Drug Deliv. and Transl. Res. (2013) 3:42–62
`DOI 10.1007/s13346-012-0108-9
`
`REVIEW ARTICLE
`
`Nasal drug delivery devices: characteristics and performance
`in a clinical perspective—a review
`
`Per Gisle Djupesland
`
`Published online: 18 October 2012
`# The Author(s) 2012. This article is published with open access at Springerlink.com
`
`Abstract Nasal delivery is the logical choice for topical
`treatment of local diseases in the nose and paranasal sinuses
`such as allergic and non-allergic rhinitis and sinusitis. The
`nose is also considered an attractive route for needle-free
`vaccination and for systemic drug delivery, especially when
`rapid absorption and effect are desired. In addition, nasal
`delivery may help address issues related to poor bioavail-
`ability, slow absorption, drug degradation, and adverse
`events in the gastrointestinal tract and avoids the first-pass
`metabolism in the liver. However, when considering nasal
`delivery devices and mechanisms, it is important to keep in
`mind that the prime purpose of the nasal airway is to protect
`the delicate lungs from hazardous exposures, not to serve as
`a delivery route for drugs and vaccines. The narrow nasal
`valve and the complex convoluted nasal geometry with its
`dynamic cyclic physiological changes provide efficient fil-
`tration and conditioning of the inspired air, enhance olfac-
`tion, and optimize gas exchange and fluid retention during
`exhalation. However, the potential hurdles these functional
`features impose on efficient nasal drug delivery are often
`ignored. With this background, the advantages and limita-
`tions of existing and emerging nasal delivery devices and
`dispersion technologies are reviewed with focus on their
`clinical performance. The role and limitations of the in vitro
`testing in the FDA guidance for nasal spray pumps and
`pressurized aerosols (pressurized metered-dose inhalers)
`with local action are discussed. Moreover, the predictive
`value and clinical utility of nasal cast studies and computer
`simulations of nasal airflow and deposition with computer fluid
`dynamics software are briefly discussed. New and emerging
`delivery technologies and devices with emphasis on Bi-
`Directional™ delivery, a novel concept for nasal delivery that
`
`P. G. Djupesland (*)
`OptiNose,
`Oslo, Norway
`e-mail: pgd@optinose.no
`
`can be adapted to a variety of dispersion technologies, are
`described in more depth.
`
`Keywords Drug delivery . Nasal . Device . Paranasal
`sinuses . Topical . Systemic . Vaccine . Nasal valve .
`Particle deposition . Clearance
`
`Introduction
`
`Intuitively, the nose offers easy access to a large mucosal
`surface well suited for drug- and vaccine delivery. However,
`factors related to the nasal anatomy, physiology and aero-
`dynamics that can severely limit this potential, have histor-
`ically been challenging to address. The most recent FDA
`guidance for nasal devices provides detailed guidelines for
`in vitro testing of the physical properties such as in vitro
`reproducibility and accuracy of plume characteristics and
`dose uniformity of mechanical liquid spray pumps and
`pressurized metered-dose inhalers (pMDIs) for nasal use
`[1]. The guidance primarily addresses in vitro testing of
`nasal sprays and pressurized aerosols for local action. The
`reference to in vivo performance is limited to the recom-
`mendation of minimizing the fraction of respirable particles
`below 9 μm in order to avoid lung inhalation of drugs
`intended for nasal delivery. Thus, although important as
`measures of the quality and reliability of the spray pump
`and pMDI mechanics, these in vitro tests do not necessarily
`predict the in vivo particle deposition, absorption, and clin-
`ical response [2]. Furthermore, the guidance offers no or
`limited guidance on nasal products for systemic absorption
`and for alternative dispensing methods like drops, liquid
`jets, nebulized aerosol, vapors, and powder formulations.
`Finally, it does not address aspects and challenges related to
`the nasal anatomy and physiology that are highly relevant
`for the device performance in the clinical setting like body
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`Drug Deliv. and Transl. Res. (2013) 3:42–62
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`43
`
`position, need for coordination, and impact of airflow and
`breathing patterns at delivery.
`The mechanical properties of different modes of aerosol
`generation are already well described in depth in a previous
`publication [3]. The anatomy and physiology of the nasal
`airway has also recently been summarized in an excellent
`recent review [4]. The aim of this paper is to take a step
`further by reviewing the characteristics of existing and
`emerging nasal delivery devices and concepts of aerosol
`generation from the perspective of achieving the clinical
`promise of nasal drug and vaccine delivery. Focus is put on
`describing how the nasal anatomy and physiology present
`substantial obstacles to efficient delivery, but also on how it
`may be possible to overcome these hurdles by innovative
`approaches that permit realization of the therapeutic potential
`of nasal drug delivery. Specific attention is given to the
`particular challenge of targeted delivery of drugs to the upper
`narrow parts of the complex nasal passages housing the
`middle meatus where the sinuses openings are located, as
`well as the regions innervated by the olfactory nerve and
`branches of the trigeminal nerve considered essential for
`efficient “nose-to-brain” (N2B) transport.
`
`Nasal anatomy and physiology influencing drug delivery
`
`Regulation of nasal airflow
`
`Nasal breathing is vital for most animals and also for human
`neonates in the first weeks of life. The nose is the normal
`and preferred airway during sleep, rest, and mild exercise up
`to an air volume of 20–30 l/min [5]. It is only when exercise
`becomes more intense and air exchange demands increase
`that oral breathing supplements nasal breathing. The switch
`from nasal to oronasal breathing in young adults appears
`when ventilation is increased to about 35 l/min, about four
`times resting ventilation [6]. More than 12,000 l of air pass
`through the nose every day [5]. The functionality of the nose
`is achieved by its complex structure and aerodynamics.
`Amazingly, the relatively short air-path in the nose accounts
`for as much as 50–75 % of the total airway resistance during
`inhalation [7, 8].
`
`The nasal valve and aerodynamics
`
`The narrow anterior triangular dynamic segment of the nasal
`anatomy called the nasal valve is the primary flow-limiting
`segment, and extends anterior and posterior to the head of
`the inferior turbinate approximately 2–3 cm from the nostril
`opening [9]. This narrow triangular-shaped slit acts as a
`dynamic valve to modify the rate and direction of the
`airflow during respiration [10, 11]. Anatomical studies de-
`scribe the static valve dimensions as 0.3–0.4 cm2 on each
`
`side, whereas acoustic rhinometry studies report the func-
`tional cross-sectional area perpendicular to the acoustic
`pathway to be between 0.5 and 0.6 cm2 on each side, in
`healthy adults, with no, or minimal gender differences
`[11–14]. The flow rate during tidal breathing creates air
`velocities at gale force (18 m/s) and can approach the speed
`of a hurricane (32 m/s) at sniffing [11, 15]. At nasal flow
`rates found during rest (up to 15 l/min), the flow regimen is
`predominantly laminar throughout the nasal passages. When
`the rate increases to 25 l/min, local turbulence occurs down-
`stream of the nasal valve [10, 11, 15]. The dimensions can
`expand to increase airflow by dilator muscular action known
`as flaring, or artificially by mechanical expansion by inter-
`nal or external dilators [16, 17]. During inhalation, Bernoulli
`forces narrow the valve progressively with increasing inspi-
`ratory flow rate and may even cause complete collapse with
`vigorous sniffing in some subjects [5]. During exhalation, the
`valve acts as a “brake” to maintain a positive expiratory
`airway pressure that helps keep the pharyngeal and lower
`airways open and increase the duration of the expiratory
`phase. This “braking” allows more time for gas exchange in
`the alveoli and for retention of fluid and heat from the warm
`saturated expiratory air [4, 17, 18]. In fact, external dilation of
`narrow noses in obstructive sleep apnea patients had benefi-
`cial effects, whereas dilation of normal noses to “supernor-
`mal” dimensions had deleterious effects on sleep parameters
`[17]. However, in the context of nasal drug delivery, the small
`dimensions of the nasal valve, and its triangular shape that
`narrows further during nasal inhalation, represent important
`obstacles for efficient nasal drug delivery.
`
`The nasal mucosa—filtration and clearance
`
`The region anterior to the valve called the vestibule is lined by
`non-ciliated squamous epithelium that in the valve region
`gradually transitions into ciliated epithelium typical of the
`ciliated respiratory epithelium posterior to the valve region
`[4, 19]. Beyond the nasal valve, the nasal turbinates divide the
`nasal cavity into slit-like passages with much larger cross-
`sectional area and surface area (Figs. 1, 2 and 3). Here, the
`predominantly laminar airflow is slowed down to speeds of
`2–3 m/s and disrupted with eddies promoting deposition of
`particles carried with the air at and just beyond the valve
`region [11]. The ciliated respiratory mucosa posterior to the
`nasal valve is covered by a protective mucous blanket
`designed to trap particles and microorganisms [4, 19].The
`beating action of cilia moves the mucous blanket towards
`the nasopharynx at an average speed of 6 mm/min (3–
`25 mm/min) [20, 21]. The large surface area and close contact
`enables effective filtering and conditioning of the inspired air
`and retention of water during exhalation (Figs. 1, 2 and 3). Oral
`breathing increases the net loss of water by as much as 42 %
`compared to nasal breathing [22]. The nasal passages were
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`Drug Deliv. and Transl. Res. (2013) 3:42–62
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`Specifically, particles larger than 3–10 μm are efficiently
`filtered out and trapped by the mucus blanket [19]. The nose
`also acts as an efficient “gas mask” removing more that 99 %
`of water-soluble, tissue-damaging gas like sulfur dioxide [23].
`Infective agents are presented to the abundant nasal immune
`system both in the mucous blanket, in the mucosa, and in the
`adjacent organized lymphatic structures making the nose at-
`tractive for vaccine delivery with potential for a longstanding
`combination of systemic and mucosal immune responses [24].
`The highly vascularized respiratory mucosa found beyond the
`valve allows exchange of heat and moisture with the inspired
`air within fractions of a second, to transform cold winter air
`into conditions more reminiscent of a tropical summer [19].
`
`The nasal cycle
`
`The physiological alternating congestion and decongestion
`observed in at least 80 % of healthy humans is called the nasal
`cycle [5, 25]. The nasal cycle was first described in the
`rhinological literature by a German physician in 1895, but
`was recognized in Yoga literature centuries before [5]. Healthy
`individuals are normally unaware of the spontaneous and
`irregular reciprocal 1–4-h cycling of the nasal caliber of the
`two individual passages, as the total nasal resistance remains
`fairly constant [26]. The autonomic cyclic change in airflow
`resistance is mainly dependent on the blood content of the
`submucosal capacitance vessels that constitute the erectile
`component at critical sites, notably the nasal valve region.
`Furthermore, the erectile tissues of the septal and lateral walls
`and the turbinates respond to a variety of stimuli including
`physical and sexual activity and emotional states that can
`modify and override the basic cyclic rhythm [4]. The cycle
`is present during sleep, but overridden by pressures applied to
`the lateral body surface during recumbency to decongest the
`uppermost/contralateral nasal passage. It has been suggested
`that this phenomenon causes a person to turn from one side to
`the other while sleeping [5, 27]. The cycle is suppressed in
`intubated subjects, but restored by resumption of normal nasal
`breathing [28]. The cycle may also cause accumulation of
`nitric oxide (NO) in the congested passage and adjacent
`sinuses and contribute to defense against microbes through
`direct antimicrobial action and enhanced mucociliary clear-
`ance [29]. Measurements have shown that the concentration
`of NO in the inspired air is relatively constant due to the
`increase in NO concentration within the more congested cav-
`ity, which nearly exactly counterbalances the decrease in nasal
`airflow [30]. In some patients, as a result of structural devia-
`tions and inflammatory mucosal swelling, the nasal cycle may
`become clinically evident and cause symptomatic obstruction
`[19]. Due to the cycle, one of the nostrils is considerably more
`congested than the other most of the time, and the vast
`majority of the airflow passes through one nostril while the
`other remains quite narrow especially at the valve region [5].
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`Fig. 1 The complex anatomy of the nasal airways and paranasal sinuses
`
`optimized during evolution to protect the lower airways from
`the constant exposure to airborne pathogens and particles.
`
`Fig. 2 Illustration of the breath-powered Bi-Directional™ technology.
`See text for detailed description
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`Drug Deliv. and Transl. Res. (2013) 3:42–62
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`45
`
`Consequently, the nasal cycle contributes significantly to the
`dynamics and resistance in the nasal valve region and must be
`taken into consideration when the efficiency of nasal drug
`delivery devices is considered.
`
`Nasal and sinus vasculature and lymphatic system
`
`For nasally delivered substances, the site of deposition may
`influence the extent and route of absorption along with the
`target organ distribution. Branches of the ophthalmic and
`maxillary arteries supply the mucous membranes covering
`the sinuses, turbinates, meatuses, and septum, whereas the
`superior labial branch of the facial artery supplies the part of
`the septum in the region of the vestibule. The turbinates
`located at the lateral nasal wall are highly vascularized with
`a very high blood flow and act as a radiator to the airway.
`They contain erectile tissues and arteriovenous anastomoses
`that allow shunting and pooling related to temperature and
`water control and are largely responsible for the mucosal
`congestion and decongestion in health and disease [19, 31].
`Substances absorbed from the anterior regions are more
`likely to drain via the jugular veins, whereas drugs absorbed
`from the mucosa beyond the nasal valve are more likely to
`drain via veins that travel to the sinus cavernous, where the
`venous blood comes in direct contact with the walls of the
`carotid artery. A substance absorbed from the nasal cavity to
`these veins/venous sinuses will be outside the blood–brain
`barrier (BBB), but for substances such as midazolam, which
`easily bypass the BBB, this route of local “counter-current
`transfer” from venous blood may provide a faster and more
`direct route to the brain. Studies in rats support that a preferen-
`tial, first-pass distribution to the brain through this mechanism
`after nasal administration may exist for some, but not all small
`molecules [32, 33]. The authors suggested that this counter-
`current transport takes place in the area of the cavernous sinus–
`carotid artery complex, which has a similar structure in rat and
`man, but the significance of this mechanism for nasally deliv-
`ered drugs has not been demonstrated in man [32, 33].
`The lymphatic drainage follows a similar pattern as the
`venous drainage where lymphatic vessels from the vestibule
`drain to the external nose to submandibular lymph nodes,
`whereas the more posterior parts of the nose and paranasal
`sinuses drain towards the nasopharynx and internal deep
`lymph nodes [4]. In the context of nasal drug delivery,
`perivascular spaces along the olfactory and trigeminal
`nerves acting as lymphatic pathways between the CNS and
`the nose have been implicated in the transport of molecules
`from the nasal cavity to the CNS [34].
`
`Innervation of the nasal mucosa
`
`The nose is also a delicate and advanced sensory organ
`designed to provide us with the greatest pleasures, but also
`
`to warn and protect us against dangers. An intact sense of
`smell plays an important role in both social and sexual
`interactions and is essential for quality of life. The sense
`of smell also greatly contributes to taste sensations [35].
`Taste qualities are greatly refined by odor sensations, and
`without the rich spectrum of scents, dining and wining and
`life in general would become dull [36]. The olfactory nerves
`enter the nose through the cribriform plate and extend
`downwards on the lateral and medial side of the olfactory
`cleft. Recent biopsy studies in healthy adults suggest that the
`olfactory nerves extend at least 1–2 cm further anterior and
`downwards than the 8–10 mm described in most textbooks
`(see Figs. 1 and 2) [37, 38]. The density decreases, but
`olfactory filaments and islets with olfactory epithelium are
`found in both the anterior and posterior parts at the middle
`turbinate. In addition, sensory fibers of both the ophthalmic
`and maxillary branches of the trigeminal nerve contribute to
`olfaction by mediating a “common chemical sense” [39].
`Branches of the ophthalmic branch of the trigeminal nerve
`provide sensory innervation to the anterior part of the nose
`including the vestibule, whereas maxillary branches inner-
`vate the posterior part of the nose as well as the regions with
`olfactory epithelium.
`The olfactory and trigeminal nerves mutually interact in a
`complex manner. The trigeminal system can modulate the
`olfactory receptor activity through local peptide release or
`via reflex mechanisms designed to minimize the exposure to
`and effects of potentially noxious substances [39]. This can
`occur by alteration of the nasal patency and airflow and
`through changes in the properties of the mucous blanket
`covering the epithelium. Trigeminal input may amplify
`odorous sensation through perception of nasal airflow and
`at the chemosensory level. Interestingly, an area of increased
`trigeminal chemosensitivity is found in the anterior part of
`the nose, mediating touch, pressure, temperature, and pain
`[39]. Pain receptors in the nose are not covered by squamous
`epithelium, which gives chemical stimuli almost direct ac-
`cess to the free nerve endings. In fact, loss of trigeminal
`sensitivity and function, and not just olfactory nerve func-
`tion, may severely reduce the sense of smell [40]. This
`should not be forgotten when addressing potential causes
`of reduced or altered olfaction.
`
`The sensitivity of the nasal mucosa as a limiting factor
`
`In addition to the limited access, obstacles imposed by its small
`dimensions and dynamics, the high sensitivity of the mucosa in
`the vestibule and in the valve area is very relevant to nasal drug
`delivery. Direct contact of the tip of the spray nozzle during
`actuation, in combination with localized concentrated anterior
`drug deposition on the septum, may create mechanical irritation
`and injury to the mucosa resulting in nosebleeds and crusting,
`and potentially erosions or perforation [41]. Furthermore, the
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`Drug Deliv. and Transl. Res. (2013) 3:42–62
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`high-speed impaction and low temperature of some pressurized
`devices may cause unpleasant sensations reducing patient ac-
`ceptance and compliance.
`The role of the high sensitivity of the nasal mucosa as a
`natural nasal defense is too often neglected when the poten-
`tial of nasal drug delivery is discussed, in particular when
`results from animal studies, cast studies, and computer fluid
`dynamics (CFD) are evaluated. Exposure to chemicals, gas-
`es, particles, temperature and pressure changes, as well as
`direct tactile stimuli, may cause irritation, secretion, tearing,
`itching, sneezing, and severe pain [39]. Sensory, motor, and
`parasympathetic nerves are involved in a number of nasal
`reflexes with relevance to nasal drug delivery [4]. Such
`sensory inputs and related reflexes are suppressed by the
`anesthesia and/or sedation often applied to laboratory ani-
`mals, potentially limiting the clinical predictive value of
`such studies. Further, the lack of sensory feedback and
`absence of interaction between the device and human sub-
`jects/patients are important limitations of in vitro testing of
`airflow and deposition patterns in nasal casts and in CFD
`simulation of deposition. Consequently, deposition studies
`in nasal casts and CFD simulation of airflow and deposition
`are of value, but their predictive value for the clinical setting
`are all too often overestimated.
`
`Targeted nasal delivery
`
`For most purposes, a broad distribution of the drug on the
`mucosal surfaces appears desirable for drugs intended for
`local action or systemic absorption and for vaccines [3].
`However, in chronic sinusitis and nasal polyposis, targeted
`delivery to the middle and superior meatuses where the
`sinus openings are, and where the polyps originate, appears
`desirable [42, 43]. Another exception may be drugs intended
`for “nose-to-brain” delivery, where more targeted delivery
`to the upper parts of the nose housing the olfactory nerves
`has been believed to be essential. However, recent animal
`data suggest that some degree of transport can also occur
`along the branches of the first and second divisions of the
`trigeminal nerve innervating most of the mucosa at and
`beyond the nasal valve [44]. This suggests that, in contrast
`to the prevailing opinion, a combination of targeted delivery
`to the olfactory region and a broad distribution to the mu-
`cosa innervated by the trigeminal nerve may be optimal for
`N2B delivery. Targeted delivery will be discussed in more
`detail below.
`
`Nasal drug delivery devices
`
`The details and principles of the mechanics of particle
`generation for the different types of nasal aerosols have
`been described in detail by Vidgren and Kublik [3] in their
`
`comprehensive review from 1998 and will only be briefly
`described here, with focus instead on technological features
`directly impacting particle deposition and on new and
`emerging technologies and devices. Liquid formulations
`currently completely dominate the nasal drug market, but
`nasal powder formulations and devices do exist, and more
`are in development. Table 1 provides an overview of the
`main types of liquid and powder delivery devices, their key
`characteristics, and examples of some key marketed nasal
`products and emerging devices and drug–device combina-
`tion products in clinical development (Table 1).
`
`Devices for liquid formulations
`
`The liquid nasal formulations are mainly aqueous solutions,
`but suspensions and emulsions can also be delivered. Liquid
`formulations are considered convenient particularly for top-
`ical indications where humidification counteracts the dry-
`ness and crusting often accompanying chronic nasal
`diseases [3]. In traditional spray pump systems, preserva-
`tives are typically required to maintain microbiological sta-
`bility in liquid formulations. Studies in tissue cultures and
`animals have suggested that preservatives, like benzalko-
`nium chloride in particular, could cause irritation and re-
`duced ciliary movement. However, more recent human
`studies based on long-term and extensive clinical use have
`concluded that the use of benzalkonium chloride is safe and
`well tolerated for chronic use [45]. For some liquid formu-
`lations, in particular peptides and proteins, limited stability
`of dissolved drug may represent a challenge [46].
`
`Drops delivered with pipette
`
`Drops and vapor delivery are probably the oldest forms of
`nasal delivery. Dripping breast milk has been used to treat
`nasal congestion in infants, vapors of menthol or similar
`substances were used to wake people that have fainted, and
`both drops and vapors still exist on the market (e.g.,
`www.vicks.com). Drops were originally administered by
`sucking liquid into a glass dropper, inserting the dropper
`into the nostril with an extended neck before squeezing the
`rubber top to emit the drops. For multi-use purposes, drops
`have to a large extent been replaced by metered-dose spray
`pumps, but inexpensive single-dose pipettes produced by
`“blow-fill-seal” technique are still common for OTC prod-
`ucts like decongestants and saline. An advantage is that
`preservatives are not required. In addition, due to inadequate
`clinical efficacy of spray pumps in patients with nasal pol-
`yps, a nasal drop formulation of fluticasone in single-dose
`pipettes was introduced in the EU for the treatment of nasal
`polyps. The rationale for this form of delivery is to improve
`drug deposition to the middle meatus where the polyps
`emerge [47, 48]. However, although drops work well for
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`47
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`Table 1 Overview of the main types of liquid and powder delivery devices, their key characteristics, and examples of some key marketed nasal
`products and emerging devices and drug–device combination products in clinical development
`Product
`Example
`Example
`stage
`substance(s)
`use/indication(s)
`
`Dosing
`
`Mechanism Actuation
`
`References
`
`Relevant website(s)
`
`LIQUID DEVICES
`Vapor
`
`Vapor inhaler
`
`Marketed
`
`Methol
`
`Rhinitis, Common cold Multidose
`
`Vaporisation
`
`Nasal
`inhalation
`
`Breath
`powered
`
`www.vicks.com
`
`50,51,114 www.ferring.com
`
`Desmopressin
`
`Diabetes incipidus
`
`Single dose Mechanical
`
`Decongestants
`
`Rhinitis, Common cold Multi-dose Mechanical
`
`Hand actuated
`
`Topical steroids
`
`Nasal polyps
`
`Single dose Mechanical
`
`Hand actuated 47,48
`
`www.gsk.com
`
`Drops
`
`Rhinyle catheter (Ferring)
`
`Multi-dose droppers (multiple)
`
`Unit-dose pipettes (multiple)
`Mechanical spray pumps
`Squeeze bottle (multiple)
`
`Marketed
`product(s)
`Marketed
`product(s)
`Marketed
`product(s)
`
`Marketed
`product(s)
`
`www.novarits.com ;
`www.afrin.com
`www,aptar.com ;
`www.rexam.com
`www.gsk.com
`www.merck.com ;
`www.az.com
`
`Multi-dose Metered-dose spray pumps (multiple)
`
`3,13,14
`
`Decongestants
`
`Rhinitis, Common cold Multi-dose Mechanical
`
`Hand actuated 3
`
`Marketed
`product(s)
`Marketed
`product(s)
`Marketed
`product(s)
`Marketed
`product(s)
`Marketed
`product(s)
`Single/duo-dose spray pumps (multiple)
`Marketed
`product(s)
`Marketed
`device
`Marketed
`device
`Marketed
`device
`Product in
`Phase 3
`
`Topicals steroids
`
`Desmopressin
`
`Allergic & Perinneal
`rhinitis
`Primary nocturnal
`enuresis
`
`Multi-dose Mechanical
`
`Hand actuated 45,52
`
`Multi-dose Mechanical
`
`Hand actuated 50,51,114 www.ferring.com
`
`Calcitonin
`
`Osteoporosis
`
`Multi-dose Mechanical
`
`Hand actuated 3
`
`www.novartis.com
`
`Ketrorolac
`
`Oxytocin
`
`Pain
`Induction of lactation
`& labor
`
`Multi-dose Mechanical
`
`Hand actuated 3
`
`www.luitpold.com
`
`Multi-dose Mechanical
`
`Hand actuated 3
`3
`
`Migraine & Cluster
`headache
`
`Single dose Mechanical
`
`Hand actuated 58,59
`
`www.defiante.com
`
`www.gsk.com ;
`www.az.com
`
`Vaccine, CRS
`
`Single dose Mechanical
`
`Hand actuated 53,54
`
`www.lmana.com
`
`Vaccine
`
`Influenza vaccine
`
`Undisclosed
`
`Single dose Mechanical
`Single/duo-
`dose
`
`Mechanical
`
`CRS with Nasal polyps Multi-dose Mechanical
`
`Hand actuated 55,56
`
`www.bd.com
`
`Hand actuated 57
`13,50,87,88
`Breath
`,91,95
`powered
`
`www.crucell.com
`
`www.optinose.com
`
`Triptans
`
`Device
`
`Vaccines
`Fluticasone
`propionate
`
`Gas propellant Hand actuated 60-62
`
`Bi-dir Multi-dose spray pump
`(OptiNose)
`Gas driven spray systems/atomizers
`Slow spray HFA pMDI's
`(Teva/3M)
`
`Marketed
`product(s)
`
`Topicals steroids Allergic rhinitis
`
`Multi-dose
`
`Not known
`
`Multi-dose
`
`Gas driven
`
`Gas driven
`
`77
`
`www.teva.com ;
`www.3m.com
`www.impelneurophar
`ma.com
`
`Topical steroids
`
`Topical drugs
`Insulin (Phase 2
`trials)
`
`Sinusitis and nasal
`polyps
`Sinusitis and nasal
`polyps
`
`Multi-dose
`
`Electical
`
`Electical
`
`68
`
`www.pari.com
`
`Multi-dose
`
`Electical
`
`Electical
`
`Alzheimer's, Sinusitis Multi-dose
`
`Electical
`
`Electical
`
`72
`42, 71,73-
`76
`References
`
`www.aerogen.com
`
`www.kurvetech.com
`
`Substances
`
`Indication(s)
`
`Dosing
`
`Mechanism Actuation
`
`Example website(s)
`
`Preclinical Not known
`Nitrogen gass driven (Impel)
`Electrically powered Nebulizers/Atomizers
`Pulsation membrane nebulizer
`Marketed
`(Pari)
`device
`Vibrating mech nebulizer
`Marketed
`(Aerogen)
`device
`Marketed
`Hand-held mechanical nebuliser
`(Kurve)
`device
`Product
`stage
`
`POWDER DEVICES
`Mechanical powder sprayers
`Powder spray device (capsule
`based) (SNBL)
`
`Powder spray device (BD)
`
`Powder sprays (Aptar/Vallois) Device
`Marketed
`device
`Marketed
`device
`
`Powder spray device (Bespak)
`Breath actuated inhalers
`
`Phase 2
`
`Zlomitriptan
`
`Migraine
`
`Singel dose Mechanical
`
`Hand actuated 81,82
`
`Not known
`
`Not known
`
`Single dose Mechanical
`
`Hand actuated 84
`
`www.snbl.com
`www.bd.com;
`www.aptar.com
`
`Not known
`
`Not known
`
`Single dose Mechanical
`
`Hand actuated 83
`
`www.bespak.com
`
`Not known
`
`Not known
`
`Single dose Mechanical
`
`Hand actuated 85
`
`www.bespak.com
`
`Multi-dosepowderinhaler(AZ)
`Single/duo dose capsule inhaler
`(Nippon-Shinyaku)
`
`Rhinocort
`Turbohaler Budesonide
`Dexamethasone
`cipecilate
`Ampomorhine
`(discont.)
`
`Twin-lizer
`
`Allergic rhinitis, Nasal
`polyps
`
`Allergic rhinits
`
`Multi-dose Mechanical
`Single/duo
`dose
`
`Mechanical
`
`Parkinson's
`
`Single/duo Mechanical
`
`Nasal
`inhalation
`Nasal
`inhalation
`Nasal
`inhalation
`
`79,80
`
`www.az.com
`www.nippon-
`shinyaku.co.jp
`www.aptar.com ;
`www.stada.de
`
`Nasal inhlaler (Aptar/Pfeiffer) Device
`Insufflators
`
`Insufflator - (Trimel)
`
`Preclinical Undisclosed
`
`Allergic rhinitis,
`
`Single dose Mechanical
`
`Breath powered Bi-directional
`delivery (OptiNose)
`
`Phase 3 trials
`
`Sumatriptan
`powder
`
`Migraine
`
`Single dose Mechanical
`
`Exhalation
`driven
`
`86
`
`www.trimelpharmaceu
`ticals.com
`
`Breath
`powered
`
`14,94,98,90 www.optinose.com
`
`Nalox1010
`Nalox-1 Pharmaceuticals, LLC
`Page 6 of 21
`
`

`

`48
`
`Drug Deliv. and Transl. Res. (2013) 3:42–62
`
`some, their popularity is limited by the need for head-down
`body positions and/or extreme neck extension required for
`the desired gravity-driven deposition of drops [43, 49].
`Compliance is often poor as patients with rhinosinusitis
`often experience increased headache and discomfort in
`head-down positions.
`
`Delivery of liquid with rhinyle catheter and squirt tube
`
`A simple way for a physician or trained assistant to deposit
`drug in the nose is to insert the tip of a fine catheter or
`micropipette to the desired area under visual control and
`squirt the liquid into the desired location. This is often used
`in animal studies where the animals are anesthetized or
`sedated, but can also be done in humans even without local
`anesthetics if care is taken to minimize contact with the
`sensitive mucosal membranes [50]. This method is, howev-
`er, not suitable for self-administration. Harris et al. [51]
`described a variant of catheter delivery where 0.2 ml of a
`liquid desmopressin formulation is filled into a thin plastic
`tube with a dropper. One end of the tube is positioned in the
`nostril, and the drug is administered into the nose as drops or
`as a “liquid jet” by blowing through the other end of the thin
`tube by the mouth [51]. Despite a rather cumbersome pro-
`cedure with considerable risk of variability in the dosing,
`desmopressin is still marketed in some countries with this
`rhinyle catheter alongside a nasal spray and a tablet for
`treatment of primary nocturnal enuresis, Von Willebrand
`disease, and diabetes insipidus.
`
`Squeeze bottles
`
`Squeeze bottles are mainly used to deliver some over-the-
`counter (OTC) products like topical decongestants. By
`squeezing a partly air-filled plastic bottle, the drug is atom-
`ized when delivered from a jet outlet. The dose and particle
`size vary with the force applied, and when the pressure is
`released, nasal secretion and microorganisms may be sucked
`into the bottle. Squeeze bottles are not recommended for
`children [3].
`
`Metered-dose spray pumps
`
`Metered spray pumps have, since they were introduced
`some four decades ago, dominated the nasal drug delivery
`market (Table 1). The pumps typically deliver 100 μl (25–
`200 μl) per spray, and they offer high reproducibility of the
`emitted dose and plume geometry in in vitro tests. The
`particle size and plume geometry can vary within certain
`limits and depend on the properties of the pump, the formu-
`lation, the orifice of the actuator, and the force applied [3].
`Traditional spray pumps replace the emitted liquid with air,
`and preservatives are therefore required to prevent
`
`contamination. However, driven by the studies suggesting
`possible negative effects of preservatives, pump manufac-
`turers have developed different spray systems that avoid the
`need for preservatives. These systems use a collapsible bag, a
`movable piston, or a compress