Pharmacology & Therapeutics 134 (2012) 366–379
`
`Contents lists available at SciVerse ScienceDirect
`
`Pharmacology & Therapeutics
`
`j o u r n a l h o m e p a g e : w w w . e l s e v i e r . c o m / l o c a t e / p h a r m t h e r a
`
`Associate editor: N. Frossard
`Intranasal drug delivery: An efficient and non-invasive route for
`systemic administration
`Focus on opioids
`Stanislas Grassin-Delyle a,b,⁎, Amparo Buenestado a,b, Emmanuel Naline a,b, Christophe Faisy a,c,
`Sabine Blouquit-Laye a,b, Louis-Jean Couderc a,b,d, Morgan Le Guen b,e,
`Marc Fischler a,b,e, Philippe Devillier a,b
`a Laboratoire de Pharmacologie, UPRES EA220, Hôpital Foch, 11 rue Guillaume Lenoir, 92150 Suresnes, France
`b Université Versailles Saint Quentin en Yvelines, UFR Sciences de la santé, France
`c Service de Réanimation Médicale, Hôpital Européen Georges Pompidou, 20 rue Leblanc, 75908 Paris cedex 15, France
`d Service de Pneumologie, Hôpital Foch, 40 rue Worth, 92150 Suresnes, France
`e Département d'Anesthésie, Hôpital Foch, 40 rue Worth, 92150 Suresnes, France
`
`a r t i c l e
`
`i n f o
`
`a b s t r a c t
`
`Keywords:
`Intranasal
`Systemic effects
`Pharmacokinetics
`Opioids
`
`Intranasal administration is a non-invasive route for drug delivery, which is widely used for the local treat-
`ment of rhinitis or nasal polyposis. Since drugs can be absorbed into the systemic circulation through the
`nasal mucosa, this route may also be used in a range of acute or chronic conditions requiring considerable
`systemic exposure. Indeed, it offers advantages such as ease of administration, rapid onset of action, and
`avoidance of first-pass metabolism, which consequently offers for example an interesting alternative to intra-
`venous, subcutaneous, oral transmucosal, oral or rectal administration in the management of pain with opi-
`oids. Given these indisputable interests, fentanyl-containing formulations have been recently approved and
`marketed for the treatment of breakthrough cancer pain. This review will outline the relevant aspects of
`the therapeutic interest and limits of intranasal delivery of drugs, with a special focus on opioids, together
`with an in-depth discussion of the physiological characteristics of the nasal cavity as well as physicochemical
`properties (lipophilicity, molecular weight, ionisation) and pharmaceutical factors (absorption enhancers,
`devices for application) that should be considered for the development of nasal drugs.
`© 2012 Elsevier Inc. All rights reserved.
`
`Contents
`
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Introduction .
`1.
`.
`.
`2. Mechanisms involved in intranasal drug delivery .
`3.
`The pharmacokinetics of intranasally administered drugs
`4.
`Therapeutic uses of intranasally administered opioids .
`5.
`Conclusions .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Declaration of conflicts of interest .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`Acknowledgments .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`References .
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`.
`.
`.
`.
`.
`.
`.
`.
`
`367
`366
`368
`367
`371
`367
`373
`368
`378
`368
`378
`369
`378
`370
`378
`370
`
`Abbreviations: IN, intranasal; i.v., intravenous; MW, molecular weight; P-gp,
`P-glycoprotein.
`⁎ Corresponding author at: Laboratoire de Pharmacologie, UPRES EA220, 11 rue
`Guillaume Lenoir, 92150 Suresnes, France. Tel.: +33 1 46 25 27 91.
`E-mail address: s.grassindelyle@hopital-foch.org (S. Grassin-Delyle).
`
`0163-7258/$ – see front matter © 2012 Elsevier Inc. All rights reserved.
`doi:10.1016/j.pharmthera.2012.03.003
`
`1. Introduction
`
`Intranasal (IN) drug delivery is usually associated with the production
`of a local effect. A typical example is the treatment of allergic or infectious
`rhinitis with antihistamines, corticoids and/or vasoconstrictors. However,
`the nasal mucosa's high degree of vascularisation and high permeability
`also enable systemic drug administration via this route—making the
`
`Nalox1011
`Nalox-1 Pharmaceuticals, LLC
`Page 1 of 14
`
`

`

`Buserelin
`Nafarelin
`Desmopressin
`
`Suprefact nasal®
`Synarel®
`Minirin®
`
`Miacalcin®
`Calcitonin
`Dihydroergotamine Diergo-spray®
`Sumatriptan
`Imigran®
`Butorphanol
`Stadol NS®
`
`Prostate cancer
`Endometriosis
`Prevention and control of polydipsia,
`polyurea and dehydratation in
`patients with diabetes insipidus
`Post-menopausal osteoporosis
`Migraine and cluster headache
`Migraine and cluster headache
`Management of pain, including
`migraine headache pain
`Instanyl®, PecFent® Breakthrough pain in patients
`with cancer
`Hormone replacement therapy
`Smoking cessation
`Labour induction and lactation
`stimulation
`Vitamin B12 deficiency
`Seasonal or H1N1 flu prevention
`
`Fentanyl
`
`Estradiol
`Nicotine
`Oxytocin
`
`Cyanocobalamin
`Influenza vaccine
`
`Aerodiol®
`Nicotrol NS®
`Syntocinon®
`
`Nascobal®
`FluMist®
`
`nose both a therapeutic target and a portal for drug delivery. Hence, IN
`drug formulations have been developed for a wide range of indications,
`including hormone replacement therapy, osteoporosis, migraine, pros-
`tate cancer and even an influenza vaccine (Table 1) (Pires et al., 2009).
`The main advantages (Table 2) of IN delivery are ease of administration,
`a rapid onset of action and the avoidance of gastrointestinal and hepatic
`first-pass effects; accordingly, the nose constitutes a very valuable route
`for the administration of active principles with low oral bioavailability.
`Conversely, the limitations of IN administration (Table 2) are related to
`the need to cross the nasal mucosa—the physiological properties of
`which (including some disease-related alterations) influence drug ab-
`sorption. Several general reviews on IN drug delivery have already been
`published (Behl et al., 1998; Illum, 2003; Graff & Pollack, 2005;
`Costantino et al., 2007; Pires et al., 2009) but none has covered all the de-
`terminant physicochemical, pharmaceutical and physiopathological pa-
`rameters in the absorption of drugs via this route, their pharmacokinetic
`consequences in man and the methods that can be used to modulate
`systemic exposure. After having presented the parameters that govern
`the pharmacokinetics of intranasally administered drugs, we shall ad-
`dress the IN absorption of opioids in general and fentanyl in particular;
`the latter's pharmacokinetic profile via the IN route enables its use in the
`treatment of breakthrough cancer pain.
`
`Table 2
`Advantages and limitations of intranasal administration of drugs for systemic delivery.
`Adapted from Arora et al.
`
`Advantages
`
`Limitations
`
`High absorption for lipophilic
`drugs with MW b1 kDa
`Avoidance of gastrointestinal and
`hepatic first-pass effect
`Plasma profile similar to the
`intravenous route: fast onset
`of action
`Ease of administration,
`non-invasive: self-medication
`
`Ease of use in patients with
`nausea and vomiting
`
`Cheap drug delivery devices
`
`Poor permeability for hydrophilic drugs or
`drugs with MW >1 kDa (peptides, proteins…)
`Absorption time limited by mucociliary
`clearance
`Low absorption surface in comparison to
`intestinal mucosa
`
`Enzymatic activity of the nasal mucosa,
`especially with proteins- and
`peptides-degrading enzymes
`Variability in the absorption in case of
`chronic alterations of the nasal mucosa or
`with simultaneous administration of
`vasoconstrictive drugs
`Local intolerance towards nasal mucosa
`
`S. Grassin-Delyle et al. / Pharmacology & Therapeutics 134 (2012) 366–379
`
`367
`
`Table 1
`Intranasally administered drugs for systemic delivery.
`
`Drug
`
`Brand
`
`Indications
`
`2. Mechanisms involved in intranasal drug delivery
`
`The four pharmacokinetic steps that influence the fate of drugs in
`the body are absorption, distribution, metabolism and elimination.
`The specific, valuable features of IN administration are mainly related
`to the drug absorption step and depend on anatomical, physiological
`and compound-related factors.
`
`2.1. Anatomical and physiological factors
`
`Each nasal fossa is divided into three segments: the vestibule, the
`atrium and the turbinate (which in turn is divided into the superior,
`middle and inferior turbinate) (Fig. 1). The respiratory zone (around
`the inferior turbinate) is the main site for systemic entry of drugs be-
`cause of its high surface area (120 to 150 cm²) and its highly vascu-
`larised and permeable chorion. The latter contains many glands
`responsible for secreting most of the nasal mucus. The epithelium cov-
`ering the nasal fossae is mainly constituted of basal cells, ciliated cells
`and mucus-secreting goblet cells (Fig. 2). The epithelial cells are held to-
`gether by intercellular tight junctions. Beating cilia transport the mucus
`towards the oropharyngeal junction, where it is swallowed.
`The nose's arterial blood supply comes from the external carotid
`system (via the sphenopalatine and facial arteries) and from the in-
`ternal carotid system (via the ophthalmic artery). The arterial blood
`flow irrigates a dense bed of capillaries and then capacitance vessels
`(i.e. large venous sinusoids) near the turbinate respiratory zone. The
`venous return involves the sphenopalatine, facial and ophthalmic
`veins and then the internal jugular vein, which in turn drains (via
`the subclavian vein and the superior vena cava) into the right heart
`chambers; this explains the absence of a hepatic first-pass effect.
`Nasal blood flow is partly controlled by the autonomic nervous sys-
`tem. Stimulation of vascular alpha-adrenergic receptors by the nor-
`adrenaline released by sympathetic nerves has a predominant role
`in the neuronal control of blood flow and leads to significant vasocon-
`striction and a decrease in blood flow. Treatment with α1-adrenergic
`antagonists induces nasal congestion in less than 5% of patients, dem-
`onstrating indirectly the catecholamine-mediated control of the nasal
`vasculature. In humans, endothelially generated endothelin also has a
`major role in controlling nasal vascular tone, as shown by the occur-
`rence of nasal congestion as a side effect of treatment with endothelin
`antagonists. Conversely, the stimulation of muscarinic or peptidergic
`receptors (e.g. with calcitonin gene-related peptide and the tachyki-
`nins) induces vasodilatation (Devillier et al., 1988; Al Suleimani &
`Walker, 2007). Changes in local vascular homeostasis (combined
`with over-secretion of mucus) can have significant repercussions on
`the absorption of intranasally administered drugs; the impact on
`therapeutic management must therefore be carefully assessed.
`The olfactory epithelium (Fig. 1) has a small surface area (1 to 5 cm²,
`accounting for only 3 to 5% of the nasal cavity's total surface area
`(Morrison & Costanzo, 1990) and is thus not significantly involved in
`the systemic absorption of drugs. However, it can enable direct access
`to the central nervous system (CNS) by by-passing the blood–brain bar-
`rier (Illum, 2004). Although the mechanisms and physicochemical
`properties that govern drug deposition in the olfactory zone are the
`same as those in the respiratory zone, the former has a much lower sur-
`face area in humans than in the animal; hence, studies in animal models
`are less relevant (Illum, 1996, 2004). A few clinical, pharmacodynamic
`studies suggest that CNS drugs can be absorbed directly through this
`zone (Born et al., 2002; Illum, 2003). However, the results of a recent
`study showed that sprays reached the olfactory epithelium in only 1
`in 15 patients (Scheibe et al., 2008). The partial obstruction of the
`nasal fossa by the turbinates prevents the deposition of drugs on the ol-
`factory epithelium as well as the nasopharynx. A general review on ste-
`roids concluded that most of the spray is deposited in the nasal cavity's
`anterior segment (the nasal floor and preturbinate zone) and middle
`segment (the turbinate zone) (Benninger et al., 2004). Furthermore,
`Nalox1011
`Nalox-1 Pharmaceuticals, LLC
`Page 2 of 14
`
`

`

`368
`
`S. Grassin-Delyle et al. / Pharmacology & Therapeutics 134 (2012) 366–379
`
`Olfactory epithelium
`
`Vestibule
`
`Atrium
`
`Middle turbinate
`
`Inferior turbinate
`
`Superior turbinate
`
`Nasopharynx
`
`Fig. 1. Representation of the different areas of the nasal cavity: vestibule, atrium, inferior, middle and superior turbinates; olfactive region and nasopharynx. Drug deposition fol-
`lowing intranasal administration mainly occurs in the respiratory zone around the inferior turbinate. Partial obstruction of the nasal cavity by the turbinates prevents at least in part
`the deposition on the olfactory epithelium and on the nasopharynx.
`
`the mechanisms of transport to the CNS through the olfactory zone are
`poorly known; they may involve either diffusion through the subarach-
`noid area or internalization of the active principles by olfactory neurons
`and then axonal transport up to the olfactory bulb (Born et al., 2002).
`This transport mechanism is slow (about 2.5 mm/h in the monkey)
`and thus cannot explain the rapid appearance of active principles in
`the brain or the cerebrospinal fluid after IN administration (Illum,
`2000).
`
`2.2. Sources of variability in intranasal absorption
`
`Absorption through the nasal epithelium takes place after deposi-
`tion of the drug by local spray administration. The proportion of the
`drug that actually crosses the epithelium thus depends variously on
`physiological, molecular and pharmaceutical factors.
`
`2.2.1. Factors influencing the site and surface area of drug absorption
`In the chronological sequence of events, the initial limitations on
`absorption are related to the drug's pharmaceutical formulation and
`the characteristics of the spray created by the pump.
`
`2.2.1.1. The volume administered. The nasal mucosa's low surface area
`limits the administration of active principles to volumes below 200 μL,
`in order to avoid direct loss of the drug via anterior or posterior run-
`
`off. For insulin preparations of between 80 and 160 μL in volume, it
`has been shown that the entire administered dose is deposited in the
`nasal cavities, with no passage to the lungs (Newman et al., 1994).
`The unit volume administered is also important because it appears
`that the administration of a single volume of 100 μL leads to deposition
`over a greater surface area than that obtained with the administration
`of two 50 μL volumes (Newman et al., 1994; Kundoor & Dalby, 2011).
`
`2.2.1.2. The particle diameter. For drugs in solution administered as a
`nasal spray, the aerodynamic diameter of the particles emitted by
`the spray device must be greater than or equal to 10 μm, in order to
`ensure impaction of the particles on the nasal mucosae and to prevent
`them from being drawn into the lower airways by inspiratory flow.
`
`2.2.1.3. The solution's viscosity. By using an anatomically accurate sili-
`cone model of the human nose and nasal cavities, Kundoor and Dalby
`showed that the deposition area decreased with sprays of increasing
`viscosity. Thus was probably due to an increase in the droplet size at
`higher viscosities (Kundoor & Dalby, 2011).
`
`2.2.1.4. The spray administration angle and plume angle. The spray ad-
`ministration and plume angles are key determinants of optimal
`drug delivery. The combination of an administration angle of 30°
`and a plume angle of 30° led to deposition primarily in the anterior
`
`Non-ciliated
`columnar cell
`
`Globet cell
`
`Basal cell
`
`Ciliated
`columnar cells
`
`Basement
`membrane
`
`Fig. 2. Representation of the different cell types constitutive of the nasal epithelium.
`
`Nalox1011
`Nalox-1 Pharmaceuticals, LLC
`Page 3 of 14
`
`

`

`S. Grassin-Delyle et al. / Pharmacology & Therapeutics 134 (2012) 366–379
`
`369
`
`region of the nose, with a deposition efficiency close to 90% (Foo et al.,
`2007).
`
`2.2.1.5. Respiratory flows. By using a device similar to the silicone nose
`mentioned above, another group showed that variations in inspiratory
`flow at the time of drug administration had only a minor influence on
`the efficacy of deposition in the turbinate zone. The absence of an effect
`of intense inhalation at the time of spraying has also been demonstrated
`(Homer & Raine, 1998).
`
`organic anions and cations have been identified (including P-
`glycoprotein (P-gp), the organic anion transporter (OAT) and the
`organic cation transporter (OCT)) and the corresponding transport
`mechanisms have been characterised in various organs (Koepsell,
`1998; Meijer et al., 1999; Inui et al., 2000; Mizuno et al., 2003), including
`the human nasal mucosa (Agu et al., 2011). The paracellular route in-
`volves crossing the tight junctions, the role of which is not only to en-
`sure mechanical cohesion of the epithelial cells but also to regulate
`molecular transport through the paracellular space.
`
`2.2.2. Factors influencing transepithelial passage
`After being deposited on the respiratory mucosa, the active principle
`must cross the epithelium to reach the systemic circulation. This
`mucus-coated anatomical barrier is notably constituted of beating, cili-
`ated cells that ensure efficient mucociliary clearance.
`
`2.2.2.1. Mucociliary clearance. Mucociliary clearance limits the drug–
`mucosa contact time by ensuring effective drainage and thus can consti-
`tute a limiting factor in the absorption of active principles. Hence, inhaled
`particles that deposit on the mucus are eliminated by this mechanism in
`15 to 30 min (Marttin et al., 1998; Illum, 2003). More exactly, it is possi-
`ble to distinguish an initial, 15- to 20-minute clearance phase (during
`which about 50% of the administered dose is eliminated from the respi-
`ratory mucosa) and a second, slower phase that enables elimination of
`drug molecules deposited on the non-ciliated epithelium of the vestibule
`and on the nasal cavity's anterior segment (Marttin et al., 1998). Major
`variations can be observed, since over 55% of the total dose may still be
`present at
`the initial
`spraying site 30 min post-administration
`(Newman et al., 1987). Furthermore, the presence of active principle in
`the nasal tissue and secretions up to 24 h after administration of a single
`dose has already been documented with a corticosteroid in aqueous
`solution—perhaps because of this compound's slow dissolution and
`high tissue binding (Bonsmann et al., 2001).
`
`2.2.2.2. Transepithelial routes. After deposition, a drug may cross the ep-
`ithelium via the transcellular route (i.e. though the epithelial cells
`themselves) and the paracellular route (i.e. through the tight junctions
`between the epithelial cells), depending on the compound's intrinsic
`physicochemical properties. For the transcellular route, the molecules
`can cross the cells by passive diffusion down a concentration gradient
`or via active, receptor- or membrane transporter-mediated processes.
`Many transporters responsible for the influx or efflux of peptides and
`
`2.2.2.3. Physicochemical properties of active principles. The three main
`physicochemical criteria involved in the epithelial passage of active
`principles are the molecular weight (MW), hydrophilicity/lipophilicity
`and degree of ionisation, which all affect the routes and mechanisms
`of transepithelial passage. The solubilization rate is also involved but
`also depends (at least in part) on the afore-mentioned physicochemical
`properties. Schematically, lipophilic molecules take the transcellular
`route, whereas hydrophilic molecules can take the transcellular or
`paracellular routes (depending on their MW) (Fig. 3). High MW is the
`limiting factor for paracellular passage through the tight junctions. For
`drugs with a MW below 300 Da, nasal absorption is rapid and hardly
`influenced by the other physicochemical properties, whereas molecules
`with a MW above 1 kDa absorb very slowly (with a bioavailability of be-
`tween 0.5% and 5%) (McMartin et al., 1987; Arora et al., 2002; Illum,
`2003; Costantino et al., 2007). For the molecules with a MW of between
`300 Da and 1 kDa (which is the case for the great majority of active
`principles),
`liposolubility is an important property for resorption
`(Arora et al., 2002; Labiris & Dolovich, 2003; Costantino et al., 2007) be-
`cause it influences passive diffusion across the epithelium. Lipophilic
`molecules can diffuse freely, whereas hydrophilic molecules have to
`use the paracellular route to cross the epithelium. Hence, there is a
`strong, positive relationship between lipophilicity and the transepithe-
`lial transport rate in in vitro models based on cultured porcine or
`human epithelial cells (Lin et al., 2005).
`Although the degree of ionisation has a weaker influence on IN ab-
`sorption, this parameter is also involved in diffusion of the drug com-
`pound because only the non-ionized fraction is diffusible and thus
`more easily absorbed (Costantino et al., 2007). It is easy to under-
`stand that for molecules like proteins (which have a high MW and,
`in most cases, a non-zero net charge at physiological pH), the diffu-
`sion mechanism is not appropriate for crossing biological barriers
`and that alternative mechanisms (via transporters or the paracellular
`
`Transcellular route
`
`Passive diffusion
`
`Transporter
`
`Receptor
`
`Transcellular route
`
`Endocytosis
`
`Transporter (OCT,AAT...)
`
`Paracellular route
`
`Tight junction passage
`
`YES
`
`N
`
`O
`
`M.W. > 1 kDa
`
`Lipophilic drug
`
`YES
`
`N
`
`O
`
`Fig. 3. Mechanisms involved in the crossing of the respiratory epithelium by xenobiotics, in function of their physicochemical properties. OCT = organic cations transporters, AAT =
`amino acids transporters.
`
`Nalox1011
`Nalox-1 Pharmaceuticals, LLC
`Page 4 of 14
`
`

`

`370
`
`S. Grassin-Delyle et al. / Pharmacology & Therapeutics 134 (2012) 366–379
`
`route) are involved. However, for small molecules that are weak acids
`or bases, the degree of ionisation can partly be controlled during sol-
`ubilization of the active principle by using the pH of the vehicle solu-
`tion to produce a non-ionized, more readily diffusible state. Since the
`average pH in the anterior and posterior nasal cavities is around 6.3
`(Washington et al., 2000), basic drugs with a pKa above 7.3 will be
`predominantly (90%) in a charged state in the absence of a buffer.
`The proportion of neutral molecules rises when the active principle
`is solubilised in a basic buffer, which thus favours membrane
`diffusion.
`The rate of dissolution in the mucus may become an absorption-
`limiting factor in terms of mucociliary clearance and is especially impor-
`tant for drugs administered as a powder or suspension. A molecule
`whose dissolution time is greater than the time required for mucociliary
`drainage to the oropharyngeal junction cannot be absorbed locally. The
`dissolution rate depends not only on the compound's pharmaceutical
`formulation (i.e. as a solution or a suspension) but also on its liposolubi-
`lity and degree of ionisation. Hydrophilic molecules are very soluble in
`mucus (which is mainly constituted of water) and are thus most sensi-
`tive to mucociliary clearance, especially since their transmembrane dif-
`fusion rate is low.
`
`2.2.2.4. Nasal blood flow. Nasal blood flow is a key factor in maintaining
`a concentration gradient at the absorption site, which in turn is essential
`for promoting drug diffusion. Vasoconstrictor or vasodilator drugs influ-
`ence the nasal blood flow and thus induce variability in the absorption
`of compounds at this site. This aspect will be discussed in more detail
`below.
`
`In any case, a molecule intended for IN administration would ideally
`have the following properties: a low MW, high lipophilicity and zero net
`charge at physiological pH. It must be soluble enough to enable delivery
`of the entire effective dose in a volume of 100 μL per nostril (i.e. a total
`of volume of 200 μL).
`
`2.2.3. Degradation and excretion of nasally administered drugs
`Before a drug enters the systemic circulation, several specific, IN
`elimination mechanisms come into play. In addition to purely physical
`phenomena (such as sneezing or anterior or posterior run-off), local
`degradation of the active principle can occur. In fact, the epithelium bar-
`rier has an impact on three levels. The first two are related to mucocili-
`ary clearance and tight junctions, which counter the crossing of this
`defensive barrier by external agents and xenobiotics. Thirdly, epithelial
`cells are equipped with protein and enzymatic machineries that are in-
`volved in the degradation and transcellular efflux of molecules. In fact,
`this could be termed a “nasal first-pass effect”. The nasal epithelium is
`equipped with enzymes responsible for the degradation of native mol-
`ecules (e.g. the endopeptidases or carboxypeptidases that degrade bra-
`dykinin or neuropeptides; Ohkubo et al., 1995, 1994) but also contains a
`large pool of enzymes involved in drug metabolism. The presence of
`many P450 cytochrome isoforms (mainly isoforms 3A, 2A6, 2A13,
`1B1, 4B1, 2C and 2F1; Ding & Kaminsky, 2003; Zhang et al., 2005) and
`other biotransformation enzymes (such as dehydrogenases, esterases,
`UDP-glucuronosyltransferase and glutathione S-transferases) (Ding &
`Dahl, 2003; Zhang et al., 2005) demonstrates the nasal mucosa's signif-
`icant metabolic capacity. Efflux systems also contribute to the excretion
`of xenobiotics. The latter's main component (P-gp, a member of the su-
`perfamily of ATP-binding cassette transporters) is expressed in the
`nasal mucosa in man (Henriksson et al., 1997; Wioland et al., 2000).
`The protein's 12 transmembrane domains form a pore in the cytoplas-
`mic membrane that serves as an ATP-dependent pump for the specific
`cellular efflux of certain substrates. It is well known that cells in the
`blood–brain barrier express P-gp, which is involved in the efflux of
`drugs crossing endothelial cells; this limits the access of drugs to the
`CNS, as has been observed with antidepressants (O'Brien et al., 2012).
`Likewise, OCTs have been identified in the human nasal mucosa and
`
`may be responsible for the efflux of organic cations such as antihista-
`mines, opioids and antibiotics (Agu et al., 2011). Even though the
`exact role of metabolic enzymes and efflux systems in the degradation
`and excretion of intranasally administered drugs is not yet fully under-
`stood, these mechanisms promote drug biotransformation and efflux
`into the extracellular milieu and thus decrease bioavailability (Graff &
`Pollack, 2003).
`
`3. The pharmacokinetics of intranasally administered drugs
`
`3.1. The main pharmacokinetic characteristics
`
`As mentioned above, a drug's physicochemical properties are key
`determinants of its ability to cross the nasal mucosa efficiently and
`thus providing adequate bioavailability for achieving the desired sys-
`temic effects, in terms of both intensity and onset of action.
`A few studies have compared the respective pharmacokinetic pro-
`files for oral or parenteral vs. IN administration of a given compound.
`When administered intranasally as drops (0.5 mL per nostril), the
`very hydrophilic drug zanamivir (log P: –3.2; MW: 332 Da) has a bio-
`availability of about 11%. The maximum plasma concentration (Cmax)
`after IN administration was only 3% of that observed with the intrave-
`nous (i.v.) route and occurred (at Tmax) after 1.8 h, versus 0.3 h with
`the i.v. route (Cass et al., 1999). The migraine drug sumatriptan
`(which is more lipophilic (log P: 0.9) than zanamivir but has a similar
`MW (295 Da)) also shows low IN bioavailability (about 16%), when
`compared with the subcutaneous route (about 100%) (Duquesnoy
`et al., 1998). It is also noteworthy that Tmax for IN administration is
`1.5 h, versus 0.17 h for the subcutaneous route—again reflecting
`slower IN absorption of this molecule. In another study, midazolam
`(a compound that is even more lipophilic than sumatriptan (log P:
`2.5; MW: 326 Da)) administered as an IN spray (0.5 mg/100 μL in
`each nostril) was found to have a bioavailability of 88% (Haschke et
`al., 2010). Tmax is 10.6 min (vs. 2.1 min when given i.v.) and the
`Cmax is about 33% of the i.v. value. Similar results were obtained
`with lorazepam (another member of the benzodiazepine family,
`with similar physicochemical properties, (log P: 2.4; MW: 321 Da))
`when administered as an IN spray (1 mg per 100 μL in each nostril).
`A bioavailability of 78% was reported, with Cmax and Tmax values of
`21.4 ng/mL and 0.5 h respectively (compared with 47.6 ng/mL and
`0.1 h, respectively, for the i.v. route) (Wermeling et al., 2001). Lastly,
`the bioavailability of the very lipophilic antipsychotic haloperidol (log
`P: 3.2; MW: 376 Da) when administered as an IN spray (2.5 mg in
`100 μL in one nostril) in a pilot study was 64%, with a Tmax of
`15 min (the same as for i.v. administration) (Miller et al., 2008).
`These latter examples with small molecules illustrate well the impor-
`tance of lipophilicity in obtaining optimal IN bioavailability.
`The IN route also has some distinctive characteristics during the
`pharmacokinetic phase that follows absorption, i.e. distribution. In
`fact, after absorption at the venous plexus that drains into the facial,
`sphenopalatine and ophthalmic veins, drugs pass through the jugular
`veins, the superior vena cava, the right heart, the lungs and the left
`heart. They are then expelled into the arterial blood flow that irrigates
`the various organs. The latter are able to extract a proportion of the
`active principle and release the rest into the venous circulation. This
`explains the arterial vs. venous differences observed in the blood con-
`centrations of various administered intranasally molecules, such as
`nicotine and fentanyl. In such cases, arterial Tmax occurs earlier and
`thus measurement of the arterial concentration appears more appro-
`priate for explaining the drug's pharmacodynamics (Gourlay &
`Benowitz, 1997; Guthrie et al., 1999; Moksnes et al., 2008).
`In conclusion, the unusual aspects of the pharmacokinetics of intra-
`nasally administered drugs are mainly due to physiological causes and
`the molecules' physicochemical properties, which lead to the observed
`variations in absorption. However, it may be preferable to modulate
`these phenomena and thus improve the bioavailability of certain active
`Nalox1011
`Nalox-1 Pharmaceuticals, LLC
`Page 5 of 14
`
`

`

`S. Grassin-Delyle et al. / Pharmacology & Therapeutics 134 (2012) 366–379
`
`371
`
`principles, whether in terms of the quantity of active principle absorbed
`or the rate at which it reaches the systemic circulation. Various methods
`can be used to this end, by adjusting the pharmaceutical formulation or
`by modulating elimination phenomena.
`
`3.2. Optimising the pharmacokinetics of intranasally administered drugs
`
`Several complementary strategies can be used to increase the bio-
`availability of intranasally administered drugs. The main objectives
`are to improve permeability and reduce excretion phenomena (enzy-
`matic degradation, efflux and mucociliary clearance). This can be
`achieved by administering other molecules (enzyme inhibitors and ab-
`sorption promoters) with the active principle or optimising the latter's
`chemical properties and pharmaceutical formulation (e.g. via the use of
`prodrugs, solubilization agents or solid/mucoadhesive formulations).
`
`3.2.1. Prodrugs
`Prodrugs (i.e. compounds that have to undergo biotransformation in
`the body before they can exert their pharmacological action) can be used
`to improve the stability and permeability of active principles that do not
`have the initially desired absorption properties. Hydrophilic groups can
`be added to improve the aqueous solubility of very lipophilic molecules.
`Conversely, the addition of hydrophobic groups increases the lipophilic-
`ity of polar molecules and thus increases their ability to cross biological
`membranes. For example, this method has been used advantageously
`to facilitate the IN absorption of peptides (desmopressin acetate) and
`corticosteroids (beclomethasone dipropionate) (Krishnamoorthy &
`Mitra, 1998) and can also confer the molecules with a degree of protec-
`tion against degradation enzymes and efflux proteins (by virtue of a
`lower binding affinity for these systems), as has been observed with es-
`terified forms of acyclovir (Yang et al., 2001).
`
`3.2.2. Solubilization agents
`The addition of excipients like cyclodextrins increases the solubility
`and stability of active principles. The cyclodextrins are cyclic, ring-
`shaped oligosaccharides with hydrophilic outer surface and a lipophilic
`internal cavity that can harbour lipophilic molecules. They not only in-
`crease the solubility of lipophilic drugs but also facilitate direct perme-
`ation through biological barriers, since the overall lipophilicity of the
`drug–cyclodextrin complex is higher than that of the molecule alone.
`This combination has been advantageously applied to IN administration
`of molecules such as midazolam (Haschke et al., 2010) and granisetron
`(Cho et al., 2010).
`
`3.2.3. Enz