cavity and allows more time for drug–receptor interactions (for local effects) or transepithelial flux (for systemic absorption). High-viscosity formulations can also reduce postnasal drip-out and run-off, with all the associated advantages. Soothing/emollient excipients in the gel may also reduce irritation. Many viscosity enhancers used for gel formation also function as bioadhesives, as they complex with the mucus layer, increasing its viscoelasticity and reducing mucociliary clearance.
Pectins are widely used in the food industry as gelling agents; their gel-forming properties have also been investigated for nasal drug delivery. PecSys® technology uses a pectin derivative, low methoxyl (LM) pectin—which has a low degree of esterification of the galacturonic acids—as an in situ gel former. The product is administered to the nasal cavity as a solution and forms a gel on contact with the nasal mucosal surface, due to the interaction of the LM pectin with the calcium ions of the mucosal fluid. PecFent® uses the PecSys® technology for the IN delivery of the opioid analgesic fentanyl, indicated for management of BTP for cancer (Fallon et al. 2011).
10.5.3 MUCOADHESIVES AND CILIASTATICS
Mucoadhesives are incorporated into formulations to attach onto the nasal mucus layer, thereby prolonging the effective contact time of the drug in the nasal cavity. Mucoadhesives for oral drug delivery are described in detail in Chapter 7 (Section 7.6.1.4), and the same principles and mechanisms apply here. As noted earlier, many gel-forming excipients also demonstrate mucoadhesive properties. Thiomers are mucoadhesive polymers being investigated as formulation excipients for a variety of epithelial routes, including for nasal, oral, buccal, and vaginal delivery. Thiol side chains can form disulfide bridges between cysteine groups on mucus, which can improve mucoadhesion up to 100-fold (Lehr 2000). The mucoadhesive effects are complemented by their in situ gelling properties, due to the oxidation of thiol groups at physiological pH values, which results in the formation of inter- and intramolecular disulfide bonds. This increased viscosity in situ further increases nasal cavity residence time. Thiomers also confer AE effects, via reversible opening of the tight junctions between cells. They further offer the potential safety advantage of being too large to be absorbed through the nasal mucosa per se, in contrast to other low-molecular-weight AEs under investigation.
An acrylated poly(ethylene glycol)-alginate copolymer has been developed for IN delivery (Davidovich-Pinhas and Bianco-Peled 2011). The presence of PEG increases the viscosity of the formulation, and also PEG chains have the ability to penetrate the mucus surface and to form hydrogen bonds with sugars on glycosylated mucus proteins. Poly(acrylic acid) also forms hydrogen bonds between its carboxylic acid groups and the sialic acid–carboxylic acid groups present in the mucus. These attributes, combined with the gelation ability of the alginate component, make the copolymer an attractive candidate for nasal mucoadhesion. Further important mucoadhesives that have demonstrated promise for IN delivery include microcrystalline cellulose, chitosan, and poloxamer 407 (Ugwoke et al. 2005). Some of these polymers have been incorporated into micro- and nanoparticles, as described in Section 10.5.5. A mucoadhesive cyclodextrin-based drug powder formulation (μCo™ Carrier) is being developed in conjunction with the Fit-lizer™ powder device (Section 10.4.3), for the nasal delivery of a variety of drugs and influenza vaccine.
A further approach to enhancing residence time in the nasal cavity is to use a reversible ciliostatic in the formulation. If the cilia stop beating, mucociliary clearance is compromised, and the drug substance remains longer in the nasal cavity. Some AEs have been shown to cause irreversible ciliostasis, e.g., laureth-9 (0.3%) and sodium deoxycholate (0.3%), although at lower concentrations the effect is reversible. Others, such as sodium glycocholate, are well tolerated.
10.5.4 OTHER FORMULATION EXCIPIENTS
Solubility enhancers: The inclusion of solubility enhancers can allow a more concentrated drug formulation to be administered, in a reduced volume. A reduced volume lessens the problems of run-off and drip-out from the nasal cavity. Increasing the solubility of the API also increases the concentration gradient across the nasal epithelium, providing a larger driving force for drug permeation via transcellular diffusion. Many AEs, being surfactants, also provide a solubilizing effect. Various formulation excipients that are used to increase drug solubility, such as cosolvents, cyclodextrins, and polymeric micelles, are described in Chapter 3.
Buffers: The normal pH in the nasal cavity is between 5.5 and 6.0. Transcellular passive diffusion across membranes is facilitated when the drug is in the unionized state; therefore, depending on the pKa of the drug, a buffer may be used to adjust the pH and facilitate the unionized form (see also Chapter 4, Box 4.1).
Enzyme inhibitors: Enzyme inhibitors may be added to a formulation to protect a labile drug such as a peptide or protein. For example, bestatine and comostate amylase have been studied in IN formulations as aminopeptidase inhibitors for calcitonin. Bacitracin and puromycin have been used to minimize enzymatic degradation of human growth hormone.
10.5.5 MICRO- AND NANOPARTICULATE DRUG DELIVERY SYSTEMS
Micro- and nanoparticulate DDS, described in detail in Chapter 5, include microspheres, nanospheres, and liposomes. All of these systems have been extensively investigated for nasal drug delivery but with limited success to date. Micro- and nanoparticles can protect an API from enzymatic degradation and provide sustained release of the drug. Many particulate systems for IN delivery incorporate a mucoadhesive polymer, such as chitosan, gelatin, or alginate, to enhance retention in the nose. Solubility enhancers and AEs can also be included within the nanoparticle construct. Targeting ligands can be attached to the surface of the carrier to enhance nasal delivery and retention. Targeting vectors specifically studied to enhance nasal delivery include lectins extracted from Ulex europaeus I, soybean, peanut, and wheat germ agglutinin.
Starch microspheres, as well as being bioadhesive, seem to draw up moisture from the surrounding cells, resulting in the nasal mucosa becoming dehydrated. This results in reversible “shrinkage” of the cells, providing a temporary physical separation of the tight junctions and thus facilitating paracellular absorption. Starch microspheres have been shown in animal studies to enhance the absorption of insulin and other proteins. Mucoadhesive multivesicular liposomes have demonstrated promise for the nasal absorption of insulin, providing protective and sustained-release effects. Many different types of liposomal gels have also been investigated for nasal delivery. A further application, introduced in Section 10.7, is the use of micro- and nanoparticles for IN vaccination.
10.6 NOSE-TO-BRAIN DRUG DELIVERY
Chapter 15 describes in detail the anatomical and physiological barrier that comprises the BBB, as well as a number of strategies to cross or bypass the BBB. Such strategies include surgical methods, as well as strategies that involve reengineering of drug molecules to exploit endogenous transport mechanisms for BBB uptake. Carrier-mediated transport mechanisms, receptor-mediated transfer systems, and molecular-based (“Trojan horse” delivery) and nanotechnology-based approaches to cross the BBB have shown promising results in animals and some are being tested in human trials. However, these strategies are often complex and molecule specific. They may also require that the engineered molecules are first delivered into the systemic circulation, which has its own challenges and limitations in terms of absorption, bioavailability, and safety.
FIGURE 10.4 The olfactory epithelium is located on the inferior surface of the cribriform plate and superior nasal conchae. The axons of the olfactory receptor cells collectively form the olfactory nerve. Noseto-brain delivery involves the transport of drug molecules along the olfactory nerve. (From Djupesland, P.G., Messina, J., and Mahmoud, R., The nasal approach to delivering treatment for brain diseases: An anatomic, physiologic, and delivery technology overview, Ther. Deliv., 5(6), 709, 2014. With permission, Future Science, Copyright 2015; Illustrator Copyright: K.C. Toverud CMI.)
The nose offers a direct route to the CNS, in which the BBB can be circumvented in a noninvasive manner (Figure 10.4). N2B transport involves the direct transport of substances into the brain, via the olfactory nerve (and possibly in some cases, via the trigeminal nerve). The olfactory epithelium is located toward the roof of the nasal cavity and contains 10–100 million olfactory receptors, i.e., bipolar neurons, which react to molecules in the inspired air and initiate impulses in the olfactory nerve. The axons of the olfactory nerve pass through tiny holes in the flat bone plate (cribriform plate) that separates the olfactory mucosa from the overlying brain tissue and immediately synapse in the olfactory bulb. Axons from the secondary neurons make up the olfactory tracts, which extend posteriorly and end in the cerebral cortex.
It was initially believed that N2B transport occurred along the olfactory and trigeminal nerves as a slow, intra-axonal process. However, emerging research shows that the transport from the nose to CNS occurs within minutes, which would suggest that the most likely mechanism is actually bulk transport, propelled by arterial pulsations, along the ensheathed channels surrounding the axons (IIiff et al. 2012). A recent review describes a number of animal and human studies confirming that a variety of biologics, including peptides and proteins, are capable of reaching the brain following nasal administration (Lochhead and Thorne 2012).
Optimized N2B delivery would thus seem to require targeted delivery to the olfactory region. However, this region, located as it is in the roof of the posterior cavity, presents significant access difficulties—the big challenge for N2B delivery is to successfully target this area. Impel NeuroPharma is developing a HFA-driven pressurized delivery device for N2B delivery, which produces a narrower plume than that of the standard nasal sprays, in order to enhance drug deposition beyond the nasal valve. A study in rats found that 50% more of the dose was deposited in the region of the rat olfactory epithelium using this device, than when using nasal drops deposited at the nares (Hoekman and Ho 2011). Evidence of enhanced transport of morphine and fentanyl from the nose to the brain was also shown. While encouraging, it should be remembered that the olfactory region in rats covers a very large fraction of the nasal mucosal surface; further, drug delivery to the nares of anesthetized rats may not be an appropriate representation of drug delivery in nonanesthetized humans.
An adaptation of the Breath Powered™ OptiNose device has been developed to optimize N2B delivery, which uses a specialized nosepiece for better insertion into the narrower, upper part of the nasal valve. Gamma-deposition studies in humans confirm enhanced delivery in the superior olfactory region. Recent pharmacokinetic and pharmacodynamic studies with this device in humans strongly suggest direct N2B delivery of oxytocin (Quintana et al. 2015).
As described in Chapter 17, the NALT forms part of the body’s common mucosal immune system. Infective agents that enter the body via the nose are presented to the abundant local nasal immune system, which comprises (1) various specialized immunocompetent cells distributed both in the mucus blanket and the mucosa per se and (2) organized lymphatic structures situated mainly in the pharynx, as a ring of lymphoid tissue known as Waldeyer’s pharyngeal ring, which includes the adenoids and palatine tonsils.
In order to achieve an optimal immune response, a vaccine should be delivered to the respiratory mucosa rich in antigen-presenting dendritic cells and to M cells located in the organized lymphatic tissues. Nasal vaccination induces both mucosal (sIgA) and systemic (IgG) immune responses, making it a highly effective immunological site. Furthermore, the mucosal sIgA response is rapid and raised not only locally in the nose, but may also induce protection in distant mucosal sites. Nasal vaccines also offer the advantages over parenteral vaccines of being more acceptable to patients, cheaper, and easier to use.
Flumist® is a single-dose nasal spray from Becton Dickinson containing a live, attenuated influenza vaccine. Flumist® is sprayed into the nose as a needle-free way to protect against influenza. The volume administered (0.5 mL) is much larger than typically used for nasal delivery (100 μL), suggesting that a substantial amount of the drug dose is actually swallowed, i.e., oral delivery rather than IN; drip-out from the nasal cavity also occurs.
Advances in nasal vaccine technologies are directed towards optimizing nasal delivery devices, as well as improving nasal formulations. The Breath PoweredTM OptiNose liquid device has shown preliminary promise in improving both local and systemic immune responses in humans for influenza vaccine, in comparison with a traditional nasal spray pump (Djupesland 2013). On the formulation front, the AE chitosan is also being investigated as a vaccine adjuvant to enhance the immune response. Chitosan nasal vaccines have been studied for influenza, pertussis, and diphtheria vaccines and shown enhanced immune responses in various animal models, in comparison to nasal vaccine formulations without chitosan (Illum 2012). Due to its positive charge, chitosan can complex with negatively charged DNA plasmids. Self-assembling nanoparticle complexes of chitosan–DNA for vaccination against respiratory syncytial virus have shown promise in preliminary studies. Other nanoparticulate adjuvants include proteasome-based adjuvants for the nasal immunization of human influenza virus and human streptococcus A, which are currently in Phase 2 clinical trials. Further nasal vaccine delivery systems are described in Chapter 17.
It can be concluded that drug delivery to the nose is a complex, challenging science, dependent on many interrelated factors, including the type of nasal delivery device, drug factors, formulation factors, and physiological and pathological factors. Understanding and addressing all of these issues is crucial to optimizing the potential of this route. In vitro studies using casts, and in vivo studies using gamma scintigraphy, continue to develop our understanding of nasal deposition and clearance processes and the factors that affect these processes, thereby allowing further optimization of the route.
Overcoming the various anatomical and physiological barriers associated with the nose is essential to optimizing therapy. Many commonly used nasal delivery devices are associated with suboptimal delivery, whereby a large fraction of the dose is deposited in the anterior cavity. Progress in the field is twofold, centering on improvements in (1) device design and (2) formulation parameters. On the device front, a new generation of nasal nebulizers offer improved drug deposition in the nose while reducing undesirable lung inhalation. HFA-based pMDIs are associated with improved delivery properties compared to the old CFC-based systems. Various new designs of nasal spray pumps are improving dose reproducibility and delivery, and the OptiNose bidirectional device provides improved nasal depostition.
Advances in formulation technology are directed toward the use of AEs to promote systemic delivery, gel-forming agents to promote drug retention within the nose, and micro- and nanoparticulate DDS to enhance the delivery of peptide and protein drugs. These improvements are driving the potential of this route forward, both for locally acting drugs and for the systemic delivery of a wide range of APIs.
The nose is continuing to show considerable promise as a site for mucosal immunization, using nasal vaccine DDS. Finally, although it is still too early to predict outcomes, the nose also offers the tantalizing possibility that it could be utilized as a direct portal of entry to the CNS, bypassing the BBB and so improving treatment for a wide range of CNS disorders.
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