Neurotherapeutics: The Journal of the American Society for Experimental NeuroTherapeutics
`
`Intranasal Delivery of Antiepileptic Medications for Treatment
`of Seizures
`
`Department of Pharmacy Practice and Science, University of Kentucky College of Pharmacy, Lexington, Kentucky 40536-0082
`
`Daniel P. Wermeling
`
`Summary: Acute isolated seizure, repetitive or recurrent seizures,
`and status epilepticus are all deemed medical emergencies. Mor-
`tality and worse neurologic outcome are directly associated with
`the duration of seizure activity. A number of recent reviews have
`described consensus statements regarding the pharmacologic treat-
`ment protocols for seizures when patients are in pre-hospital,
`institutional, and home-bound settings. Benzodiazepines, such as
`lorazepam, diazepam, midazolam, and clonazepam are considered
`to be medications of first choice. The rapidity by which a medi-
`cation can be delivered to the systemic circulation and then to the
`brain plays a significant role in reducing the time needed to
`treat seizures and reduce opportunity for damage to the CNS.
`Speed of delivery, particularly outside of the hospital, is
`enhanced when transmucosal routes of delivery are used in
`place of an intravenous injection.
`Intranasal transmucosal delivery of benzodiazepines is use-
`ful in reducing time to drug administration and cessation of
`seizures in the pre-hospital setting, when actively seizing pa-
`
`tients arrive in the emergency room, and at home where care-
`givers treat their dependents. This review summarizes factors to
`consider when choosing a benzodiazepine for intranasal admin-
`istration,
`including formulation and device considerations,
`pharmacology and pharmacokinetic/pharmacodynamic pro-
`files. A review of the most relevant clinical studies in epilepsy
`patients will provide context for the relative success of this
`technique with a number of benzodiazepines and relatively less
`sophisticated nasal preparations. Neuropeptides delivered intra-
`nasally, crossing the blood-brain barrier via the olfactory sys-
`tem, may increase the availability of medications for treatment
`of epilepsy. Consequently, there remains a significant unmet
`medical need to serve the pharamcotherapeutic requirements of
`epilepsy patients through commercial development and mar-
`keting of intranasal antiepileptic products. Key Words: Intra-
`nasal, drug delivery, antiepileptic medications, treatment of
`seizures,
`emergency
`pharmacotherapy,
`benzodiazepines,
`blood-brain barrier.
`
`INTRODUCTION
`
`Patients with a life-threatening or unstable condition
`presenting to pre-hospital, emergency service field per-
`sonnel or hospital emergency facilities will have an in-
`travenous (IV) line established for rapid administration
`of medications. Organized health care has developed
`standards of care and assessment and treatment protocols
`for a variety of conditions to stabilize the patient as
`rapidly as possible. Clearly, patients experiencing epi-
`leptic seizures have a medical emergency and require
`prompt medical care.1– 4 Several consensus statements
`have been published describing pharmacologic treatment
`protocols for patients presenting with seizures or in sta-
`tus epilepticus. The guidelines provide recognition of the
`need for prompt treatment and recommendations for var-
`
`Address correspondence and reprint requests to: Daniel P. Wermel-
`ing, Pharm.D., Associate Professor, Department of Pharmacy Practice
`and Science, University of Kentucky College of Pharmacy, Lexington,
`KY 40536-0082. E-mail: dwermel@uky.edu.
`
`ious transmucosal routes of benzodiazepine delivery
`when IV access has not yet been established.5–9 The
`marketing of diazepam rectal gel is made in recognition
`of the need for noninjection-based delivery; however, the
`aesthetics of rectal delivery are not popular with patients
`and caregivers.
`Intranasal administration of antiepileptic medications,
`in particular benzodiazepines, has been studied with var-
`ious preparations. Intranasal midazolam has been exten-
`sively studied in epilepsy patients and is recommended
`in some consensus guidelines as an alternative drug de-
`livery technique for prompt treatment.10 –12
`This review provides an overview of the consider-
`ations necessary for nasal delivery of antiepileptic med-
`ications. An understanding of nasal anatomy and physi-
`ology is required to appreciate the operating limitations
`of intranasal drug administration. Ad-hoc preparations or
`products for registration must consider designs that inte-
`grate the medication and its chemistry, the formulation,
`and the administration device to work successfully. Early
`
`352
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`NASAL DELIVERY OF AEDS
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`353
`
`stage studies in healthy volunteers are important steps in
`determining if appropriate pharmacokinetic and pharma-
`codynamic properties and safety profile will lend them-
`selves to treating seizures. Clinical experience in treating
`epileptic patients with various preparations suggests this
`is a rapid-acting and effective drug-delivery alternative.
`
`Nasal anatomy as related to intranasal
`drug delivery
`Intranasal sprays of medication intended for systemic
`drug absorption are generally designed to target the tur-
`binates on the medial wall of the nasal cavity (FIG. 1).
`The turbinates serve as a baffle in which inspired air is
`humidified and filtered. This region of the nasal cavity is
`covered with a thin mucus layer, a monolayer ciliated
`epithelium, with an abundant underlying blood supply.13
`These conditions are ideal to permit passive diffusion
`(transcellular) of medications with certain chemical char-
`acteristics across cell membranes and into the blood-
`stream. Some medications also transit to the bloodstream
`by passing through the tight-cell junctions between cells
`(paracellular).
`To reach the turbinates, the nasal spray device must be
`inserted fully into the nasal vestibule with the atomizer
`tip placed at the nasal valve, and then aimed laterally
`toward the turbinates.14 Activation of the device ejects
`
`FIG. 1. Anatomy of the nasal cavity and relation to the brain.
`
`the liquid as an atomized spray or plume. The bulk of the
`spray impacts the anterior and inferior portions of the
`nasal cavity as a simple ballistic missile. The smallest
`particles, less than 10 microns in size, may be carried by
`air currents more superiorly in the nasal cavity and im-
`pact on the superior turbinate and possibly reach the
`olfactory region and nerve.15,16 There is substantial evi-
`dence in animals, and some evidence in man, that the
`olfactory nerve can absorb or actively transport medica-
`tions to the central nervous system via the olfactory bulb
`(nose to brain theory). Differences in animal and human
`nasal apparatus anatomy, and certain characteristics of
`the medication, seem to play roles as to whether medi-
`cation is transported to the brain via this mechanism, and
`if a pharmacologic effect is observed.17
`Under ideal conditions, most medication is absorbed
`from the nasal cavity and into the bloodstream within 15
`to 20 minutes, thus generally avoiding the first-pass gut
`metabolism.18 Medication remaining in the nasal cavity
`beyond this time is subject to elimination via various
`enzyme systems present within the nasal mucus and by
`swallowing. A second absorption phase can be observed
`with nasally administered medications having incom-
`plete nasal absorption that are not subject to high first-
`pass gut metabolism.
`Nasal physiologic changes during pathologic condi-
`tions, such as polyposis and allergic and vasomotor rhi-
`nitis, could theoretically alter the biopharmaceutics of
`intranasal medications intended for systemic drug ad-
`ministration.13 Physical obstruction of the nasal pas-
`sage(s) due to prior trauma and subsequent deflection of
`the passageways is another possibility. Last, increases in
`mucus production and changes in mucociliary clearance
`rates could affect bioavailability.
`Pharmaceutical
`regulatory agencies have required
`studies of the effect of rhinitis on nasal drug delivery
`biopharmaceutics. It has been demonstrated that there is
`a lack of effect of nasal mucosal inflammation on the
`absorption of hydromorphone, butorphanol, buserelin,
`and triamcinolone acetonide, with the exception reported
`for desmopressin.13,19,20 Inconsistent results have been
`reported on the biopharmaceutical disposition of these
`medications when pretreatment with oral or topical de-
`congestants was administered. Small but statistically
`measurable changes in rate or extent of absorption have
`been reported when decongestants were coadminis-
`tered.13
`Increased nasal mucus production is commonly observed
`with actively seizing patients and could be clinically rele-
`vant to intranasal drug administration for treatment of sei-
`zures. Holsti et al.21 recognized this consideration in their
`pre-hospital treatment protocol that called for suction of
`mucus from the nasal cavity prior to administration of in-
`tranasal midazolam. Pre-treatment nasal cavity suctioning
`was likely contributory to the success observed in rapidly
`
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`354
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`WERMELING
`
`aborting seizure activity after intranasal midazolam admin-
`istration.
`
`DESIGN OF NASAL PRODUCTS FOR
`SYSTEMIC DRUG ADMINISTRATION
`
`Many intranasal delivery products are designed to serve
`certain purposes or unmet medical needs. Clearly, a nasal
`spray can remove the needle from drug administration, as is
`the case with the conversion of the protein calcitonin from
`a daily injection to a nasal spray. Furthermore, beyond just
`removing the needle from delivery, intranasal products are
`designed for rapid action, such as those products designed
`to treat migraine headache (sumatriptan, butorphanol,
`zolmitriptan, and dihydroergotamine) or pain in general
`(fentanyl, hydromorphone).18,22
`What makes each of the aforementioned products suc-
`cessful is that their design satisfied several fundamentals
`necessary for intranasal delivery (Table 1).18 First, there
`must be a selection of drug candidates based on their
`pharmacologic and therapeutic properties. In the case of
`benzodiazepines, there are at least four reasonable alter-
`natives to consider: 1) diazepam, 2) lorazepam, 3) clon-
`azepam, and 4) midazolam. The rationale for choosing
`one versus another based purely on pharmacology is
`beyond the scope of this article. However, ease of pass-
`ing the blood-brain barrier, receptor occupancy, speed of
`absorption, and clearance rate properties must be consid-
`ered. One may also wish to consider choices based on
`prior clinical performance and current marketing within
`a Food and Drug Administration-approved label for
`treatment of acute seizures (e.g., diazepam and loraz-
`epam are qualified in this regard).
`Physical-chemical properties of the candidates must
`also be considered. Water-solubility is important for for-
`mulation considerations. Log P, derived from the octa-
`nol/water partition coefficient, is a surrogate for lipophi-
`licity, and a potential for compounds to diffuse across
`biologic membranes. Unfortunately, benzodiazepines
`have limited water solubility at pH 5 to 7, the pH of nasal
`secretions, and where most nasal solutions are formu-
`
`Table 1. Chemistry and Formulation Issues Affecting
`Intranasal Medication Bioavailability and Tolerability
`
`● Potent medication, ⬍20 mg per dose
`● Molecular weight, ⬍1000 Daltons
`● Excellent water solubility
`● pKa and pH control of aqueous solutions
`● Osmolality—isotonic to slightly hypertonic
`● Stability in processing and storage
`● Compatibility with sprayer components
`● Use of special excipients to manage
`X Solubility
`X Stability
`X Permeation
`
`Neurotherapeutics, Vol. 6, No. 2, 2009
`
`lated. These medications have sufficient lipophilic char-
`acter to readily cross biologic membranes.
`Benzodiazepines satisfy the potency requirement in
`that typical doses are all less than 20 mg. The dose must
`have sufficient solubility to be administered in approxi-
`mately 100 ␮L to 200 ␮L (1 spray per naris) of solution.
`The nasal cavity can retain 100 to 150 ␮L without caus-
`ing immediate run-off out the front of the nose or down
`the nasopharynx. Water is the preferred solvent, but
`many medications, including the benzodiazepines, do not
`have sufficient water solubility to formulate a nasal prod-
`uct. Although midazolam injection is prepared in an
`aqueous solvent system, the solution is buffered to an
`irritating pH 3 as a requirement to maintain drug in
`solution and to prevent instability of the core-ring struc-
`ture from uncoupling. Additional solubilization strate-
`gies are necessary, including the use of organic co-sol-
`vents, excipients, such as cyclodextrins or other agents to
`from water-soluble inclusion complexes or preparation
`of emulsions.
`Design of the formulation must account for other fac-
`tors as well. It is useful to design the formulation to be
`isotonic to slightly hypertonic to optimize absorption and
`tolerability. Viscosity-enhancing agents, such as methyl-
`cellulose, can promote retention in the nasal cavity by
`slowing the ciliary movement of mucus. Surfactants or
`polymers can be used to enhance transmembrane perme-
`ation. Last, the drug and formulation have to be stable in
`the device during processing (i.e., sterilization and stor-
`age, thus possibly requiring stabilizers).
`The choice of delivery device for the medication is
`another critical consideration. FIG. 2 depicts a number of
`different nasal spray devices. Squeeze bottles are avail-
`able, but have no metering device appropriate to admin-
`ister potent systemic medications such as benzodiaz-
`epines. Multi-dose bottles are available for chronic drug
`administration; this is not a likely consideration regard-
`ing seizure emergencies. A standard syringe with a Luer
`fitting to accept a nasal atomizer has been used to draw
`up and administer injection-based drug solutions into the
`nasal cavity for opiate overdoses, acute pain, and to
`deliver midazolam injection to the nasal cavity of a seiz-
`ing patient. Unit-dose devices similar to those used for
`migraine treatment are also available and being used in
`development of benzodiazepine nasal spray products.
`The choice of device depends on factors such as intended
`clinical use, setting, and stability with the drug and for-
`mulation, among others.
`Ideally, a well-designed formulation must not induce
`localized toxicity with acute or chronic use. For example,
`chronic vasoconstriction, irritation, or inflammation can
`induce tissue damage, including ulceration, epistaxis, na-
`sal-septal defects, and fistulae. Formulations should not
`cause damage to the cilia.23 Due to the water insoluble
`nature of benzodiazepines, a common approach to nasal
`
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`NASAL DELIVERY OF AEDS
`
`355
`
`FIG. 2. Representative nasal sprayers.
`
`delivery formulations is to use organic solvents or co-
`solvents with water. For acute use there is a risk of
`transient irritation from such formulations. Although not
`ideal, the risk-benefit assessment likely still favors use of
`such products in treatment of life-threatening circum-
`stances such as seizures. Chronic or daily use of an
`irritating product could lead to more serious sequelae
`from nasal delivery.
`The concept of direct entrance to the CNS has been
`considered for nasal drug delivery.15–17 Neuroproteins24
`and other medications that do not readily cross the blood-
`brain barrier after systemic administration are considered
`targets for this drug delivery application. The challenges
`with nose to brain transit of medications are that: 1) the
`medication must be very potent, 2) the device must op-
`timize an ability of the spray to reach the most superior
`
`portions of the nasal cavity, 3) sufficient medication must
`reach the olfactory nerve, 4) a mechanism of transport
`must be available, and 5) the medication must reach
`relevant brain structures and be able to diffuse through
`the brain parenchyma to the relevant receptors.
`
`PHARMACOKINETICS
`AND PHARMACODYNAMICS OF
`NASAL BENZODIAZEPINES IN
`HEALTHY VOLUNTEERS
`
`The first studies of intranasal delivery of benzodiaz-
`epine formulations were performed in healthy volun-
`teers. The purpose of the trials was to generate systemic
`exposure and local tolerance data for various formulation
`approaches. Table 2 provides some comparative data that
`
`Table 2. Pharmacokinetics of Selected Benzodiazepine Formulations Administered Intranasally
`
`Drug
`
`Clonazepam
`Lorazepam
`Lorazepam
`Midazolam
`Midazolam
`Midazolam
`Midazolam
`Diazepam
`
`Dose (mg)
`
`1.0
`2.0
`4.0
`5.0
`5.0
`3.4
`0.25 mg/kg
`7.0
`
`Formulation
`
`Cmax (ng/mL)
`
`tmax (min)
`
`F (%)
`
`B-CDE/H2O
`Prop. Gly.
`Cremophor El
`PEG 400/Prop. Gly.
`Prop. Gly./H2O
`SBE-CDE
`Aqueous injection
`PEG 300
`
`6.3
`21.4
`18.7
`80
`71
`51
`147
`179
`
`17.5
`30
`135
`10
`14
`15
`25
`42
`
`45
`77.7
`51
`72.5
`83
`71
`50
`42
`
`⫽ maximum plasma concentration; F ⫽ absolute bioavailability comparing nasal dose to an intravenous dose; PEG ⫽ polyethylene glycol;
`Cmax
`Prop. Gly. ⫽ propylene glycol; tmax
`⫽ time to maximum plasma concentration; SBE-CDE ⫽ sulfobutylether-beta-cyclodextrin.
`
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`356
`
`WERMELING
`
`FIG. 3. Midazolam plasma concentrations after 5 mg via intravenous, intramuscular, and intranasal administration. SD ⫽ standard
`deviation. (Adapted from Wermeling,30 2006.)
`
`examines formulation approaches and the resulting phar-
`macokinetic measurements.25–34 The main consider-
`ations from these data might be whether maximum
`plasma concentrations represented by Cmax are within
`ranges known to produce pharmacologic effects, and the
`second consideration is whether the concentrations are
`achieved rapidly enough to be appropriate for treating a
`seizure. Well-designed nasal preparations may demon-
`strate a pharmacokinetic profile in which the rate and
`extent of drug exposure is superior to intramuscular in-
`jection and approximates IV infusion (FIG. 3).30 The
`bioavailability, representing the extent of absorption
`compared to an IV dose may not be as relevant.
`The data for intranasal administration of benzodiaz-
`epines suggests that certain formulations could be appro-
`priate for treating seizures. The evidence is indirect in the
`sense that some formulations produce rapid plasma lev-
`els that are associated with IV or other routes of admin-
`istration. Moreover, some studies collected pharmacody-
`namic information such as psychomotor or cognitive
`impairment studies, or sedation scoring, in conjunction
`with pharmacokinetic sampling. The pharmacodynamic
`data can be compared with dose and concentration data
`of the original studies of benzodiazepine effects on EEG
`beta wave (13–30 Hz) activity. Greenblatt et al.35 estab-
`lished that the degree of impairment on digital-symbol
`substitution tests was directly correlated with the degree
`of change in new-onset beta wave activity after triazolam
`administration. Moreover, Lindhardt et al.32 demonstrated
`comparable changes in EEG amplitude in the 16 to 35 Hz
`range comparing 4 mg intranasal to 5 mg intravenous di-
`
`Neurotherapeutics, Vol. 6, No. 2, 2009
`
`azepam. Thus, these early studies examining formulation
`strategy, biopharmaceutics, and local tolerance were sug-
`gestive that nasal delivery of benzodiazepines could have a
`role in treatment of seizures.
`
`EXPERIENCE WITH INTRANASAL DELIVERY
`OF BENZODIAZEPINES FOR TREATMENT
`OF SEIZURES
`
`Studies demonstrating nasal delivery of midazolam to
`treat seizures, as compared with other benzodiazepines,
`are by far the most prevalent in the biomedical literature.
`O’Regan et al.36 was the first to publish success using
`this method by administering 0.2 mg/kg of the midazo-
`lam injection solution intranasally. The results demon-
`strated successful abolition of seizures in 14 of 19 chil-
`dren with difficult to treat seizures. There was a 60%
`reduction in spike counts per minute and the appearance
`of beta-wave activity within 175 seconds of drug admin-
`istration.
`Many additional articles describe intranasal delivery
`of midazolam in case reports or open-label studies with
`relatively small numbers of patients. However, in aggre-
`gate, the studies are universally positive in their patient
`outcomes of rapid treatment and cessation of seizures.
`Three articles of similar construct compared intranasal
`midazolam with intravenous diazepam for cessation of
`seizures rates and time to cessation.37–39 Each research
`team reached the same conclusions: 1) midazolam injec-
`tion administered nasally was equally effective as IV
`diazepam in seizure cessation, and 2) intranasal midazo-
`
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`NASAL DELIVERY OF AEDS
`
`357
`
`lam reduced time to cessation of seizures by eliminating
`the need to establish IV access.
`Bhattacharyya et al.40 conducted a controlled trial of
`intranasal midazolam to rectal diazepam in children.
`There was a shorter time to seizure cessation in the
`midazolam group. Intranasal midazolam had a superior
`tolerability profile with lower incidences of drowsiness,
`nausea, and respiratory depression.
`Similar outcomes have been reported when 0.2
`mg/kg IV midazolam administered intranasally was
`compared with rectal diazepam in children in the pre-
`hospital setting.21 In addition to the aforementioned
`advantages from Bhattacharyya et al.,40 the investiga-
`tors demonstrated that midalozam-treated patients
`were less likely to be seizing on presentation to the
`emergency department, needed less additional seizure
`medication, had a lower incidence of intubation, or
`were less likely to be admitted to the hospital or
`intensive care unit.
`Intranasal drug delivery has been readily accepted by
`the layman as demonstrated by the considerable usage of
`over-the-counter and prescription products. Nasal drug
`delivery of midazolam for treatment of seizures in the
`home-bound setting has been successful in preliminary
`studies.41– 43 Clearly, morbidity and mortality, the inten-
`sity of health-care resources and expenses associated
`with treatment of epileptic patients could be reduced if
`an effective and safe transmucosal treatment was avail-
`able for use by caregivers.
`Lorazepam injection administered by intranasal spray
`was compared to intramuscular paraldehyde for pro-
`tracted seizures in children of sub-Saharan Africa.44
`Children randomized to lorazepam received 100 mcg/kg
`(drawn up into a syringe with a nasal spray adapter).
`Seventy-five percent of the lorazepam patients had sei-
`zures stop within 10 minutes. The most significant find-
`ing may have been that there was a great difference in
`favor of intranasal lorazepam for the reduction of need-
`ing two or more additional rescue anticonvulsant agents.
`The authors believe their intranasal lorazepam system is
`an ideal primary health-care facility, first-line anticon-
`vulsant agent, by satisfying the following criteria: quick
`acting, minimal cardiopulmonary side-effects, long-last-
`ing effect, and inexpensive.
`Intranasal delivery of benzodiazepines has been rec-
`ommended in treatment guidelines when IV access has
`not yet been established. Table 3 provides a general
`guideline that clinicians may wish to consider if nasal
`delivery of benzodiazepines is to be used in their prac-
`tice. Many of the key concepts are directly provided from
`the literature. Most importantly, development of proto-
`cols for nonphysicians will assist in keeping this a safe
`drug-delivery practice.
`
`Table 3. Key Concepts for Clinical Use of Intranasal
`Benzodiazepine Delivery
`
`● The choice of medication based on pharmacology,
`regulatory, and clinical experience
`● Highly concentrated, stable drug solution
`X 100 –200 uL delivery volume per spray for
`commercial products
`X As concentrated as available for injection solution
`products
`● Choose an appropriate nasal spray device
`X Atomizers distribute spray across the nasal mucosa
`X Use both naris to increase absorption surface area
`● Desirable pharmacokinetic and pharmacodynamic
`profiles
`X Rapid absorption
`X Sufficient duration to permit dosing of other
`medications
`● Develop assessment, administration, and monitoring
`protocols and training guides
`X Emergency room and transport settings
`X Home-bound setting for patients and caregivers
`
`CONCLUSIONS
`
`Benzodiazepines, although generally water-insoluble,
`can be designed into appropriate nasal delivery candi-
`dates. Preparations for clonazepam, diazepam,
`loraz-
`epam, and midazolam have been described. Clinical re-
`searchers have investigated with considerable success
`the potential for injectable benzodiazepine solutions to
`serve as a surrogate for optimally designed nasal spray
`formulations to treat seizures. The availability of low-
`tech nasal spray devices has facilitated this research and
`permitted translation of this technique into emergency
`medicine practice in some locales. Midazolam, perhaps
`due to its rapid absorption and action in the CNS, appears
`to be the medication of choice at this time. Lorazepam
`has been shown to be a suitable alternative if recurrence
`of seizures is a potential concern. Additional research is
`needed to better define the optimal dose of these medi-
`cations for nasal administration. Although promising re-
`sults have been achieved, additional research into the
`utility of this technique for home-bound treatment is also
`warranted.
`The emergency medical community is striving to im-
`prove the care of the seizure patient by examining the
`drug-delivery techniques to reduce the time to treatment
`and cessation of seizures. The literature demonstrates an
`unmet medical need exists to provide well-designed na-
`sally delivered benzodiazepines for the treatment sei-
`zures.
`
`REFERENCES
`1. Lowenstein DH, Alldredge BK. Status epilepticus. N Eng J Med
`1998;338:970 –976.
`2. Lowenstein DH, Bleck T, Macdonald RL. It’s time to revise the
`definition of status epilepticus. Epilepsia 1999;40:120 –122.
`3. Wang HC, Chang WN, Chang HW, et al. Factors predictive of
`outcome in posttraumatic seizures. J Trauma 2008;64:883– 888.
`
`Neurotherapeutics, Vol. 6, No. 2, 2009
`AQUESTIVE EXHIBIT 1151 Page 0006
`
`

`

`358
`
`WERMELING
`
`4. Stavem K, BJornaes H, Langmoen IA. Long-term seizures and
`quality of life after epilepsy surgery compared with matched con-
`trols. Neurosurgery 2008;62:326 –334.
`5. Logroscino G, Hessdorffer DC, Cascino G, et al. Time trends in
`incidence, mortality, and case-fatality after first episode of status
`epilepticus. Epilepsia 2001;42:1031–1035.
`6. Feen ES, Bershad EM, Suarez JI. Status Epilepticus. South Med J
`2008;101:400 – 406.
`7. Pang T, Hirsch L. Treatment of convulsive and nonconvulsive
`status epilepticus. Cur Treat Options Neurol 2005;7:247–259.
`8. Smith B. Treatment of status epilepticus. Neurol Clin 2001;19:
`347–369.
`9. Ericksson K, Kalviainen R. Pharmacologic management of con-
`vulsive status epilepticus in childhood. Expert Rev Neurotherapeu-
`tics 2005;5:777–783.
`10. Wolfe T, Macfarlane T. Intranasal midazolam therapy for pediatric
`status epilepticus. Am J Emerg Med 2006;24:343–346.
`11. Meierkord H, Engelsen B, Gocke K, et al. EFNS guideline on the
`management of status epilepticus. Eur J Neurol 2006;13:445– 450.
`12. Prasad K, Krishman P, Al-Roomi K, et al. Anticonvulsant therapy
`for status epilepticus. Br J Clin Pharmacol 2007;63:640 – 647.
`13. Illum L. Nasal Clearance in Health and Disease. J Aerosol Med
`2006;19:92–99.
`14. Merkus P, Ebbens FA, Muller B, Fokkens WJ. Influence of anat-
`omy and head position on intranasal drug deposition. Eur Arch
`Otorhinolaryngol 2006;263:827– 832.
`15. Illum L. Transport of drugs from the nasal cavity to the central
`nervous system. Eur J Pharm Sci 2000;11:1–18.
`16. Illum L. Is nose to brain transport of drugs a reality? JPP 2004;
`56:3–17.
`17. Merkus F, van den Berg MP. Can nasal drug delivery bypass the
`blood-brain barrier? Questioning the direct transport theory. Drugs
`2007;8:133–144.
`18. Constantino HR, Illum L, Brandt G, et al. Intl J Pharmaceutics
`2007;337:1–24.
`19. Davis GA, Rudy AC, Archer SA, Wermeling DP, McNamara PJ.
`Effect of fluticasone propionate nasal spray on bioavailability of
`hydromorphone hydrochloride in patients with allergic rhinitis.
`Pharmacotherapy 2004;24:26 –32.
`20. Davis GA, Rudy AC, Archer SM, Wermeling DP, McNamara PJ.
`Bioavailability and pharmacokinetics of intranasal hydromorphone
`in patients experiencing vasomotor rhinitis. Clin Drug Invest 2004;
`24:1–7.
`21. Holsti M, Sill B, Firth S, et al. Prehospital intranasal midazolam for
`the treatment of pediatric seizures. Ped Emerg Care 2007;23:148 –
`153.
`22. Rudy AC, Coda BA, Archer SM, Wermeling DP. A multiple dose
`phase 1 study of intranasal hydromorphone hydrochloride in
`healthy volunteers. Anesth Analg 2004;99:1379 –1386.
`23. Van den Donk HJ, van den Huervel AG, Zuidema J, Merkus FW.
`The effects of nasal drops and their additives on human nasal
`mucociliary clearance. Rhinology 1982;20:127–137.
`24. Kubek MJ, Domb AJ, Veronesi MC. Attenuation of kindled sei-
`zures by intranasal delivery of neuropeptide-loaded nanoparticles.
`Neurotherapeutics 2009;6:359 –371.
`25. Loftsson T, Gudmundsdottir H, Sigurjonsdottir JF, et al. Cyclo-
`dextrin solubilization of benzodiazepines: formulation of midazo-
`lam nasal spray. Int J Pharm 2001;212:29 – 40.
`26. Knoester PD, Jonker DM, Van Der Hoeven RT, et al. Pharmaco-
`kinetics and pharmacodynamics of midazolam administered as a
`
`concentrated intranasal spray. A study in healthy volunteers. Br J
`Clin Pharmacol 2002;53:501–507.
`27. Gudmundsdottir H, Sigurjonsdottir JF, Masson M, et al. Intranasal
`administration of midazolam in a cyclodextrin based formulation:
`bioavailability and clinical evaluation in humans. Pharmazie 2001;
`56:963–966.
`28. Dale O, Nilsen T, Loftsson T. Intranasal midazolam: a comparison
`of two delivery devices in human volunteers. J Pharmacy Pharma-
`col 2006;58:1311–1318.
`29. Burstein AH, Modica R, Hatton M, et al. Pharmacokinetics and
`pharmacodynamics of midazolam after intranasal administration.
`J Clin Pharmacol 1997;37:711–718.
`30. Wermeling D, Record K, Kelly T, et al. Pharmacokinetics and
`pharamcodynamics of a new intranasal midazolam formulation in
`healthy volunteers. Anesth Analg 2006;103:344 –349.
`31. Schols-Hendriks MWG, Lohman JJHM, Janknegt R, et al. Absorp-
`tion of clonazepam after intranasal and buccal administration. Br J
`Clin Pharmacol 1995;39:449 – 451.
`32. Lindhardt K, Gizurarson S, Stefansson SB, et al. Electroencepha-
`lographic effects and serum concentrations after intranasal and
`intravenous administration of diazepam to healthy volunteers. Br J
`Clin Pharmacol 2001;52:521–527.
`33. Lau SWJ, Slattery JT. Intl J Pharmaceutics. Absorption of diaze-
`pam and lorazepam following intranasal administration. Int J Phar-
`maceutics 1989;54:171–174.
`34. Wermeling DP, Miller JL, Archer SM, et al. Bioavailability and
`pharmacokinetics of lorazepam after intranasal,
`intravenous,
`and intramuscular administration. J Clin Pharmacol 2001;41:
`1225–1231.
`35. Greenblatt D, Gan L, Harmatz, et al. Pharmacokinetics and phar-
`macodynamics of single-dose triazolam: EEG compared with dig-
`ital symbol substitution test. Br J Clin Pharmacol 2005;60:244 –
`248.
`36. O’Regan M, Brown J, Clarke M. Nasal rather than rectal benzo-
`diazepines in the management of acute childhood seizures. De-
`velop Med and Child Neurol 1996;38:1037–1045.
`37. Mittal P, Manohar R, Rawat A. Comparative study of intranasal
`midazolam and intravenous diazepam sedation for procedures and
`seizures. Ind J Pediatrics 2006;73:975–978.
`38. Mahmoudian T, Zadeh M. Comparison of intranasal midazolam
`with intravenous diazepam for treating acute seizures in children.
`Epilepsy Behav 2004;5:253–255.
`39. Lahat E, Goldman M, Barr J, et al. Comparison of intranasal
`midazolam with intravenous diazepam in treating febrile seizures
`in children: prospective randomized study. BMJ 2000;321:83– 87.
`40. Bhattacharyya M, Kalra V, Gulati S. Intranasal midazolam vs
`rectal diazepam in acute childhood seizures. Pediatric Neurology
`2006;34:355–359.
`41. Wilson MT, Macleod S, O’Regan ME. Nasal/buccal midazolam
`use in the community. Arch Dis Child 2004;89:50 –51.
`42. Harbord MG, Kyrkou NE, Kyrkou MR, Kay D, Coulthard KP. Use
`of intranasal midazolam to treat acute seizures in paediatric com-
`munity settings. J Paediatr Child Health 2004;40:556 –558.
`43. Jeannet PY, Roulet E, Maeder-Ingvar M, Gehri M, Jutzi A, De-
`onna T. Home and hospital treatment of acute seizures in children
`with nasal midazolam. Eur J Paediatr Neurol 1999;3:73–77.
`44. Ahmad S, Ellis J, Kamwendo H, Molyneux E. Efficacy and safety
`of intranasal lorazepam versus intramuscular paraldehyde for pro-
`tracted convulsions in children: an open label trial. Lancet 2006;
`367:1591–1597.
`
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