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`D 20485
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`armaceutlcal Selences
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`o
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`Volume 56
`December 2001
`
`,
`
`
`In this Issue
`Editors
`
`0 Pharmaceutical applications of supercritical carbon dioxide
`(Revlew)
`—
`.
`o Hlstamine H3-receptor antagonists
`.
`.
`.
`.
`.
`.
`0 Optimization of capillary electrophoretlc analySIS
`o Capillary electrophoretic analysis of sesquiterpenes
`f
`V l
`'
`rom a erlana
`
`0 Fluid-bed melt granulation
`0 Phosphatidylcholine peroxidation in multilamellar liposomes
`0 Evaluation of an intranasal formulation of midazolam
`0 Osmotic pump tablets of naproxen sodium
`0 Penetration rates bf different magnesium salts
`0 Inhibition of neutrophil elastase by phenolic compounds
`
`5
`
`I
`
`I
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`I
`
`P. Pflegel (Greifswald)
`Editor-in-Chief
`T. Dingermann (Frankfurt am Main)
`Editor—in-chief
`H Derendorf (Gainesville)
`Editor North America
`..
`A- Helmstadter (ESChbom)
`Editorial advisory board
`
`A. Arancibia (Santiago, Chile)
`M~ Brewster (Beerse, Belgium)
`W- Charmfil (VlctOI‘la, AUStraha)
`G Fri/hzlziibgggigig, 3:32:33
`(131‘ ngliiiéfiflfi$fi2kGiflifig
`H.-D.l Holtje (Dfisseldorf Germany)
`0. Hoshino (Tokyo, Japan)
`J. Jurenitsch (Wien, Austria)
`G. Lee (Erlangen, Germany)
`V. Linck Bassani (Porto Alegre, Brazil)
`T. Loftsson (Reykjavik, Iceland)
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`K. Mohr (Bonn. Germany)
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`E. Mutschler (Frankfurt, Germany)
`P. Nuhn (Halle, Germany)
`H.-H. Otto (Greifswald, Germany)
`C. Reppas (Athens, Greece)
`A. Sakr (Cincinnati, USA)
`P. C. Schmidt (Tiibingen, Germany)
`W. Schunack (Berlin, Germany)
`W. Siegmund (Greifswald, Germany)
`J. P. Surmann (Berlin, Germany)
`R. Vistelle (Reims, France)
`
`r
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`Govi-Verlag
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`Pharmazie 56 (2001) 12
`AQUESTIVE EXHIBIT 1127 Page 0002
`AQUESTIVE EXHIBIT 1127 Page 0002
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`ORIGINAL ARTICLES
`
`Department of Ophthalmology‘, National University Hospital, Faculty of Pharmacyz,
`National University Hospital, University of Iceland, Reykjavik, Iceland
`
`and Department of Anaesthesiology3,
`
`lntranasal administration of midazolam in a cyclodextrin based
`formulation: bioavailability and clinical evaluation in humans
`
`H. GUDMUNDSDOTTIRI, J. F. SIGURJONSDO‘ITIRZ, M. MASSONZ, O. FJALLDALa, E. STEFANSSONI and T. LOFTSSON2
`
`lntranasal administration of midazolam has been of particular interest because of the rapid and reliable onset of action,
`predictable effects, and avoidance of injections. The available intravenous formulation (Dormicum® IV solution from
`Hoffmann-La Roche) is however less than optimal for intranasal administration due to low midazolam concentration and
`acidity of the formulation (pH 3.0—3.3). In this study midazolam was formulated in aqueous sulfobutylether-[3~cyclodex-
`trin buffer solution. The nasal spray .was tested in 12 healthy volunteers and compared to intravenous midazolam in an
`open crossover trial. Clinical sedation effects, irritation, and serum drug levels were monitored. The absolute bioavailabil-
`ity of midazolam in the nasal formulation was determined to be 64 :l: 19 % (mean :l: standard deviation). The peak serum
`
`concentration from nasal application, 42 :: 11 ng ml”, was reached within 10—15 min following administration and clin-
`ical sedative effects were observed within 5 to 10 min and lasted for about 40 min. Intravenous administration gave
`clinical sedative effects within 3 to 4 min, which lasted for about 35 minutes. Mild to moderate, transient irritation of
`nasal and pharyngeal mucosa was reported. The nasal formulation approaches the intravenous form in speed of absorp-
`tion, serum c0ncentration and clinical sedation effect. No serious side effects were observed.
`
`ity of midazolam in the new midazolam nasal spray and
`to determine the clinical sedative effects in healthy volun-
`teers.
`
`2. Investigations and results
`
`Mean midazolam serum concentration curves following
`both modes of administration are shown in the Fig.
`All values shown are the mean values :l:
`the standard
`deviation of
`the mean. The maximum midazolam
`
`(range
`concentration was 42.1 :: 11.2 ng ml‘1
`plasma
`29~72 ng m1"1), 15.5 :l:7.9 min (range 5—30 min)
`fol-
`lowing intranasal administration. Area under the curve di-
`vided by the dose (in mg) of midazolam administered
`(AUC/dose) was calculated to be 1981 :l:487 ng ml"1
`min mg“1
`following intravenous
`administration
`and
`1209i279 ng ml“ min mg"1 following intranasal ad-
`ministration. The approximate 95% confidence interval
`was from 1705 to 2257 ng ml“1 min mg‘1 dose and from
`1052 to 1367 ng m1‘1 min mg"1 dose for the AL'C fol-
`lowing intravenous and intranasal midazolam, respectively.
`
`
`uuu«a
`
`1. Introduction
`
`Due to their well—defined anxiolytic properties, benzodi-
`azepines are among the most popular sedatives for use
`before surgery and anaesthesia. Midazolam, a short-acting,
`water—soluble benzodiazepine, has been demonstrated to
`be a safe and effective preanesthetic anxiolytic agent [1]
`and its clinical efficacy is well documented after intrave—
`nous [2, 3], intramuscular [4], intranasal [5—7], oral [8, 9]
`and rectal [10] administration.
`.
`The available p ental drug formulation (Dorrnicum® IV
`solution from H ffmann—La Roche) is however less than
`optimal for intranasal use due to the low concentration of
`midazolam as well as the acidic pH (pH 3.3) of the for-
`mulation [11]. Nasal
`irritation [12], discomfort within
`the throat area as well as bitter taste are common com—
`
`plains following the intranasal administration. The large
`volume needed and accordingly extended administration
`time add to the unpleasant side effects from the avail-
`able parenteral formulation when used for intranasal appli-
`cation.
`
`By formulating midazolam in a solution containing sulfo-
`butylether-B—cyclodextrin and hydroxypropyl methylcellu—
`lose, the solubility of midazolam (and therefore the mida-
`zolam concentration in the dosage form) was increased
`dramatically [13]. This enhanced solubility could be ob-
`tained at a higher pH (pH 4.3) than previously reported
`for the parenteral drug formulation used as intranasal mid-
`azolam dosage forms. Cyclodextrins and their derivatives
`have been extensively studied for their use as pharmaceu—
`tical excipients. Constructed of (it-1,4 linked glucose units,
`they form cone shaped cylinders with hydrophilic exterior
`surface and a hydrophobic inner cavity. This allows cyclo—
`dextrins to form inclusion complexes with a lipophilic
`moiety of the midazolam molecule, increasing the aqueous
`solubility of midazolam dramatically without affecting the
`drug’s pharmacological properties [13—15]. The addition
`of small amounts of water-soluble polymers, such as hy-
`droxypropyl methylcellulose,
`to the solution further in-
`creases the solubility of midazolam in the aqueous cyclo-
`dextrin solution [16, 17]. 'The main objectives of the
`present study were to determine the absolute bioavailabil-
`
`Pharmazie 56 (2001) 12
`
`Time (min)
`
`Fig: Serum concentration-time profiles following administration of mida-
`zolam intranasal (O) (0.06 mg/kg) and intravenous (I) (2 mg). Each
`point represents the mean :l: standard deviation
`
`963
`AQUESTIVE EXHIBIT 1127 Page 0003
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`AQUESTIVE EXHIBIT 1127 Page 0003 [I
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`s..E0.)UCO
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`ORIGINAL ARTICLES
`
`Table 1: Distribution of sedative scores after intravenous and intranasal midazolam administration (n = 12)
`Time in minutes after administration
`Sedation
`Contr.
`Admin.
`score
`—5
`
`
`15 20 25 30 35 65 55 60
`
` 10 2
`
`
`10
`
`
`
`
`
`
`IV—Values
`
`
`
`
`
`GUI-PWNH
`
`
`
`12
`12
`12
`
`
`IN—Values
`
`
`GUI-kWh.)—
`
`
`12
`
`* Comparison of distribution of sedation scores between control (5 min before adm.) and post—administration using Wilcoxon’s test (*P < 0.05)
`! Comparison of distribution of sedation scores between groups IV vs. IN using Mann-Whitney test (!P < 0.05, !!P < 0.01)
`
`This gave a mean intranasal midazolam bioavailability of
`64 :i:19%. Mean terminal half-life (tm) following intrave-
`nous midazolam administration was 107.8 :1: 30.9 min and
`128.8 i 54.0 min following intranasal midazolam admini—
`stration. The approximate 95% confidence interval was
`90 min to 125 min and 98 min to 159 min for the tug va—
`lues following intravenous and intranasal midazolam ad-
`ministration,
`respectively.
`In one half of the group of
`twelve participants the initial sedative effect was seen
`within 5—10 min, and for one additional participant within
`15 min, following intranasal drug administration. Maximal
`sedative effects were attained from 15—20 min and these
`continued until 55—60 min after administration. Five of
`the above mentioned participants showed initial sedative
`effect within 2—3 min following intravenous drug adminis-
`tration and approximate maximal sedative effects were at-
`tained from 3—4 min until 35—40 min after administration.
`The other members of the group, namely five participants,
`experienced minor or no sedative effects following either
`intranasal or intravenous drug administration. Comparison
`of distribution of sedative scores between control and post
`administration midazolam using Wilcoxson’s test, revealed
`statistically significant differences (p < 0.05) from base—
`line from 8 min through 50min post administration for
`
`the intranasal group. Similarly, there were statistically sig—
`nificant differences (p < 0.05) in sedation from baseline
`from 3 min through 40 min post administration in the in-
`travenous group. Comparison of difference of sedative ef-
`fects between the intranasal and intravenous groups using
`Mann-Whitney test, revealed statistically significant differ-
`ences (p < 0.05) from 3 to 4 min and from 40 to 50 min
`post administration (Table 1).
`No clinically significant symptoms of a midazolam pir—
`dose like respiratory depression or cardiovascular dep s-
`sion were seen in any of the volunteers. No volunteer
`complained of nausea or vomiting but approximately one
`half of the subjects reported mild to moderate discomfort
`and/or pain within either the nasal passage or throat area
`following intranasal midazolam—cyclodextrin administra—
`tion. Comparison of distribution of nose and throat dis-
`comfort scores during and after study-drug administration
`using Wilcoxson’s test, revealed (p < 0.05) significant dif-
`ferences the first 4min after administration in the nasal
`
`_
`
`passage and the first 15 min in the throat area respectively
`(Table 2). No clinically relevant changes in arterial oxygen
`saturation, heart rate and blood pressure and following
`both intravenous and intranasal midazolam administrations
`were demonstrated. In both groups, all subjects had recov-
`
`Table 2: Distribution of nose and throat discomfort scores after intranasal midazolam administration (n = 12)
`I___—_____—___—_______._.—_—_—.————————-——-——
`Discom.
`Contr.
`Admin.
`Time in minutes after administration
`
`score
`
`30
`25
`20
`15
`10
`8
`S
`4
`3
`1
`0
`—5
`__________________._____________._—_—-——————-—-———
`
`43
`
`NOSE —Yalues
`
`1
`l
`l
`2
`3
`4
`3
`3
`2
`3
`2
`3
`2
`2
`2
`3
`l
`1 2
`12
`l 2
`12
`12
`l2
`9
`9
`7
`7
`6
`6
`5
`0
`___________—____________.__.________———
`*
`*
`a:
`*
`*
`
`
`4 3
`
`THROAT —Values
`
`2
`6
`9
`7
`2
`1
`2
`2
`3
`7
`O
`12
`7
`7
`6
`5
`5
`1
`1
`3
`4
`12
`12 ‘
`12
`
`=1:
`:1:
`a:
`*
`*
`*
`>1:
`:1:
`
`
`5
`
`3
`2
`
`4
`2
`
`3
`4
`
`3
`4
`
`* Comparison of distribution of discomfort scores between control (5 min before adm.) and post-administration using Mlcoxon’s test (*P < 0.05)
`
`964
`
`Pharmazie 56 (2001) 12
`AQUESTIVE EXHIBIT 1127 Page 0004
`AQUESTIVE EXHIBIT 1127 Page 0004
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`W O
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`RIGINAL ARTICLES
`
`ered from sedation and were fully awake and alert within
`150—180 min of the initial drug administration.
`
`3. Discussion
`
`The nose is a unique route of drug delivery into the body.
`The nasal cavity is highly accessible to sprays and drops,
`there is a large surface area (approximately 160 cm2) [18]
`through which absorption can occur. Intranasal midazolam
`is absorbed through the highly vascularized nasal mucosa
`[19, 20] directly into the systemic circulation, thus bypassing
`first pass hepatic metabolism. This results in a faster peak
`plasma concentration and a higher bioavailability than can
`be achieved after oral or rectal administrations [21, 22].
`The intranasal route has been extensively described and
`the successful use of intranasal midazolam, although still
`unlicensed via this route, has been reported in children
`undergoing dental procedures [7], anaesthesia induction
`[5, 22—25], and minor surgery [9, 26]. In adult patients,
`intranasal midazolam has been used for the management
`of claustrophobia during magnetic resonance imaging
`[27], for endoscopic procedures [28] for dental surgery [6.
`29] and this administration looks promising for short-term
`management of seizures [30, 31].
`This study demonstrates that it is possible to achieve ef-
`fective intranasal delivery of midazolam using a drug de—
`livery system based on cyclodextrin complexation with a
`bioavailability of the midazolam—cyclodextrin-nasal spray
`of 64 i: 19%. In a previous study in six healthy volunteers
`the bioavailability of the nasal spray was determined to be
`73 :l: 7% [13]. There are some indications that the abso—
`lute bioavailability of midazolam from the nasal cavity is
`dose dependent,
`i.e.
`that
`the bioavailability increases
`somewhat with increasing close but this study was the first
`clinical trial for this nasal-spray formulation and therefore
`the dose was kept at a minimum (0.06 mg/kg). Compara-
`tive pharrnacokinetic studies in adults demonstrate that
`bioavailability after oral administration is from 44% to
`68% [32, 33] (depending on dose given) and a single re—
`port of pharmacokinetic data following buccal administra-
`tion of 5 mg midazolam in adults shows a bioavailability
`of 74.5% [34]. Another single report of pharrnacokinetic
`data following intranasal administration of midazolam
`(0.15 mg/kg body weight) in adults demonstrates that un-
`der optimal conditions absorption of midazolam via the
`nasal mucosa can be virtually complete, with a bioavail-
`ability of 83% [35] but more often a combined nasal/gas—
`trointestinal absorption occurs, following intranasal mida-
`zolam administration, due to the large volume used, with
`a bioavailability quoted between 50 and 57% [24, 36].
`This new, more concentrated (17 mg/ml) nasal spray for-
`mulation made it possible to obtain clinically sedative ef-
`fect in adult patients using only 200—300 ul (based on
`body weight) compared with 2—3 ml, using the conven-
`tional
`intravenous (5 mg/ml) solution [29, 36, 37]. The
`sedation levels in our study were evaluated under ideal
`circumstances with no adverse stimuli and the clinical ef—
`fect documented based on the individual sedation assessed
`
`by the participants. Approximately 10—15 min following
`administration of the nasal spray seven out of twelve parti-
`cipants demonstrated satisfactory sedation status where as
`the other participants experienced minor or no sedative
`effects throughout the study, so clearly the individual re—
`sponses to midazolam plasma concentration differ, accord—
`ing to our study. The same subgroup of participants had a
`clinical sedative effect from both intranasal and intrave-
`
`nous administration and the other subgroup found no se—
`
`Pharmazie 56 (2001) 12
`
`dative effect from every formulation, which indicates the
`individual difference in people’s response to midazolam.
`Additionally a relationship between plasma midazolam
`concentration and clinical effects could not been clearly
`established, following either intranasal or intravenous ad-
`ministration, but some researchers suggest
`that sedation
`may be associated with plasma midazolam concentrations
`greater than 30—100 ng/ml [38, 39].
`The administration time for this new nasal-spray-formula-
`tion was less than 1 min. The majority of the participants
`reported mild to moderate irritation within the nasal pas-
`sage and/or throat area following nasal—spray administra-
`tion. The irritation is most likely due to the bitterness of
`midazolam. Based on a preliminary double blind/rando-
`mised study six volunteers could not differentiate between
`saline and the vehicle administered intranasally by a Pfeif—
`fer, “unit dose” device. Evaluation of subjective irritation
`is always difficult but discomfort level in our study was
`scored mild to moderate that is not as severe as previously
`reported [9, 12, 40]. No other side effects were observed
`in the nose and local symptoms such as sneezing and
`coughing were not observed in this study.
`In conclusion, the pharrnacokinetic data presented in our
`study demonstrate that the midazolam-cyclodextrin nasal
`spray formulation approaches the intravenous form in
`speed of absorption and serum concentration. By formulat-
`ing midazolam in a solution containing sulfobutylether-[B-
`cyclodextrin and hydroxypropyl methylcellulose, the solu—
`bility is increased dramatically at a higher pH (pH 4.3)
`and this unique property, as well as the ease of administra-
`tion, offers
`significant advantages over currently used
`treatment modalities for sedation.
`
`4. Experimental
`4.1 Materials and methods
`
`Sulfobutylether—B-cyclodextrin was kindly donated by CyDex Inc. (USA),
`hydroxypropyl methylcellulose 4000 was obtained from Mecobenzon
`(Denmark) and midazolam from Sifa (Ireland). All other chemicals used
`were of pharmaceutical grade (European Pharmacopeia, 3rd Edition,
`1997). The midazolam nasal spray was formulated in a sulfobutylether-[S-
`cyclodextrin-hydroxypropyl methylcellulose aqueous solution. Midazolam
`base (1.7 g) was added to 100 m1 of an aqueous solution containing 14 g
`sulfobutylether-[S-cyclodextrin, 0.1 g hydroxypropyl methylcellulose, 0.02 g
`benzalkonium chloride, 0.1g ethylenediaminetetraacetic acid and 0.73 g
`phosphoric acid. The pH of the formulation was adjusted to pH 4.20—4.35
`with sodium hydroxide. The solution was heated in an autoclave at 121 °C
`for 40 min to promote the complexation [13, 16]. The resulting solution
`was then filtered through a 0.45 urn membrane and aseptically divided into
`amber crimp cap vials. Finally, the vials and their contents were sterilised
`in an autoclave at 121 °C for 20 min. The nasal spray was prepared at the
`facilities of Icelandic Pharmaceuticals (Iceland).
`
`4.2. Study protocol
`
`The protocol was an open crossover trial, approved by the local ethics
`committee of the National University Hospital and the State Committee on
`Pharmaceuticals in Iceland. Before enrolment, all volunteers gave written
`informed consent. Twelve healthy volunteers were chosen among 18 Cau-
`casian students who applied for participation, on the basis of normal liver
`and kidney function. as reflected in normal creatinine and bilirubin blood
`values and no history or signs of a cold within the two weeks prior to the
`first experimental day. They were prohibited from using any drugs with
`known metabolic interactions with midazolam such as tranquilizers or alco-
`hol 2 days prior to and during the study. The mean age of the volunteers
`was 25.8 years (range 19—37 years) and the mean weight was 73.0 kg
`(range 55—92 kg). Five female and seven male volunteers were included in
`this study. Volunteers reported to the study unit at 10:00 AM each study
`day after an 8—hour fasting period. They continued to fast until 2h after
`administration of the study drug. Electrocardiography and blood oxygena—
`tion monitors were affixed and an intravenous cannula inserted into a fore-
`arm vein for collection of blood samples. Baseline blood samples were
`obtained 5 min prior to administration of the study medication, according
`to protocol. The participants received either intravenous or intranasal appli-
`cation in the first part of the study and the other application was carried
`
`965
`AQUESTIVE EXHIBIT 1127 Page 0005
`AQUESTIVE EXHIBIT 1127 Page 000
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`54
`
`—
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`
`ORIGINAL ARTICLES
`
`Table 3: Rating scale for evaluation of discomfort in mucous
`membranes in nose and throat
`
`range and the 95% confidence interval were also presented. The SPSS
`statistical program was used to analyze the results.
`
`Score
`
`Discomfort level
`
`0
`1
`2
`3
`4
`
`No difference between nasal spray and saline
`Minor discomfort
`Some discomfort
`Major discomfort
`Burning pain
`
`Table 4: Rating scale for evaluation of sedative effect
`
`Score
`
`Behaviour and signs
`
`Classification
`
`1
`
`2
`
`3
`
`4
`
`5
`
`6
`
`Sleeping. No response to patting
`on the shoulder.
`
`Sleeping. No reponse to calling by
`name two or three times.
`Responds to patting on the shoulder.
`
`Eyes closed, dull reaction.
`Responds when addressed.
`
`Eyes open and closed by turns,
`dull reaction. Responds to verbal
`ti
`1
`.
`.
`s m“ “S
`Eyes open, dull reaction.
`Responds to verbal stimulus.
`
`(1,2) - Asleep
`
`(3) — Drowsy
`
`(4,5) — Sedated
`
`Normal reaction.
`
`(6) — Normal
`
`Irritable with body movement.
`7.8 — E 't d
`) me
`(
`Highly irritable with considerable
`body movement.
`
`out 7 days later. For intravenous administration the volunteers received
`2 mg Dormicum® (IV solution from Hoffmann-La Roche) via an injection
`into a peripheral vein in the contralateral arm. To guarantee a complete
`washout of midazolam between investigations a period of at least 7 days
`was maintained between the two forms of administration. For intranasal
`administration the volunteers received 0.06 mglkg (193—323 ul, based on
`body weight) dose of midazolam-cyclodextrin via a nasal spray, with half
`of the study drug instilled rapidly into one nostril, and the remainder into
`the other nostril over 1 min. The spray bottle device, “Unit dose" closed
`system, from Pfeiffer, delivered a fine aerosol and was held at an angle of
`approximately 45° to the vertical with the nozzle held at an angle of ap-
`proximately 5° to the sagittal plane, pointing slightly towards the nasal
`septum and introduced as far as possible into the nostrils without causing
`pain. There was some spillage of the midazolam dose in one subject. Since
`the amount spilled could not be quantified, this subject was omitted from
`the calculations for peak concentrafion (Cp max) and the time to reach peak
`level (tum). After administration of study medication (0 h) blood samples
`(5 ml) were collected from the intravenous catheter at 5, 10, 15, 20, 30,
`60, 120, 180, 240, and 360 min. Samples were centrifuged for 10 min, and
`serum harvested and frozen at —20 °C until analyzed for midazolam con-
`centration. At each sampling point the volunteers were questioned regard-
`ing nasal mucosa irritation (Table 3) and degree of sedation (Table 4).
`Vital signs,
`including heart rate, blood pressure, oxygen saturation and
`respiratory rate were monitored continuously and registered at 5 min inter-
`vals during 2 h after drug administration. Serum samples were assayed for
`midazolam by reverse-phase HPLC at
`the Medicinsk Laboratorium AIS
`(Copenhagen, Denmark). Standard methods were used to calculate the
`pharmacokinetic parameters. The serum level from intravenous and intrana—
`sal application was compared for each participant. The maximum midazo-
`lam serum concentration (Cp max) and the time to reach it (tum) were ob-
`tained from the serum concentration profiles. The area-under—curve (AUC)
`was calculated using the linear trapezoidal method, the absolute bioavail—
`ability (F) was calculated as the percent of AUCmMsa] over AUCmmcnous
`ratio within the 0—360 min time period.
`
`4.3. Statistical analysis
`Results were analyzed using the Student’s t-test (paired—samples t-test and
`independent-sample t—test) and the non-parametric tests Wilcoxon’s t-test (2
`related samples test) and-Whitney U-test (2 independent samples test). The
`level of significance was set at p < 0.05. The mean, standard deviation,
`
`Acknowledgements: The authors would like to thank Professor Magnus
`Johannsson for his invaluable assistance. This study was supported by The
`Icelandic Research Fund for Graduate Students and the University of Ice-
`land Research Fund.
`
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`
`Received June 8, 2001
`Accepted July 4, 2001
`
`Thorsteinn Loftsson
`Faculty of Pharmacy
`University of Iceland
`PO. Box 7210
`127 Reykjavik
`Iceland
`thorstlo@hi.is
`
`Pharmazie 56 (2001) 12
`AQUESTIVE EXHIBIT 1127 Page 0006
`AQUESTIVE EXHIBIT 1127 Page 0006
`
`