`
`Copyright © 2009 The Authors
`Journal compilation © 2009 Blackwell Munksgaard
`ACTA NEUROLOGICA
`SCANDINAVICA
`
`Clinical Commentary
`Pharmacokinetics and tolerability of
`intranasal diazepam and midazolam in
`healthy adult volunteers
`
`Ivaturi VD, Riss JR, Kriel RL, Cloyd JC. Pharmacokinetics and
`tolerability of intranasal diazepam and midazolam in healthy adult
`volunteers.
`Acta Neurol Scand 2009: 120: 353-357.
`© 2009 The Authors Journal compilation © 2009 Blackwell Munksgaard.
`
`V. D. Ivaturi'?, J. R. Riss',
`R. L. Kriel’, J. C. Cloyd’?
`‘Center for Orphan Drug Research and 7Departmentof
`Experimental and Clinical Pharmacology, University of
`Minnesota, Minneapolis, MN, USA
`
`Objective — The purposeofthis pilot study was to determine the
`pharmacokinetics and tolerability of an investigational diazepam
`(DZP) formulation and a parenteral midazolam (MDZ) formulation
`following intranasal(i.n.) administration for the efficient treatment of
`seizure emergencies. Methods — Each subject received 5 mg of DZP
`and MDZ via both i.n. and intravenous routes in a four-way,
`randomized crossovertrial. Blood samples were collected over 48 h.
`DZP and MDZ concentrations were measured using HPLC. Using
`analog scales, subjects rated tolerability (0 = no change from
`normal; 10 = maximum intolerability) and pain (0 = no pain;
`4 = extremepain) prior to and 0, 5, 15, 60 min, and 8 h after
`administration. Results — The Cmax and Tmax values for in. DZP and
`MDZ were 179.2 ng/ml and 28.8 min vs 62.8 ng/ml and 21.6 min,
`respectively. Immediately following in. administration, subjects
`reported tolerability scores of 6.75 and 6.0, and identical pain scores,
`3.2, for DZP and MDZ,respectively. Conclusion - Both formulations
`were rapidly absorbed following i.n. administration with transient
`discomfort. DZP had a longer half-life, which may result in an
`extended duration of action. Further studies in large patient
`populations to evaluate the safety after long term use, efficacy and
`pharmacokinetics of in. DZP are warranted.
`
`Key words: diazepam; intranasal; midazolam;
`pharmacokinetics; tolerability
`
`Vijay D. Ivaturi, Center for Orphan Drug Research,
`Rm 4-208, McGuire Translational Research Facility,
`2001 6th St. SE, College of Pharmacy, University of
`Minnesota, Minneapolis, VIN 55455, USA
`Tel.: 612 624 1861
`Fax: 612 626 9985
`e-mail: ivatu001@umn.edu
`
`Presented as a poster at the American Academyof
`Neurology, April 2006,‘Bioavailability and tolerability of
`a novel intranasal diazepam formulation in healthy
`volunteers’.
`
`Accepted for publication January 5, 2009
`
`Introduction
`
`Individuals with uncontrolled epilepsy represent
`one of the greatest challenges in the management
`of this disorder (1, 2). These patients are particu-
`larly prone to status epilepticus (SE) as well as
`prolonged or cluster seizures which are in them-
`selves serious conditions that can evolve into SE
`(3).
`Intravenously administered benzodiazepines
`(BZDs) are widely used for the treatmentofseizure
`emergencies. When given within 30 min ofseizure
`onset, intravenous(i.v.) BZDs are effective in more
`than 80% of patients (3, 4). However, i.v. admin-
`istration requires skilled personnel and transport to
`a medical
`facility which can delay initiation of
`
`therapy (5). Treatment delay is associated with
`longer seizure duration, greater difficulty in termi-
`nating the
`seizure, prolonged hospitalization,
`higher mortality, and reduced quality oflife (3, 6).
`Administration of BZDs by other routes could
`permit earlier
`initiation of therapy outside of
`medical facilities. Rectal administration of diaze-
`pam (DZP) for the treatment of seizure emergen-
`cies is safe and effective, reduces medical costs, and
`improves quality of life, but many patients and
`their caretakers are reluctant to consider this mode
`of therapy especially when the patient
`is in a
`location which is socially embarrassing (7-10).
`The availability of a fast-acting intranasal (i.n.)
`treatment that can be easily administered by the
`
`353
`
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`
`
`Ivaturi et al.
`
`patient or a caregiver would greatly improve the
`management ofseizure disorders. Essential char-
`acteristics for an in. drug delivery system in the
`treatment of seizure emergencies include: patients
`must be able to tolerate the formulation; admin-
`istration volume of 0.5 mlorless; rapid, consistent
`absorption; and easy administration by non-med-
`ical caregivers and patients.
`The purpose of this study was to evaluate the
`pharmacokinetics and tolerability of in. adminis-
`tered DZP and midazolam (MDZ)in healthy adult
`volunteers.
`
`Methods
`
`The study was approved by the Institutional
`Review Boards at
`the University of Minnesota
`and Hennepin County Medical Center. Four
`healthy, non-pregnant women aged 20-24 years
`participated in the
`study. Subjects provided
`informed consent and were compensated for par-
`ticipation. Subjects were excluded if they were in
`poor health, unwilling or unable to receive in. or
`i.v. medications, pregnant, smokers, allergic to
`DZP or MDZ,or had narrow-angle glaucoma.
`Subjects’
`treatment
`sequence was
`randomly
`assigned using a latin-square design. The study
`consisted of a four-way, randomized, single-blind,
`crossover design in which subjects received 5 mg
`doses of in. DZP, in. MDZ, i.v. DZP and i.v.
`MDZ. Subjects were admitted to the clinical
`research unit located at Hennepin County Medical
`Center and remainedthere for 8 h on four separate
`occasionsafter a minimum 1-week washoutperiod.
`Commercial
`formulations were used for
`tv.
`administration of DZP and MDZ. The in. DZP
`formulation consisted of an investigational super-
`saturated solution containing 40 mg/ml of DZP,
`glycofurol and water. The injectable MDZ formu-
`lation (Smg/ml) wasalso used for in. administra-
`tion. The in. doses of 5 mg were administered
`using a 1.0 ml syringe such that 0.125 ml of the
`DZPsolution and 1 ml of the MDZ solution were
`dripped slowly into either one of the nostrils.
`Intranasal administration of normal saline (0.5 ml)
`given with a 1.0 ml dropper served as a control to
`comparetolerability of the drugs. Using a 10-point
`Global Tolerability Analog Scale, each subject
`rated overall
`tolerability of the in.
`(drug and
`normal saline) and i.v. doses (drug only) at 5 min
`prior to and 0, 5, 15, 60 min and 8 h after drug
`administration. A score of 10 was considered the
`least tolerable. This scale is analogous to Visual
`Analog Scales and has been adapted from a
`previous study evaluating the tolerability of a
`nasal formulation (11). Subjects also completed
`
`354
`
`a pain and subjective discomfort questionnaire for
`the in. administrations. Using a 4 point analog
`scale with 4 representing extreme pain or discom-
`fort, subjects rated specific pain characteristics:
`burning, stinging, and throbbing at —15, 0, 5, and
`15 min.
`for pharmacokinetic
`Blood samples of 5 ml
`analysis were collected, by means of a catheter
`inserted into a forearm vein,
`into glass tubes
`containing ethylenediamine tetraacetic acid as
`anticoagulant at —5, 0, 1, 5, 10, 20, 30, 60 min
`and 8h. For DZP, additional
`samples were
`obtained at 24 and 48 h. Within 15 min of collec-
`tion, the blood samples were spun in a centrifuge,
`and plasma was carefully separated. Plasma sam-
`ples were stored at —80°C pending analysis.
`
`Drug assay
`Plasma samples were analyzed for MDZ and DZP
`concentrations using an Agilent 1100 series HPLC
`system (Agilent Technologies, Palo Alto, CA,
`USA) with a C4 column. The mobile phase for
`the system consisted of 40% acetonitrile and 60%
`phosphate buffer (pH-6.0). The flow rate of the
`mobile phase was 0.5 ml/min and the injection
`volume was 50 pl. Standard curves were prepared
`over the range of 5-500 ng/ml and quality control
`samples containing 15 (low), 50 (medium) and
`250 ng/ml (high) of DZP and MDZ were prepared
`separately with blank human plasma.
`An aliquot of 0.2 ml of the plasma was added toa
`12 x 75 mm glass tube. A sample of NaOH (200 ul)
`and the internal standard lorazepam (200 pl) were
`added and the solution was mixed well. A 2 ml
`volume of ether was poured in the tube as an
`extracting solvent and vortex mixed for 1 min and
`then centrifuged for 10 min at 769 g. A sample of
`the organic layer was collected and evaporated until
`dry with nitrogen at 34°C, and then 200 pl of
`the HPLC mobile phase was addedto dissolve the
`residue. After 30s of vortex mixing, 50 pl of the
`sample solution wasinjected into the HPLC system.
`The standards for DZP and MDZ were analyzed
`on separate days and the mean coefficients of
`variation were 5.6% and 5.0%, respectively. The
`mean coefficients of variation for the intraday
`variation of DZP and MDZ quality control
`samples were 8.6% and 7.5%, respectively.
`
`Pharmacokinetic analysis
`
`Concentration—-time data of DZP and MDZ were
`examined using non-compartmental pharmacoki-
`netics analysis with WinNonLin software (version
`5.2; Pharsight Corporation, Mountain View, CA,
`
`AQUESTIVE EXHIBIT 1028
`
`AQUESTIVE EXHIBIT 1028 page 0002
`
`page 0002
`
`
`
`- Table 1 Mean (SD) pharmacokinetic parameters af diazepam (DZP) and mi-
`dazolam (MDZ)in healthy volunteers following intravenous {i.v.) and intranasal (i.n.)
`administration of 5 mg dose
`
`
`
` PK parameter iv. DZP in. DZP iv. MDZ in. MDZ
`
`
`
`
`
`
`
`Intranasal diazepam and midazolam
`
`IN 02?(n = 3}
`
`2007
`eooo
`= 160
`">o
`g/m
`(
`
`Concentration(n
`
`oooa 40 |204
`
`BoPonooseentanttsateen
`(ng/ml)Nrd+wao36
`Concentration
`
`oF
`
`0
`
`e
`Mt...
`1
`
`5
`
`ptintuiiuinguunnnniinunimennnnnentpsoammianangamamnnnt,
`10
`15
`20
`30
`60
`Time(min)
`
`IN MDZ (n= 3)
`
`80:
`70°
`
`ooOo
`
`21.6 + 7.63
`-
`28.8 + 20.96
`-
`Trax (min)
`165.2 + 96.42" 628 + 14.51
`179.2 +885
`344.0 + 92.81"
`Gmox (g/m!)
`
`
`
`
`59.1 + 7.76 22.4 + 3.45 0.9 + 0.60Haif-life (h) 3.0 + 0.74
`
`*Concentration 5 min after injection.
`
`250
`
`200
`
`100
`
`
`
`Concentration(ng/ml)
`
`—~@- IN MDZ (n = 3)
`8 IN DZP (1 = 3)
`
`wy
`
`?
`
` 0
`
`1
`
`5
`
`15
`10
`Time (min)
`
`20
`
`30
`
`60
`
`15
`10
`Time (min)
`
`20
`
`30
`
`60
`
`Figure 2, Concentration time profiles (0-60 min) of individual
`subjects (2 = 3) for intranasal midazolam and diazepam.
`
`Figure 1. Comparison of mean intranasal diazepam and
`midazolam concentration vs time profile.
`
`Globaltolerability scores
`
`USA). The terminal rate constant (Az) was deter-
`mined from the slope of the terminal
`log-linear
`portion of the plasma-—concentration—time curve,
`and the terminal half-life (¢,/2) was calculated as
`In2/(Az). Maximum plasma concentrations (Cmax)
`and time to maximum concentration (Tmax) were
`determined by direct observation of the data.
`Meansand standard deviations for the parameters
`were also obtained using the descriptive statistics
`tool in WinNonlin version 5.2.
`
`Scores
`
`
`
`WIN O2P
`SIN MDZ
`
`
`
`
`
`Baseline
`O min
`
`
`60 min
`
`15 min
`Smin
`Time (min)
`
`Results
`
`Four women, aged 20-24 years entered the study.
`Onesubject dropped out dueto travel conflicts after
`completing the i.n. DZP arm and was excluded from
`all group analyses. The pharmacokinetic parameters
`for the three subjects are summarized in Table 1. The
`mean concentration-time profiles are shown in
`Fig. 1 and the individual subject’s concentration
`time profiles for both in. DZP and MDZ are shown
`in Fig. 2. The average i.n. DZP Crax and Tmax Were
`179.2 + 8.8 ng/ml and 28.8 + 20.9 min,
`respec-
`tively. The average in. MDZ Cy, and Trax were
`62.8 + 14.5 ng/ml and 21.6 + 7.6 min,
`respec-
`tively. The Cnax and Tax ofthe subject who dropped
`out of the study were 109.48 ng/ml and 20 min,
`respectively following in. DZP administration.
`
`Figure 3. Comparison of mean globaltolerability scores after
`intranasal administration (7 = 3).
`
`Immediately following i.n. administration, sub-
`jects reported an average global tolerability score
`of 6.75 and 6.0 for DZP and MDZ,respectively,
`which were statistically not different (P > 0.05)
`(Fig. 3). Within 15 min, scores decreased to 3.3
`and 1.5, respectively, which eventually returned to
`baseline (Fig. 3).
`Subjects rated both formulations as causing
`considerable pain with a maximum score of 3.2
`immediately following nasal administration. Fifteen
`minutes later, the mean pain score for both drugs
`was 1.2. Posterior nasal drainage and watery eyes
`were reported byall subjects.
`
`355
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`AQUESTIVE EXHIBIT 1028
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`
`Ivaturi et al.
`
`Discussion
`
`Using PubMedwith key terms‘intranasal midazo-
`lam and diazepam’, we found no published reports
`directly comparing in. DZP and in. MDZ.
`Various MDZ formulations given i.n. have been
`investigated with most studies using the commer-
`cially available injectable MDZ solution (12, 13).
`These
`studies with doses between
`10-20 mg
`(2-4 ml) reported Cyax and Tmax values in the
`range of 147-192 ng/ml and 14-25 min, respec-
`tively. The absorptive area of the nose limits the
`volume administered to approximately 0.1-0.3 ml
`per nostril although smaller volumesare preferable
`(14). When the commercially available injectable
`MDZ solution is given in., volumes exceeding
`0.20 ml are required in order to administer a
`clinically relevant dose (12). This could affect both
`bioavailability and Cyax. Highly concentrated
`investigational nasal MDZ formulations, including
`a water and propylene glycol admixture (pH 4)
`(15),
`and a
`solution containing 14% (w/v)
`sulfobutylether B-cyclodextrin (pH 4.3) (16) have
`also been studied in humans. Although these
`formulations permit administration of smailer
`volumes(0.20.3 ml), there was no distinguishable
`difference in the values of Cmax and Tinax-
`Three previousstudies have investigated in. DZP
`in humans. Gizurarson et al. compared ani.n. 2 mg
`dose of a 20 mg/ml DZPsolution dissolved in 5%
`glycofurol in polyethylene glycol 200 with the same
`dose given i.v. (17). Blood samples were collected
`for 5h following drug administration. The mean
`bioavailability was 50.4 + 23.3% with a time to
`peak concentration of 18 + 11 min. All subjects
`complained of nasal discomfort immediately fol-
`lowing drug administration, but
`the discomfort
`resolved within 30 min. Lindhardt et al. evaluated
`an in. formulation of DZP in polyethylene glycol
`300 in seven healthy volunteers. Using a crossover
`design, they compared 4 and 7 mgi-n. doses with a
`5 mg iv. dose and collected blood samples for
`60 min after drug administration. The in. formula-
`tion had a relative bioavailability of45% and 42%, a
`Cmax Of 99 and 179 ng/ml and a Tax of 18 and
`42 min for the 4 and 7 mg doses, respectively (18).
`Given that the half-life of DZP ranges from 24 to
`48 h, their bioavailability valuesare likely an under-
`estimate ofthe actual extent of absorption. Lau and
`Slattery, using a 10 mg dose of DZP dissolved in
`CremophorEL,reported a bioavailability of 78%
`with a Cmax of 175 ng/ml and a Ta, of 1 h(19). A
`recent study by Cloyd et al. (20) determined the
`pharmacokinetics and dose proportionality of 5 and
`10 mg doses of an i.n. administered DZP formula-
`tion compared with i.v. administration in eight
`
`356
`
`healthy volunteers using a crossover design. The
`formulation used was a 40 mg/mlsupersaturated
`solution of DZP in glycofural-water cosolvent
`mixture. Each subject received two in. and oneiv.
`dose of DZP and blood samples were collected up to
`48 h after dosing. The mean Cmax, Tmax and t)/2
`were 134.3+61.9 ng/ml,
`55.6 + 60.3 min, and
`49.1 +20.4h for the 5mg dose, and 247.0 +
`60.9 ng/ml, 39.3 + 38.1 min, and 57.0 + 28.0 h
`for the 10 mg dose. Using analog scales, subjects
`rated tolerability (0 = no change from normal;
`10 = maximum intolerability) prior to and 0, 5, 15,
`60 min, and 8h after administration. The mean
`tolerability scores observed were 4.4 and 4.7 for the 5
`and 10 mgdoses. Both these scores dropped downto 3
`and 2.5, 15 min post-dose and to 1, 60 min post-dose.
`The pharmacokinetic parameters for iv. DZP
`and i.v. MDZ shownin Table 1 are comparable
`to those reported in the literature (21). The rela-
`tionship between DZP pharmacokinetics
`and
`pharmacodynamics is complex. Following rapid
`i.v. administration,
`relatively high plasma DZP
`concentrations occur prior to distribution to vari-
`ous body compartments including the central ner-
`vous system (CNS). This makes correlation of DZP
`levels with seizure control difficult. In contrast, the
`absorption of DZP following rectal or nasal admin-
`istration, although relatively rapid, does permit
`equilibration of DZP concentrations between
`plasma and the CNS. Milliganet al. rectally admin-
`istered a 20 mg dose of DZP solution or placebo to
`10 adults with epilepsy and then observed spike
`wave activity and measured plasma concentrations.
`Rectal DZP significantly reduced EEG spike fre-
`quencies within 20 min at a mean serum DZPlevel
`of 210 ng/ml. The mean Chax of DZP was
`413 ng/ml and the mean Tiax was 32 min (22).
`Based on these results, subsequent controlled clin-
`ical
`trials using similar doses, and presumably
`similar plasma DZP concentrations, have demon-
`strated that rectal DZP is cffective in treating acute
`repetitive seizures (8).
`Although we administered 5 mg DZPi-n. in this
`study, doubling the dose to 10 mg by giving 5 mg
`DZP into each nostril should result in concen-
`trations >200 ng/ml
`that are attained within
`5—10 min,
`It
`is unclear whether prolonged serum DZP
`concentrations are needed to achieve and maintain
`seizure control. The longer elimination haif-life of
`DZP compared with MDZ as shownin the results
`conveys a theoretical advantage in preventing
`subsequentseizure recurrence. In controlled inves-
`tigations DZPis effective in treatment of seizure
`emergencies (8, 23). Such studies have yet to be
`conducted with MDZ.
`
`AQUESTIVE EXHIBIT 1028
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`page 0004
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`
`
`All subjects reported moderate discomfort with
`both formulations. This is a major
`limitation
`of both the injectable MDZ solution and the
`investigational DZP formulation.
`Measures to improve comfortlevel or tolerabil-
`ity are needed for greater patient acceptance.
`Nonetheless, some patients and caretakers would
`prefer the transient discomfort of the present i.n.
`formulations to rectal administration of medica-
`tion in public settings. Similar views have been
`expressed in a comparative study of in. MDZ and
`rectal DZP (10). Intranasal DZP maybe usefulin
`the treatmentof seizure emergencies. However,this
`was a small study of healthy volunteers which
`precludes generalization to clinical use and further
`research is needed to improve tolerability of the
`formulation and to characterize the appropriate
`dose.
`
`Acknowledgements
`
`We thank Dennis Weller for helping with the HPLC analysis.
`Funding for this study was generously provided by Parents
`Against Childhood Epilepsy (PACE) and the Epilepsy Foun-
`dation.
`
`References
`
`1. Dopson WE. Epilepsy, Cerebral Palsy and IQ. In: PeLtock
`JM, Dopson WE, Bourceois BFD,eds. Pediatric Epilepsy,
`Diagnosis and Therapy, 2nd edn. New York: Demos, 2001;
`613-27.
`2. SHinnar S, Maytat J, L K. Recurrent status epilepticus in
`children. Ann Neurol 1992;31:598-694.
`3. Lowenstein D, ALLDREDGE B. Status epilepticus. N Engl J
`Med 1998;338:970-6.
`4. Riss J, Ctovo J, Gates J, Couuins S. Benzodiazepines in
`epilepsy:
`pharmacology
`and pharmacokinetics. Acta
`Neurol Scand 2008;118:69-86.
`5. Jorpan K. Status epilepticus. A perspective from the neu-
`roscience intensive care unit. Neurosurg Clin N Am 1994,
`§:671-86.
`6. Attprepce B. Effect of prehospital treatment on the out-
`come of status epilepticus in children. Pediatr Neurol
`1995;12:213-6.
`7. O’Dett C, Suinnar S, Batrapan-Gir KR etal. Rectal
`diazepam gel
`in the home management of seizures in
`children. Pediatr Neurol 2005;33: 166-72.
`8. Drreruss F, Rosman N, Croyvn J et al. A comparison of
`rectal diazepam gel and placebo for acute repetitive
`seizures. N Engl J Med 1998;338:1869-75.
`9. Kriec R, Croyp J, Hapsatt R, Cartson A, Floren K, Jongs-
`Saete C. Home use of rectal diazepam for cluster and
`
`Intranasal diazepam and midazolam
`
`10.
`
`12.
`
`14.
`
`15.
`
`prolonged seizures: efficacy, adverse reactions, quality of
`life and cost analysis. Pediatr Neurol 1991;7:13-7.
`Buarracuaryya M, Kara V, Gurati S.
`Intranasal mi-
`dazolam vs rectal diazepam in acute childhood seizures.
`Pediatr Neurol 2006;34:355-9.
`. DINGEMANSE J, SOUBROUILLARD C, Paris J, Pisano P, Buin O.
`Pronounced effect of caprylocaproyl macrogolglyce-
`rides on nasal absorption of IS-159, a peptide serotonin
`1B/1D-receptor agonist. Clin Pharmacol Ther 2000;68:
`114-21.
`Burstew AH, Monica R, Hatton M, Forrest A, Genco FM.
`Pharmacokinetics and pharmacodynamics of midazolam
`after intranasal administration. J Clin Pharmacol 1997;37:
`711-8.
`Ipvatc J. Pharmacokinetics of
`. Byorxman S, Ricemar G,
`midazolam given as an intranasal spray to adult surgical
`patients. Br J Anaesth 1997;79:575-80.
`Romeo VD, peMeretes J, Sieno AP, Pimpctaskar HK, Bent
`CR. Effects of physicochemical properties and other fac-
`tors on systemic nasal drug delivery. Adv Drug Deliv Rev
`1998;29:89-1 16.
`Knoester PD, Jonxer DM, Van Der Hoeven RT et al.
`Pharmacokinetics and pharmacodynamics of midazolam
`administered as a concentrated intranasal spray. A study
`in healthy volunteers. Br
`J Clin Pharmacol 2002;53:
`501-7.
`. Lorrsson T, Gupmunpsportir H, Sicurionspotmir JF etal.
`Cyclodextrin solubilization of benzodiazepines: formula-
`tion of midazolam nasal spray. Int J Pharm 2001;212:
`29-40.
`Gizurarson S, Guppranpsson F, Jonsson H, Becucaarp E.
`Intranasal administration of diazepam aiming at
`the
`treatment of acute seizures: clinical trials in health volun-
`teers. Biol Pharm Bull 1999;22:425—7.
`. Linpyarpt K, Gizurarson S, Steransson SB, Otarsson DR,
`Becucaarp E. Electroencephalographic effects and scrum
`concentrations after intranasal and intravenous adminis-
`tration of diazepam to healthy volunteers. Br
`J Clin
`Pharmacol 2001 ;52:521-7.
`Lau S, SLatrery J. Absorption of diazepam and lorazepam
`following intranasal administration. Int J Pharm 1989,
`54:171-4.
`Ivaturi V, Riss J, Kriet R, Cioyp J. Bioavailability and
`tolerability of
`intranasal diazepam in healthy adult
`volunteers. Epilepsy Res. 2009,in press.
`Anperson GD, Mutter JW. Benzodiazepines; chemistry,
`biotransformation, and pharmacokinetics. In: Levy RH,
`Mattson RH, Metorum BS, Perucca E, eds. Antiepileptic
`drugs, 5 edn. Philadelphia: Lippincott Williams & Wilkins,
`2002;187—206.
`Mitucan N, Dutton S, Oxtey J, Ricuens A. Absorption of
`diazepam from the rectum andits effect on interictal spikes
`in the EEG. Epilepsia 1982;23:323~31.
`Kriet RL, Croyp JC, Pertock JM, MitcHetL WG, CEeREGHINO
`JJ, Rosman NP. Rectal diazepam gel for treatment of acute
`repetitive seizures. The North American Diastat Study
`Group. Pediatr Neurol 1999;20:282-8.
`
`17.
`
`19.
`
`20.
`
`2i.
`
`22.
`
`23.
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`AQUESTIVE EXHIBIT 1028
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`AQUESTIVE EXHIBIT 1028 page 0005
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`page 0005
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`