International Journal of Pharmaceutics 337 (2007) 1–24
`
`Mini-review
`Intranasal delivery: Physicochemical and therapeutic aspects
`Henry R. Costantino a,∗
`, Lisbeth Illum b, Gordon Brandt a, Paul H. Johnson a, Steven C. Quay a
`a Nastech Pharmaceutical Company, Inc., Bothell, WA 98021, USA
`b IDentity, Nottingham, UK
`Received 3 January 2007; received in revised form 19 March 2007; accepted 22 March 2007
`Available online 25 March 2007
`
`Abstract
`
`Interest in intranasal (IN) administration as a non-invasive route for drug delivery continues to grow rapidly. The nasal mucosa offers numerous
`benefits as a target issue for drug delivery, such as a large surface area for delivery, rapid drug onset, potential for central nervous system delivery,
`and no first-pass metabolism. A wide variety of therapeutic compounds can be delivered IN, including relatively large molecules such as peptides
`and proteins, particularly in the presence of permeation enhancers. The current review provides an in-depth discussion of therapeutic aspects of
`IN delivery including consideration of the intended indication, regimen, and patient population, as well as physicochemical properties of the drug
`itself. Case examples are provided to illustrate the utility of IN dosing. It is anticipated that the present review will prove useful for formulation
`scientists considering IN delivery as a delivery route.
`© 2007 Elsevier B.V. All rights reserved.
`
`Keywords: Intranasal drug delivery; Nasal mucosa; Pharmacokinetics; Physicochemical properties
`
`Contents
`
`1.
`2.
`
`Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Therapeutic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.1.
`Local delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.2. Vaccine delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.3.
`Systemic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.4. Chronic versus acute therapeutic use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.5. CNS delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.6.
`Factors related to patient population . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.6.1.
`Effect of nasal inflammation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.6.2. Nasal physiology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.6.3. Variability of IN dosing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7. Case examples of therapeutic areas sutiable for intranasal delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.1. Morphine for breakthrough cancer pain . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.2.
`Treatments for migraine and cluster headaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.3. Acetylcholinesterase inhibitors for Alzheimer’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.4. Apomorphine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.5. Anti-nausea and motion sickness medications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.6. Cardiovascular drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.7.
`Sedative agents (non-emergency situation) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.8.
`Examples for application in an emergency situation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2.7.9.
`Systemic delivery of macromolecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`∗
`
`Corresponding author. Tel.: +1 4259083686.
`E-mail address: rcostantino@Nastech.com (H.R. Costantino).
`
`0378-5173/$ – see front matter © 2007 Elsevier B.V. All rights reserved.
`doi:10.1016/j.ijpharm.2007.03.025
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`3. Drug characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.
`Physicochemical characteristics. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.1. Molecular weight . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.2. Hydrophobicity/hydrophilicity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.3. Chemical and physical stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.4. Biochemical stability . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.1.5.
`Solubility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3.2. Role of transporters, efflux systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`4. Concluding remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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`1. Introduction
`
`2.1. Local delivery
`
`Intranasal (IN) administration represents a viable option for
`local and systemic delivery of diverse therapeutic compounds
`(Behl et al., 1998a,b; Costantino et al., 2005; Hussain, 1998;
`Illum, 2000, 2003, 2004; Pontiroli, 1998; Sayani and Chien,
`1996; Song et al., 2004; Wearley, 1991). The large surface
`area of the nasal mucosa affords a rapid onset of therapeutic
`effect, potential for direct-to-central nervous system delivery,
`no first-pass metabolism, and non-invasiveness; all of which
`may maximize patient convenience, comfort, and compliance.
`Although the nasal mucosa poses a permeation barrier to high-
`molecular-weight therapeutics such as peptides and proteins, the
`tight junctions that form this barrier to paracellular drug deliv-
`ery can be reversibly and safely opened (Johnson and Quay,
`2005). IN delivery is non-invasive, essentially painless, does
`not require sterile preparation, and is easily and readily adminis-
`tered by the patient or a physician, e.g., in an emergency setting.
`Furthermore, the nasal route may offer improved delivery for
`“non-Lipinski” drugs (Johnson and Quay, 2005). Due to such
`factors, marketed IN formulations exist for a variety of low- and
`high-molecular-weight drugs (e.g., peptides and proteins), and
`there are other products under development.
`Given these positive attributes, it is logical to consider IN
`administration when developing new therapeutics, or when
`extending the life or improving the profile of an existing drug.
`In order to assess the desirability and viability of such an
`approach, a series of questions regarding the drug and its use
`should be addressed. Is the drug intended for local or systemic
`delivery? Will the drug be delivered chronically or acutely?
`Is the patient population needle-na¨ıve? Are the physicochem-
`ical properties of the drug suitable for intranasal delivery and
`can clinically relevant bioavailability be achieved (an important
`aspect for peptides and proteins)? These questions are consid-
`ered below in light of their impact on a drug’s suitability for IN
`development.
`
`2. Therapeutic considerations
`
`Therapeutic considerations are paramount when selecting the
`dosing route. Such considerations include the pharmaceutical
`target (e.g., local versus systemic), the dosing frequency, and the
`patient population. In some cases, IN delivery may not only be
`possible, but may also be the preferred mode of administration.
`
`IN is a logical delivery choice for local (or topical) treat-
`ment. Prominent examples are decongestants for nasal cold
`symptoms, and antihistamines and corticosteroids for allergic
`rhinitis (Bloebaum, 2002). Examples of nasal products with
`widespread use in this area include the histamine H1-antagonist
`levocabastine (e.g., Janssens and Vanden-Bussche, 1991), the
`anti-cholinergic agent ipratropium bromide (e.g., Milford et al.,
`1990), and steroidal anti-inflammatory agents such as budes-
`onide (e.g., Stanaland, 2004), mometasone furoate (e.g., van
`Drunen et al., 2005), triamcinolone (Lumry et al., 2003), and
`beclomethasone (Lumry et al., 2003).
`As reviewed by Salib and Howarth (2003), IN corticosteroids
`and antihistamines have minimal potential for systemic adverse
`effects (as opposed to oral therapy), primarily due to the fact that
`relatively low doses are effective when administered topically.
`For instance, the recommended therapeutic dosage of IN anti-
`histamines does not cause significant sedation or impairment of
`psychomotor function, whereas these effects may be seen upon
`oral dosing (for which a much larger dose is required). Such
`factors make IN delivery of antihistamines and corticosteroids
`an attractive and typically preferred route of administration,
`particularly if rapid symptom relief is required.
`
`2.2. Vaccine delivery
`
`The nasal mucosa has received some attention as a vaccina-
`tion route. Presentation of a suitable antigen with an appropriate
`adjuvant to the nasal-associated lymphoid tissue (NALT) has
`the potential to induce humoral and cellular immune responses
`(Zuercher et al., 2002). This approach may be a particularly
`effective approach to achieving rapid mass immunization, for
`instance in children and/or in developing countries and disaster
`areas (Roth et al., 2003). IN immunization may lead to devel-
`opment of local, as well as systemic, immunity. Furthermore,
`vaccination via the IN route does not require a sterile product
`or a sterile dosing technique (a distinct advantage in developing
`areas of the world).
`An example of an IN vaccine is FluMist®, a cold-
`adapted live influenza virus (e.g., Kemble and Greenberg,
`2003). This product is given as one or two doses over the
`influenza season via a syringe sprayer. Additional examples
`of human efficacy testing of IN vaccines includes those tar-
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`geted against adenovirus-vectored influenza (Van Kampen et
`al., 2005), proteosome-influenza (Treanor et al., 2006), influenza
`A (Treanor et al., 1992), influenza B (Obrosova-Serova et al.,
`1990), meningococcal outer membrane vesicle (Oftung et al.,
`1999), and a combination respiratory syncytial virus (RSV) and
`parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine
`(Belshe et al., 2004).
`Effective nasal immunization requires an effective antigen
`and/or a potent mucosal adjuvant or carrier. Research in this area
`includes exploring various IN excipients such as chitosan (Read
`et al., 2005), chitin (Hasegawa et al., 2005), galactoseramide (Ko
`et al., 2005), and biodegradable polymers (Koping-Hoggard et
`al., 2005). It is important to note that even for active antigens,
`IN delivery may not elicit an immune response in the absence
`of an effective adjuvant (McCluskie and Davis, 1998). In fact, it
`has been suggested that IN dosing can be effective for inducing
`nasal mucosal (Harrison et al., 2004; Mestecky et al., 2005) and
`oromucosal (e.g., Meritet et al., 2001) tolerance for a variety of
`molecules, including therapeutic peptides and proteins.
`
`2.3. Systemic delivery
`
`Positive attributes of IN systemic delivery include a rela-
`tively large surface area for drug absorption, rapid drug onset, no
`first-pass metabolism, and non-invasiveness to maximize patient
`comfort and compliance. Specific pharmacokinetic attributes of
`IN delivery are reviewed elsewhere (Costantino et al., 2005).
`As discussed in the various case studies below, IN adminis-
`tration provides an alternative route for systemic delivery of
`drugs more conventionally delivered by oral or (for poorly orally
`absorbed compounds such as peptides and proteins) injection
`routes.
`
`2.4. Chronic versus acute therapeutic use
`
`When deciding on a delivery route, it is important to con-
`sider the dosing regimen for the drug. Is the intended use acute
`or chronic? For an acute indication, the advantage of patient
`comfort and compliance afforded by IN dosing (as compared
`with injections) may not be a major factor. Even so, there are
`advantages to IN dosing in certain acute situations. One example
`is the case of an emergency room setting, where the avoidance
`of accidental needle stick potential is desired (Wolfe and Barton,
`2003).
`Other examples of acutely dosed therapeutics that have been
`explored for IN administration include epinephrine (Bleske
`et al., 1996) and cardiovascular agents such as nitroglycerin
`(Landau et al., 1994). In principal, IN administration is suit-
`able for either acute or chronic use over a wide range of lengths
`of course and frequency of therapy. Dosing frequencies of cur-
`rent marketed IN products range from those dosed relatively
`infrequently, e.g., weekly dosing for Nascobal® Spray (for
`the treatment of vitamin B12 deficiencies), to multiple times
`daily, e.g., two sprays per nostril two to three times daily for
`ATROVENT® Nasal Spray (indicated for symptomatic relief
`of rhinorrhea associated with allergic and nonallergic perennial
`rhinitis). IN dosing may be particularly suited for the circum-
`
`stance of a chronic application for a non-orally bioavailable drug
`to be given to a needle-na¨ıve patient population.
`
`2.5. CNS delivery
`
`IN delivery of drugs targeting the central nervous system
`(CNS) is currently an area of great interest, as reviewed else-
`where (Illum, 2004; Vyas et al., 2005). Improved delivery to the
`brain via the IN route has been reported for some low-molecular-
`weight drugs (Sakane et al., 1991, 1994, 1995; Kao et al., 2000;
`Chow et al., 2001; Al-Ghananeem et al., 2002; Costantino et al.,
`2005; Barakat et al., 2006), as well as therapeutic peptides and
`proteins (Frey et al., 1997; Dufes et al., 2003; Banks et al., 2004;
`Thorne et al., 2004; Ross et al., 2004; Lerner et al., 2004).
`However, it should be noted that there are also cases for which
`there was no evidence found for preferential delivery to the brain
`via IN dosing (van den Berg, 2005; van den Berg et al., 2004a,b;
`Yang et al., 2005). Therefore, the potential for preferential brain
`delivery for IN dosing may be drug-specific, or may depend on
`the study methods employed (van den Berg, 2005). In addition to
`the potential for “nose to brain” delivery, IN drugs can enter via
`a “nose to systemic circulation to brain” pathway (see Fig. 1).
`In this case, it is necessary for the drug to readily permeate the
`blood–brain barrier (BBB) from the circulation. In order for this
`to be achieved, the drug (or prodrug) must exhibit satisfactory
`passive or active transport across the tight junction barriers of
`the BBB. For example, an insulin transporter across the BBB
`has been described (Banks, 2004).
`
`2.6. Factors related to patient population
`
`Yet another factor in considering IN delivery for a therapeutic
`indication is the patient population. For example, if IN delivery
`is being considered as an alternative to injections, what is the
`patient population’s experience with injections, and what is their
`
`Fig. 1. Schematic of nasal drug delivery. IN drugs formulated as solutions,
`suspensions, or powders can be administered to the nasal cavity (local action),
`can transport across the epithelial tissue to enter the blood (systemic drugs),
`and for drugs that cross the blood–brain barrier (BBB), can subsequently enter
`the brain (CNS applications). Direct delivery of IN drugs to the brain has been
`proposed, but is not universally established in the literature.
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`preferred route of administration? It is believed that IN delivery
`is favored over injections, e.g., for insulin where a 67% patient
`preference was reported compared to injections (Frauman et al.,
`1987), although this may not always be the case, e.g., for a new
`intranasal fentanyl formulation where a 29% patient preference
`was reported (Paech et al., 2003). It is interesting to note in this
`context that calcitonin was first introduced as a subcutaneously
`delivered product, but intranasal formulations are now more
`widely used because of improved tolerability compared to injec-
`tions (Munoz-Torres et al., 2004). As noted above, IN dosing
`may be particularly suited for chronic dosing to a needle-na¨ıve
`patient population, as well as when oral dosing is problematic.
`
`2.6.1. Effect of nasal inflammation
`A common question regarding IN dosing and the intended
`patient population is whether inflammation of the nasal mucosa
`(e.g., patients with rhinitis) affects drug bioavailability. Vari-
`ous studies suggest that intranasal drug pharmacokinetics and/or
`pharmacodynamics are not affected by the presence of rhinitis.
`These studies include the examination of intranasal formulations
`of low-molecular-weight compunds (e.g., dihydroergotamine
`(Humbert et al., 1996), zolmitriptan (Dowson et al., 2005), and
`butorphanol (Shyu et al., 1993)), as well as peptide drugs (e.g.,
`buserelin (Larsen et al., 1987) and desmopressin (Greiff et al.,
`2002)).
`
`2.6.2. Nasal physiology
`Various aspects of nasal physiology and their workings,
`such as nasal anatomy, airflow, resistance, and the nasal cycle
`(wherein the turbinates (see below) alternatively swell and con-
`gest from side to side) may have a potential impact on IN
`delivery. Reviews of this subject can be found elsewhere (e.g.,
`Mygind and Dahl, 1998; Jones, 2001). Briefly, the nasal cavity is
`divided by the nasal septum (comprised of bone and cartilage),
`with each half opening at the face (via the nostrils). There is also
`a connection to the oral cavity provided by the nasopharynx. The
`anterior and posterior vestibules, the respiratory region, and the
`olfactory region are the three main areas of the nasal cavity. The
`lateral walls comprise a folded structure (refered to as the nasal
`labial folds or conchae). This folded structure further comprises
`the superior, median, and inferior turbinates, providing a total
`surface area of about 150 cm2 in humans.
`The epithelial tissue within the nasal cavity is relatively
`highly vascularized, and thus provides a potential conduit for
`drug delivery. The cellular makeup of the nasal epithelial tissue
`consists mainly of ciliated columnar cells, non-ciliated columnar
`cells, goblet cells and basal cells, with the proportions varying
`in different regions of the nasal cavity. Ciliated cells facilitate
`the transport of mucus towards the nasopharynx. Basal cells,
`which are poorly differentiated, act as stem cells to replace other
`epithelial cells. Goblet cells, which contain numerous secretory
`granules filled with mucin, produce the secretions that form the
`mucus layer.
`
`2.6.3. Variability of IN dosing
`Inter- and intra-subject variability in pharmacokinetics and/or
`pharmacodynamics is an important consideration when choos-
`
`ing the delivery route. Different administration routes should be
`compared (e.g., IN, oral, injection), and viable options are those
`with variability commensurate with the expected therapeutic
`window. Variability can be affected by numerous factors, includ-
`ing those arising from the patient, delivery device, formulation,
`and the drug itself. For low-molecular-weight drugs, IN dosing
`can provide pharmacokinetics with relatively high bioavailabil-
`ity and relatively low variability, which in many cases is similar
`to or lower than oral or even injection administration (e.g., Coda
`et al., 2003). However, for high-molecular-weight drugs such
`as peptides and proteins, IN pharmacokinetics exhibit relatively
`low bioavailability and relatively high variability compared to
`injections (Adjei et al., 1992). This can be ameliorated by the
`use of permeation enhancers (vide infra) which can enhance
`bioavailability and reduce variability (Hinchcliffe et al., 2005).
`
`2.7. Case examples of therapeutic areas sutiable for
`intranasal delivery
`
`The following sections provide case examples of therapeutic
`areas suitable for IN delivery. While the therapeutic areas are
`diverse, the common theme among them is an advantage for IN
`dosing, such as patient convenience and preference, rapid drug
`onset, avoidance of GI-related side-effects, and more consistent
`delivery for disease states associated with gastric dysmotility.
`These case examples range from products in exploratory devel-
`opment to marketed therapeutic products.
`
`2.7.1. Morphine for breakthrough cancer pain
`Patients with chronic cancer pain often manifest both incident
`and continuous pain. Incident pain, also described as “break-
`through pain”, is typical of rapid onset, is severe in intensity,
`and has an average duration of 30 min. Various researchers have
`reported on the investigation of IN morphine to treat this debili-
`tating condition (Illum et al., 2002; Pavis et al., 2002; Fitzgibbon
`et al., 2003). Morphine has relatively low oral bioavailability
`due to extensive first-pass metabolism. Therefore, IN delivery
`provides an attractive option due to the avoidance of first-pass
`metabolism, non-invasiveness, and rapid onset of action. An
`example of human PK for IN, oral, and injection (IM) dos-
`ing of morphine is presented in Fig. 2. The data illustrate that
`IN dosing achieves a similarly fast drug onset (Tmax ∼ 15 min)
`compared with IM dosing, and is much faster than oral deliv-
`ery (Tmax ∼ 50 min). As for any analgesic, speed of onset for IN
`morphine is highly desired for breakthrough cancer pain, since
`rapid onset of significant pain relief is critical.
`
`2.7.2. Treatments for migraine and cluster headaches
`Patients with recurrent migraine or cluster headaches may
`have difficulty managing their disease, and in extreme situations
`may require emergency room visits to control the pain. When
`compared with oral delivery, IN dosing provides very rapid
`drug onset, which is a critical factor for controlling headaches,
`as well as providing improved bioavailability. Similar to mor-
`phine for breakthrough cancer pain, IN analgesics for headache
`are most effective when the onset of action is rapid, and IN
`dosing provides a distinct advantage over oral dosing in this
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`pass through the GI tract, and as a result, has very poor oral
`bioavailability (Gillis et al., 1995). The intravenous (IV) and
`intramuscular (IM) routes provide improved bioavailability and
`rapid drug onset, but at the cost of invasiveness, pain, and incon-
`venience. IN butorphanol offers a convenient alternative to IV
`and IM delivery and has been successfully developed commer-
`cially (marketed as STADOL NS®).
`Other IN drugs have been explored for migraine and headache
`treatment (see Rapoport et al., 2004). Examples of drugs tested
`in humans include IN capsaicin for cluster headache treatment
`(Fusco et al., 1994), and migraine treatment using IN dihydroer-
`gotamine (Treves et al., 1998) and IN lidocaine (Maizels et al.,
`1996).
`
`2.7.3. Acetylcholinesterase inhibitors for Alzheimer’s
`disease
`Kays Leonard et al. (2005) have reported on the development
`of IN galantamine, an acetylcholinesterase inhibitor indicated
`for the treatment of Alzheimer’s disease. Pharmacokinetic test-
`ing revealed rapid drug onset for IN administration compared
`with conventional oral dosing. As with other drugs in its class,
`galantamine dosed orally has a clinically significant level of
`mechanism-based gastrointestinal (GI) side-effects such as nau-
`sea and vomiting. IN dosing dramatically reduced the emetic
`response, presumably as a result of avoidance of drug contact
`in the GI tract. Specifically, there was an order of magnitude
`reduction in emetic events (Fig. 3).
`Patani et al. (2005) have explored an IN formulation of
`a heptylene-linked bis-tacrine analog (bis-THA). A series of
`investigations were conducted to examine various physico-
`chemical properties (e.g., partition coefficient) of bis-THA
`compared with the parent molecule (tacrine). Permeation stud-
`ies conducted using excised pig nasal mucosa revealed that
`the nasal mucosa was amenable for systemic delivery of
`bis-THA, and delipidization studies suggested that lipophilic
`components in the absorptive mucosa played a role in drug
`permeation.
`
`Fig. 3. Relative emetic response (in ferrets) for oral vs. IN dosing of galantamine.
`Oral dosing results in over a 10-fold increase in emetic responses. Data from
`Costantino et al. (2005).
`
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`Fig. 2. PK parameters for morphine in humans: (A) Tmax (min), (B) Cmax
`(ng/mL) and (C) AUClast (min pg/mL). Data are shown for intramuscular (IM)
`dosing at 2.5 mg (white), intranasal (IN) dosing at 2.5 mg (striped) and oral
`dosing at 10 mg (grey). Data from Costantino et al. (2005).
`
`regard. As an example, IN zolmitriptan for migraine treatment
`has been reported to provide significantly more rapid onset of
`therapeutic drug levels (Yates et al., 2002) and headache relief
`(Charlesworth et al., 2003) compared with oral dosing. Another
`important advantage of intranasal administration of drugs for
`treating migraines is that the therapeutic condition slows gas-
`tric emptying and hence oral drug absorption is compromised
`(Dahlof, 2002). Both oral and IN zolmitriptan are available com-
`mercially (under the trade name ZOMIG®). However, for this
`and other related applications, IN delivery provides a convenient
`and potentially more effective mode of dosing (Rapoport et al.,
`2004).
`Butorphanol tartrate is another analgesic agent suitable for
`IN delivery. Butorphanol is extensively metabolized upon first-
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`2.7.4. Apomorphine
`Apomorphine represents another example of a therapeutic
`agent in which various routes, including IN delivery, have been
`explored. Apomorphine is a dopamine receptor agonist with a
`high affinity for D1 and D2 receptor subtypes at sites within
`the brain known to be involved in the mediation of erection. It is
`currently approved for several indications, including an injection
`for the acute treatment of “off” episodes associated with Parkin-
`son’s disease (Johnston et al., 2005). Various in vivo studies have
`shown that the erectile effects of apomorphine are mediated at
`dopamine receptors in various nuclei of the hypothalamus and
`midbrain (Allard and Giuliano, 2001).
`A case study describing IN apomorphine can be found else-
`where (Costantino et al., 2005). IN apomorphine is absorbed
`as rapidly as subcutaneous (SC) injection. The rapid onset for
`IN apomorphine is desirable for either erectile dysfunction or
`Parkinson’s disease indications. Compared with sublingual (SL)
`dosing, IN delivery resulted in increased absorption, i.e., the
`bioavailability of SL apomorphine was only 56% that of IN apo-
`morphine. Interestingly, the rates of significant adverse events
`were reduced dramatically after changing the route of admin-
`istration to IN, even for a similar systemic exposure. For SL
`delivery, observed rates of nausea and vomiting were about
`18–22% and 1–4%, respectively. In contrast, following IN deliv-
`ery of a dose corresponding to about the same AUC as the SL
`dose, the incidence of nausea (3%) was nearly an order of mag-
`nitude less compared to sublingual delivery, and there were no
`incidences of vomiting.
`
`2.7.5. Anti-nausea and motion sickness medications
`Treatments for nausea and motion sickness represent
`additional therapeutic areas in which IN delivery provides
`advantages, including rapid onset and potentially more consis-
`tent dosing, compared to oral dosing due to issues with gastric
`dysmotility. IN metaclopramide has been explored for a variety
`of indications, including the prevention of postoperative nausea
`and vomiting (for a review see Ormrod and Goa, 1999). For IN
`dosing, both the absorption and elimination curves were similar
`to oral and IM administration (10 mg dose for all groups); it was
`concluded that oral and IN delivery were bioequivalent (Citron
`et al., 1987). In another related human PK comparison, Wenig
`(1988) reported similar Cmax values for meclizine given by IN
`(10 mg), oral (10 mg) and IM (5 mg) routes. It was also reported
`that IN meclizine in rats and dogs provided similar PK to IV dos-
`ing and provided a more rapid onset and higher bioavailability
`compared with oral administration (Chovan et al., 1985).
`Scopolamine, an antimuscarinic agent indicated for motion
`sickness, is another example of a drug in this area that is suitable
`for IN dosing (case study discussed by Costantino et al., 2005).
`Scopolamine has very low oral bioavailability due to extensive
`first-pass metabolism. Transdermal delivery provides an option,
`but this route of administration results in very slow onset and
`an unnecessarily prolonged effect, with significant side-effects
`including dry mouth, drowsiness, and blurred vision. Ahmed et
`al. (2000) reported on the human PK and side-effect profile of
`various IN scopolamine formulations. Compared with the trans-
`dermally delivered drug, IN scopolamine exhibited a more rapid
`
`onset. Although a variety of side-effects have been reported for
`transdermal scopolamine, no significant adverse effects were
`observed for the various IN formulations tested. Currently,
`IN scopolamine and IN