Available online at www.sciencedirect.com
`
`_,,
`·:;- ScienceDirect
`
`ELSEVIER
`
`International Journal of Pharmaceutics 337 (2007) 1- 24
`
`INTERNATIONAL JOURNAL OF
`PHARMACEUTICS
`
`www.elsevier.com/locate/ijpharm
`
`Mini-review
`Intranasal delivery: Physicochemical and therapeutic aspects
`
`Henry R. Costantino a,*, Lisbeth Ill um b , Gordon Brandt a, Paul H. Johnson a, Steven C. Quay a
`
`a Nastech Pharmaceutical Company, Inc., Bothell, WA 98021, USA
`b !Dentity, 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; Physicochernical properties
`
`Contents
`
`Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`1.
`2. Therapeutic considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2
`2.1. Local delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2
`2.2. Vaccine delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`2
`2.3. Systemic delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`2.4. Chronic versus acute therapeutic use . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
`3
`2.5. CNS delivery . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`2.6. Factors related to patient population. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3
`2.6.1. Effect of nasal inflammation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`2.6.2. Nasal physiology .... . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`2.6.3. Variability of IN dosing .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`2.7. Case examples of therapeutic areas sutiable for intranasal delivery................... . ................ .. ............. . ... 4
`2. 7.1. Morphine for breakthrough cancer pain. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
`2.7.2. Treatments for migraine and cluster headaches............ . .............. . ..... . ............... . ............... 4
`2.7.3. Acetylcholinesterase inhibitors for Alzheimer's disease.. .............. . ..... .. ............... .. .. ......... . . ... 5
`2.7.4. Apomorphine................................ . ................................... . . .. ...... . .... .. .... ... ... 6
`2.7.5. Anti-nausea and motion sickness medications.......... . ...... . ............ . ................. .. ................ 6
`2.7.6. Cardiovascular drugs ...... .... ... . ......... .. .... ... ............ ... .............. .. .. .. . . ....... . . .. . .. .. .. . 6
`2.7.7. Sedative agents (non-emergency situation) . ... .. ..... ........... .... ............ ... . .. ............... .. ........ 6
`2.7.8. Examples for application in an emergency situation...................... .. ............. ... ... . ...... . .. . ... .... 7
`2.7.9. Systemic delivery of macromolecules. .. .... .. .............. . ............... . ...... . . . ...... . ... . ........ . .... 7
`
`• Corresponding author. Tel.: +14259083686.
`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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`Sa 8
`3. Drug characteristics. ....... 0... ccc cece cece eee eens
`Sa 8
`3.1.
`Physicochemical characteristics...................020005
`Lene nee e eee e ene eee e eee n sence eee n eee e nee es
`9
`3.1.1. Molecular weight ........... 00... cee eee eee eee
`Sa 10
`3.1.2. Hydrophobicity/hydrophilicity .................
`Le ee eee eee ene eee ee eee eee e eee e eee e nent e teens
`11
`3.1.3. Chemical and physical stability.................
`SR 11
`3.1.4. Biochemical stability ......................0005
`Ln ene n eee eee eee e eee sence sete nent beeen ee
`12
`3.1.5.
`Solubility ........ 0. eee eee
`Le eee e ee een ence eee e eben eee eens e een ee eee
`15
`3.2. Role of transporters, efflux systems ...................-.
`Bence eee eee ences eee eee teen teen eenenes
`17
`4. Concluding remarks ............ 0... c cece eee ence eee e ee neee
`Sa 17
`Acknowledgement ............. ese eee cece eee n cence neeeeee
`Sa 17
`References ....... 0. cece ccc ence eee e een e eee enes
`
`
`1. Introduction
`
`2.1. Local delivery
`
`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
`widespreadusein this area include the histamine Hj -antagonist
`levocabastine (e.g., Janssens and Vanden-Bussche, 1991), the
`anti-cholinergic agent ipratropium bromide(e.g., Milford etal.,
`1990), and steroidal anti-inflammatory agents such as budes-
`onide (e.g., Stanaland, 2004), mometasone furoate (e.g., van
`Drunenetal., 2005), triamcinolone (Lumry et al., 2003), and
`beclomethasone (Lumry etal., 2003).
`Asreviewed by Salib and Howarth (2003), IN corticosteroids
`and antihistamines have minimalpotential for systemic adverse
`effects (as opposedto oral therapy), primarily dueto the factthat
`relatively low doses are effective when administered topically.
`For instance, the recommended therapeutic dosage of IN anti-
`histamines doesnot cause significant sedation or impairmentof
`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 symptomrelief is required.
`
`2.2. Vaccine delivery
`
`The nasal mucosahas received someattention as a vaccina-
`
`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 mucosaaffords 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 permeationbarrier to high-
`molecular-weight therapeutics such as peptides andproteins, 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, andis easily and readily adminis-
`tered by the patient or a physician,e.g., in an emergencysetting.
`Furthermore, the nasal route may offer improved delivery for
`“non-Lipinski” drugs (Johnson and Quay, 2005). Due to such
`factors, marketed IN formulationsexist 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 andits use
`should be addressed. Is the drug intended for local or systemic
`tion route. Presentation of a suitable antigen with an appropriate
`delivery? Will the drug be delivered chronically or acutely?
`adjuvant to the nasal-associated lymphoid tissue (NALT) has
`Is the patient population needle-naive? Are the physicochem-
`the potential to induce humoraland cellular immuneresponses
`ical properties of the drug suitable for intranasal delivery and
`(Zuercher et al., 2002). This approach may beaparticularly
`can clinically relevant bioavailability be achieved (an important
`effective approach to achieving rapid mass immunization, for
`aspect for peptides and proteins)? These questions are consid-
`instance in children and/or in developing countries and disaster
`ered below in light of their impact on a drug’s suitability for IN
`areas (Roth et al., 2003). IN immunization maylead to devel-
`development.
`opmentof 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 thosetar-
`
`2. Therapeutic considerations
`
`Therapeutic considerations are paramount whenselecting the
`dosing route. Such considerations include the pharmaceutical
`target (e.g., local versus systemic), the dosing frequency, and the
`patient population. In somecases, IN delivery may not only be
`possible, but may also be the preferred mode of administration.
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`3
`
`stance of a chronic application for a non-orally bioavailable drug
`to be given to a needle-naive patient population.
`
`2.5. CNS delivery
`
`geted against adenovirus-vectored influenza (Van Kampenet
`al., 2005), proteosome-influenza(Treanoret al., 2006), influenza
`A (Treanoret al., 1992), influenza B (Obrosova-Serovaetal.,
`1990), meningococcal outer membranevesicle (Oftungetal.,
`1999), and a combination respiratory syncytial virus (RSV) and
`parainfluenza 3 virus (PIV3) live, attenuated intranasal vaccine
`(Belsheetal., 2004).
`Effective nasal immunization requires an effective antigen
`and/ora potent mucosal adjuvantorcarrier. Research inthis area
`includes exploring various IN excipients such as chitosan (Read
`et al., 2005), chitin (Hasegawaet 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 immuneresponsein 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 (Harrisonet al., 2004; Mesteckyet al., 2005) and
`oromucosal (e.g., Meritet et al., 2001) tolerance for a variety of
`molecules, including therapeutic peptides andproteins.
`
`2.3. Systemic delivery
`
`IN delivery of drugs targeting the central nervous system
`(CNS) is currently an area of great interest, as reviewed else-
`where(Illum, 2004; Vyaset al., 2005). Improved delivery to the
`brainvia the IN route has been reported for some low-molecular-
`weight drugs (Sakaneet al., 1991, 1994, 1995; Kaoetal., 2000;
`Chowetal., 2001; Al-Ghananeemetal., 2002; Costantinoetal.,
`2005; Barakat et al., 2006), as well as therapeutic peptides and
`proteins (Freyet al., 1997; Dufeset al., 2003; Banksetal., 2004;
`Thorneet al., 2004; Rosset al., 2004; Lerneret al., 2004).
`However,it should be noted that there are also cases for which
`there was no evidence foundfor preferential delivery to the brain
`via IN dosing (van den Berg, 2005; van den Bergetal., 2004a,b;
`Yanget 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).
`Positive attributes of IN systemic delivery includearela-
`In this case,it is necessary for the drug to readily permeate the
`tively large surface area for drug absorption, rapid drug onset, no
`blood-brain barrier (BBB) from thecirculation. In orderfor this
`first-pass metabolism, and non-invasiveness to maximizepatient
`to be achieved, the drug (or prodrug) must exhibit satisfactory
`comfort and compliance. Specific pharmacokineticattributes of
`passive or active transport across the tight junction barriers of
`IN delivery are reviewed elsewhere (Costantinoet al., 2005).
`the BBB. For example, an insulin transporter across the BBB
`As discussed in the various case studies below, IN adminis-
`has been described (Banks, 2004).
`tration provides an alternative route for systemic delivery of
`drugs more conventionally delivered by oral or (for poorly orally
`absorbed compounds suchas peptides and proteins) injection
`routes.
`
`2.6. Factors related to patient population
`
`Yet anotherfactor in considering IN delivery for a therapeutic
`indicationis 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 whatis their
`
`Transepithelial
`absorption
`
`_Blood
`
`Systemic
`drugs
`
`Transport across
`the BBB
`
`Locally acting drugs
`
`Nasal Cavity
`
`I
`I
`I
`Potential
`“nose- 19
`to-brain”
`|
`.
`
`I IV
`
`v
`
`
`Brain
`
`
`
`CNS drugs
`
`Nasal
`delivery
`device
`
`
`Di
`liquid,
`
`a ae
`suspension,
`or powder
`
`
`
`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 (CNSapplications). Direct delivery of IN drugsto the brain has been
`proposed,butis not universally established in the literature.
`
`2.4. Chronic versus acute therapeutic use
`
`Whendeciding on a delivery route, it is important to con-
`sider the dosing regimenfor 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
`advantagesto IN dosing in certain acutesituations. 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 examplesof acutely dosed therapeutics that have been
`explored for IN administration include epinephrine (Bleske
`et al., 1996) and cardiovascular agents such as nitroglycerin
`(Landauet 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 dosedrelatively
`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 beparticularly suited for the circum-
`
`
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`
`preferred route of administration?It is believed that IN delivery
`is favored overinjections, e.g., for insulin where a 67% patient
`preference was reported comparedto injections (Frauman etal.,
`1987), although this may not alwaysbethe case,e.g., for a new
`intranasal fentanyl formulation where a 29% patient preference
`wasreported (Paechetal., 2003). It is interesting to note in this
`context that calcitonin wasfirst introduced as a subcutaneously
`delivered product, but intranasal formulations are now more
`widely used because of improvedtolerability comparedto injec-
`tions (Munoz-Torres et al., 2004). As noted above, IN dosing
`maybeparticularly suited for chronic dosing to a needle-naive
`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-
`ousstudies suggest that intranasal drug pharmacokinetics and/or
`pharmacodynamicsare not affected by the presenceofrhinitis.
`Thesestudies include the examinationofintranasal formulations
`of low-molecular-weight compunds(e.g., dihydroergotamine
`(Humbert et al., 1996), zolmitriptan (Dowsonetal., 2005), and
`butorphanol (Shyuetal., 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. Reviewsof this subject can be found elsewhere(e.g.,
`Mygindand Dahl, 1998; Jones, 2001). Briefly, the nasal cavityis
`divided by the nasal septum (comprised of boneandcartilage),
`with each half openingat the face (via the nostrils). There is also
`aconnection tothe oral cavity provided by the nasopharynx. The
`anterior and posterior vestibules, the respiratory region, and the
`olfactory region are the three main areasof 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. cm? in humans.
`The epithelial tissue within the nasal cavity is relatively
`highly vascularized, and thus provides a potential conduit for
`drug delivery. The cellular makeupofthe nasal epithelial tissue
`consists mainlyof 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. Basalcells,
`whichare poorly differentiated, act as stem cells to replace other
`epithelial cells. Goblet cells, which contain numeroussecretory
`granulesfilled with mucin, producethe secretions that form the
`mucuslayer.
`
`2.6.3. Variability ofIN dosing
`Inter- and intra-subjectvariability in pharmacokinetics and/or
`pharmacodynamicsis 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 numerousfactors, 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 manycasesis 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
`intranasaldelivery
`
`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 cancerpain often manifest both incident
`and continuouspain. 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 morphineto treat this debili-
`tating condition (Illum et al., 2002; Pavis et al., 2002; Fitzgibbon
`et al., 2003). Morphine hasrelatively low oral bioavailability
`due to extensive first-pass metabolism. Therefore, IN delivery
`provides an attractive option due to the avoidanceoffirst-pass
`metabolism, non-invasiveness, and rapid onset of action. An
`example of human PK for IN,oral, and injection (IM) dos-
`ing of morphineis 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 muchfaster than oral deliv-
`ery (Tmax ~ 50 min). As for any analgesic, speed of onset for IN
`morphineis highly desired for breakthrough cancerpain, since
`rapid onsetof significantpain reliefis critical.
`
`2.7.2. Treatments for migraine and cluster headaches
`Patients with recurrent migraine or cluster headaches may
`havedifficulty managingtheir disease, and in extremesituations
`may require emergency room visits to control the pain. When
`compared with oral delivery, IN dosing provides very rapid
`drug onset, which isa critical factor for controlling headaches,
`as well as providing improved bioavailability. Similar to mor-
`phine for breakthrough cancerpain, 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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`5
`
`(A) 60.0
`
`20.0
`
`
`
`0.0
`
`
`Oral
`(min*pg/mL) Oral
`AUClast
`
`=C) 1500
`
`1200
`
`900
`
`600
`
`300
`
`Delivery Route
`
`Fig. 2. PK parameters for morphine in humans: (A) Tmax (min), (B) Cmax
`(ng/mL) and (C) AUClast (min pg/mL). Data are shownfor 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 Costantinoetal. (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 headacherelief
`(Charlesworthet al., 2003) compared with oral dosing. Another
`important advantage of intranasal administration of drugs for
`treating migrainesis 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 otherrelated applications, IN delivery provides a convenient
`and potentially more effective mode of dosing (Rapoport et al.,
`2004).
`Butorphanoltartrate is another analgesic agent suitable for
`IN delivery. Butorphanolis extensively metabolized uponfirst-
`
`pass through the GItract, and as a result, has very poororal
`bioavailability (Gillis et al., 1995). The intravenous (IV) and
`intramuscular (IM)routes provide improvedbioavailability and
`rapid drug onset, butat the cost of invasiveness, pain, and incon-
`venience. IN butorphanoloffers a convenient alternative to IV
`and IM delivery and has been successfully developed commer-
`cially (marketed as STADOL NS®).
`OtherIN drugshave been explored for migraine and headache
`treatment (see Rapoport et al., 2004). Examples of drugs tested
`in humansinclude IN capsaicin for cluster headache treatment
`(Fuscoet al., 1994), and migraine treatment using IN dihydroer-
`gotamine (Treveset al., 1998) and IN lidocaine (Maizels etal.,
`1996).
`
`2.7.3. Acetylcholinesterase inhibitors for Alzheimer’s
`disease
`Kays Leonardetal. (2005) have reported on the development
`of IN galantamine, an acetylcholinesterase inhibitor indicated
`for the treatment of Alzheimer’s disease. Pharmacokinetictest-
`ing revealed rapid drug onset for IN administration compared
`with conventional oral dosing. As with other drugsin its class,
`galantamine dosedorally has a clinically significant level of
`mechanism-basedgastrointestinal (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 GItract. 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.
`
`15
`
`10
`
`
`
`
`
`Relativeincidenceofemeticresponses
`
`Oral
`
`IN
`
`Group
`
`Fig.3. Relative emetic response(in ferrets) for oral vs. IN dosing ofgalantamine.
`Oral dosing results in over a 10-fold increase in emetic responses. Data from
`Costantinoet al. (2005).
`
`AQUESTIVE EXHIBIT 1118 Page 0005
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`6
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`H.R. Costantinoetal. / International Journal ofPharmaceutics 337 (2007) 1-24
`
`2.7.4. Apomorphine
`Apomorphine represents another example of a therapeutic
`agent in which variousroutes, including IN delivery, have been
`explored. Apomorphine is a dopaminereceptor agonist with a
`high affinity for D; and D2 receptor subtypes at sites within
`the brain knownto be involvedin the mediation of erection.It is
`
`currently approvedfor severalindications, including an injection
`for the acute treatmentof “off” episodes associated with Parkin-
`son’s disease (Johnstonet al., 2005). Variousin vivo studies have
`shownthat the erectile effects of apomorphine are mediated at
`dopaminereceptors in various nuclei of the hypothalamus and
`midbrain (Allard and Giuliano, 2001).
`A case study describing IN apomorphine can be foundelse-
`where (Costantino et al., 2005). IN apomorphine is absorbed
`as rapidly as subcutaneous (SC)injection. The rapid onset for
`IN apomorphineis desirable for either erectile dysfunction or
`Parkinson’s disease indications. Comparedwith sublingual (SL)
`dosing, IN delivery resulted in increased absorption,i.e., the
`bioavailability of SL apomorphine wasonly 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 asthe SL
`dose, the incidence of nausea (3%) wasnearly an order of mag-
`nitude less comparedto sublingual delivery, and there were no
`incidences of vomiting.
`
`2.7.5. Anti-nausea and motion sickness medications
`
`for nausea and motion sickness represent
`Treatments
`additional
`therapeutic areas in which IN delivery provides
`advantages, including rapid onset and potentially more consis-
`tent dosing, comparedto oral dosing due to issues with gastric
`dysmotility. IN metaclopramide has been explored fora 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 dosefor all groups); it was
`concludedthat oral and IN delivery were bioequivalent (Citron
`et al., 1987). In another related human PK comparison, Wenig
`(1988) reported similar Cyax values for meclizine given by IN
`(10 mg), oral (10 mg) and IM (5 mg)routes. It was also reported
`that IN meclizinein rats and dogs provided similar PK to IV dos-
`ing and provided a morerapid onset and higherbioavailability
`compared with oral administration (Chovanetal., 1985).
`Scopolamine, an antimuscarinic agent indicated for motion
`sickness, is another exampleofa drugin this area that is suitable
`for IN dosing (case study discussed by Costantinoet al., 2005).
`Scopolaminehas very low oral bioavailability due to extensive
`first-pass metabolism. Transdermaldelivery 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. Ahmedet
`al. (2000) reported on the human PKandside-effect profile of
`various IN scopolamine formulations. Compared with the trans-
`dermally delivered drug, IN scopolamine exhibited a more rapid
`
`onset. Althougha 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 promethazine are being explored for
`treating motion sickness in flight, including astronautical appli-
`cations (Putcha, 2006).
`Hussain et al.
`(2000) reported IN administration of the
`anti-emetic agent ondansetronin rats. IN ondansetron was com-
`pletely absorbed; plasma concentration-timeprofiles for IN and
`IV were comparable. If these findings translate to human expe-
`rience, IN ondansetron would provide a favorable alternative to
`oral dosing (absolute bioavailability of about 60%) (Roila and
`Del Favero, 1995).
`
`2.7.6. Cardiovascular drugs
`Thefeasibility of IN administration as an alternative route for
`administering cardiovascular drugs has been widely investigated
`(for a review see Landauetal., 1994). IN nitroglycerin has been
`exploredclinically for controlling the hemodynamic response to
`orotracheal intubation (Groveret al., 1987; Hwanget al., 1995).
`Another exampleis provided by IN propanolol,a drug useful for
`immediate B-blockadepriorto exercise in patients with angina.
`IN dosing of propanolol provides a PK profile in termsof rapid-
`ity and bioavailability that is very similar to IV administration,
`whereasoral dosing results in an order of magnitude decrease in
`bioavailability due to substantial first-pass metabolism (Hussain
`et al., 1980a,b). In a human clinical study, it was concluded that
`IN propranololwaseffective in providing immediate B-blockade
`and improvingexercise tolerancein patients with anginapectoris
`(Landauet al., 1993).
`In addition, IN nifedipine was shownto be more suitable than
`oral delivery for perioperative blood pressure control (Kubota