A SPECIAL ARTICLE
`
`Intestinal Performance of
`Two Mesalamine Formulations
`in Patients with Active Ulcerative
`Colitis as Assessed by Gamma
`Scintigraphy
`
`by Atul Sinha, Denise J. Ball, Alyson L. Connor, Jeremy Nightingale, Ian R. Wilding*
`
`Treatment of inflammatory bowel disease (IBD) with mesalamine requires that suit i-
`dent drug is delivered to the site of active disease. The technique of gamma scintigra-
`phy has been used to visualize the intestinal transit and drug delivery of Pentasa® (con-
`trolled-release) and Asacol® (delayed-release) in patients with active ulcerative colitis.
`Seven patients received Pentasa® (250 mg). Release of Pentasa® microspheres from the
`capsules was rapid resulting in dispersion throughout the small intestine. Six patients
`received Asacol® (400 mg). Disintegration of the Asacol® tablet occurred in the termi-
`nal ileum in five patients. In one patient the tablet was defecated intact due to rapid
`small intestinal transit. Delivery of mesalamine from Asacol® requires sufficient resi-
`dence time in the terminal ileum (pH 7.5) to allow tablet disintegration to occur in the
`last segment of the small intestine. Delivery of Pentasa® is less affected by transit time
`and, therefore, results in reliable drug delivery to the small and large intestine.
`
`INTRODUCTION
`
`Inflammatory bowel disease (IBD) is a collective term
`
`for the two conditions: Crohn's disease and ulcerative
`colitis. Crohn's disease is a transmural inflammatory
`disease that can affect the small intestine only (30%),
`the colon only (25%), or both the small intestine and the
`
`Denise J Ball Ph.D., Ian R Wilding Ph.D., Alyson L
`Connor Ph.D., Pharmaceutical Profiles Ltd., Rudding-
`ton, Nottingham, UK. Atul Sinha MRCP and Jeremy
`Nightingale M.D., FRCP, Leicester Royal Infirmary,
`Infirmary Close, Leicester, UK.
`
`*Correspondence: iwilding@pharmprofiles.co.uk
`
`56 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`colon at the same time (40%). Ulcerative colitis is an
`inflammatory disease of the colonic mucosa with no
`known cause, which affects in all cases the rectum and
`possibly more proximal regions of the colon.
`Mesalamine (5-aminosalicylic acid [5ASA]) is an
`anti-inflammatory agent and is an established treatment
`for IBD. The precise mechanism of action of
`mesalamine is not known, but it is generally agreed that
`its main effect is exerted topically at the site of inflam-
`matory lesions. Maintaining high intra-luminal drug
`concentrations at the site of the lesions has been shown
`to be clinically important (1). Oral formulations cur-
`rently on the market are designed to avoid significant
`(continued on page 58)
`
`SALIXN00012354
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 1
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`(continued from page 56)
`
`systemic exposure, either by controlled-release (e.g.
`Pentasa®), delayed-release (e.g. Asacol®) or the use of
`pro-drugs (olsalazine, balsalazide).
`The U.S. marketed form of Pentasa® consists of a
`hard gelatin capsule containing ethylcellulose coated
`microspheres, which arc released following disintegra-
`tion of the capsule in the stomach. The individual
`microspheres act as discrete controlled-release units,
`designed to release mesalamine via d i ffusion of the
`drug through the semi-permeable ethylcellulose mem-
`brane. This allows mesalamine to be released at a vir-
`tually constant rate, and in predictable amounts to both
`the small and large intestine. In comparison, Asacol®
`tablets are enteric coated with an acrylic-based resin
`(Eudragit-S) which dissolves rapidly at relatively high
`values of pH 7 and above (3) and, therefore, are
`designed to deliver mesalamine specifically to the ter-
`minal ileum and colon.
`Colonic targeting utilizing enteric coating was
`developed on the understanding that pH increased pro-
`gressively from the stomach (pH 2-3) and small intes-
`tine (pH 6.5-7) to the colon (pH 7-8) (4). However,
`subsequent pH telemetric technology demonstrated that
`the highest pH levels (pH 7-8) in the gastrointestinal
`tract are found in the terminal ileum (5). In addition,
`bacterial fermentation of polysaccharides results in a
`lowering of pH (6.4 ± 0.6) in the right colon. Falling-
`borg et al, 1989 (6) reported that in 25% of healthy vol-
`unteers the pH of the gastrointestinal tract never reaches
`pH 7. Therefore, it has been suggested that change in
`lumina pH is not a reliable mechanism to deliver drug
`specifically to the colon (7,8). Variability in intraluminal
`pH has also been reported in patients with ulcerative
`colitis. These radiotelemetry studies have shown that
`right colon pH ranged from 2.3 to 7.3, and was lower in
`a number of patients with active disease (6,9,10,11).
`Gamma scintigraphy has been described as an ele-
`gant technique for the investigation of the locality of in
`vivo release (12), and has become the method of choice
`for investigating the fate of pharmaceutical dosage
`[forms] in the body (13). Phannacokinetic evaluation
`alone for locally acting oral products does not provide
`sufficient information about the behavior of the formu-
`lation in the gastrointestinal tract. The ability to visual-
`ize the drug delivery process in a non-invasive manner
`fills a significant void in current understanding.
`
`58 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`A scintigraphic study in healthy volunteers has
`previously been performed to compare the location of
`mesalamine delivery from Asacol® and Pentasa® in
`the gastrointestinal tract under fed and fasted condi-
`tions (14). The site of disintegration of the Asacol®
`preparation in the gastrointestinal tract was found to be
`highly variable, with the location of complete break up
`of the tablet ranging from the small intestine to the
`splenic flexure. However, the Pentasa® capsule per-
`formed more consistently with dispersion of the
`microspheres throughout the entire gastrointestinal
`tract from small intestine through to distal colon. The
`aim of the current study was therefore to compare the
`intestinal performance of two mesalamine formula-
`tions (Asacol® and Pentasa®) in patients with active
`ulcerative colitis.
`
`MATERIAL AND METHODS
`
`Formulation Radiolabelling
`The Asacol® tablets (400 mg mesalamine) were radio-
`labelled utilizing a previously validated approach which
`consisted of inserting approximately 5 mg indium-111
`("'In) radiolabelled (1MBq) Amberlite 1RP69A ion
`exchange resin into a micro-hole that had been drilled
`on the edge of each tablet (14). The micro-holes were
`sealed with cyanoacrylate. In vitro dissolution testing
`was performed to verify that the drill and fill procedure
`did not adversely affect the performance of the tablets.
`The Pentasa® capsules (250 mg mesalamine) were
`radiolabelled by replacing a small quantity of the cap-
`sule fill weight (circa 5% w/w) with "'In radiolabelled
`(1MBq) ethylcellulose coated non-pareil pellets. The
`surrogate radiolabelled pellets were equivalent in size
`and surface coating to the marketed Pentasa® micros-
`pheres.
`
`STUDY DESIGN
`The Leicestershire Royal Infirmary Ethics Committee
`approved the study and administration of radioactivity
`was authorized by the UK Department of Health, Lon-
`don. Each patient provided written informed consent
`before taking part in the study. Thirteen patients with
`
`SALIXN00012355
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 2
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`Table 1
`Details of patients who participated in the study
`
`No.
`
`Sex
`
`Disease Location
`
`Year
`Diagnosed
`
`Radiolabelled
`Regimen
`
`Concomitant
`Medication
`
`Duration
`Between
`Recruitment
`and Dosing
`
`01
`02
`03
`
`04
`
`05
`
`06
`
`07
`
`08
`
`09
`
`10
`
`11
`12
`
`13
`
`M
`
`Left sided
`Left sided
`Proctitis
`
`Proctitis
`
`Extensive
`
`Left sided
`
`Extensive
`
`Extensive
`
`Extensive
`
`Extensive
`
`Extensive
`Extensive
`
`From rectum to descending colon
`Rectum and sigmoid colon
`Severe at rectum to minimal activity
`at sigmoid and descending colon
`Rectum
`
`Whole colon, especially the caecum
`and ascending colon
`Rectum, sigmoid colon and upper
`descending colon
`From sigmoid colon to transverse
`colon
`Whole colon
`
`From rectum to hepatic flexure,
`but severe to transverse colon
`From rectum to hepatic flexure
`
`From rectum to hepatic flexure
`From rectum to transverse colon
`
`Extensive
`
`From rectum to hepatic flexure
`
`2001
`1999
`
`2001
`1995
`
`1993
`
`2001
`
`2001
`1999
`
`2001
`1974
`
`1960
`2001
`
`1989
`
`Pentasa
`Pentasa
`
`Asacol
`Pentasa
`
`Asacol
`
`Asacol
`
`Asacol
`Pentasa
`
`Asacol
`Pentasa
`
`Pentasa
`Pentasa
`
`Asacol
`
`Asacol 400mg
`Asacol 400mg
`
`Pentasa 2g
`Asacol 1.2g
`Prednisolone 40mg
`
`Pentasa 3g
`
`Pentasa 3g
`
`Pentasa 3g
`Asacol 2.4g
`Prednisolone 40mg
`
`Pentasa 4g
`Asacol 2.4g
`Prednisolone 40mg
`Sulphasalazine 1.5g
`Asacol 2.4g
`Prednisolone 40mg
`Sulphasalazine 4g
`Prednisolone 40mg
`
`8 days
`8 days
`
`5 days
`3 days
`
`3 days
`
`3 days
`
`3 days
`3 days
`
`5 days
`3 days
`
`5 days
`3 days
`
`3 days
`
`active ulcerative colitis participated in the investiga-
`tion (Table 1).
`The study was a single-dose, open-label, random-
`ized, parallel-group study. Thirteen patients, ten male
`and three female, were randomized at baseline to
`receive a single oral dose of either radiolabelled
`Asacol® (400 mg mesalamine) or Pentasa® (250 mg
`mesalamine) as part of an ongoing treatment regimen
`(Table 1). Six patients were administered radiolabelled
`Asacol® and seven patients were administered radiola-
`belled Pentasa®. The maintenance treatment for all thir-
`teen patients was either mesalamine (dose range 1.2g to
`2.4 g) or sulphasalazine (dose range 1.5 g to 4 g).
`Patients who were randomized to receive radiolabelled
`Asacol® as the test treatment were administered Pen-
`tasa® as the maintenance medication and vice versa.
`
`This was to ensure that the radiolabelled dosage form
`could be distinguished from the maintenance medica-
`tion when recovered from feaces. Five of the thirteen
`patients also received 40 mg prednisolone, which was
`prescribed by the recruiting physician based on the
`symptomatic profile on entry into the study. All patients
`were dosed with the experimental agent between three
`to eight days after recruitment to ensure evaluation of
`product performance during a period of disease relapse.
`The patients arrived at the Clinical Unit at approx-
`imately 07:00. For each patient an anatomical marker
`containing 0.05 MBq "In was taped to the skin anteri-
`orly where the mid-clavicular line met the right costal
`margin. This was done so that the marker lay in
`approximately the same transverse plane as the
`pylorus. For patients receiving radiolabelled Pentasa®,
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003 59
`
`SALIXN00012356
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 3
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`an equivalent posterior marker was taped to the skin,
`directly in line with the anterior marker. This was to
`permit the assessment of transit of the pellets from
`both the anterior and posterior aspects. Patients were
`administered either a single Asacol® tablet or
`Pentasa® capsule radiolabelled with 1MBq "'In at
`approximately 08:00. Each preparation was adminis-
`tered orally with 200 mL water. Patients were fasted
`from midnight on the day prior to dosing and remained
`fasted until four hours post-dose.
`Scintigraphic images (50-second duration) were
`recorded using a gamma camera (General Electric
`Maxicamera) with a large field of view and fitted with
`a medium energy parallel hole collimator. Single iso-
`tope scanning was carried out with the gamma camera.
`Images were recorded at approximately 15-minute
`intervals until eight hours post-dose, 30-minute inter-
`vals until twelve hours post-dose, hourly until 16 hours
`post-dose, and then at 24 and 36 hours post-dose. The
`image at 36 hours was not acquired if all radioactivity
`had been defecated by this time.
`
`Analysis of Recovered Material
`From the time of dosing, patients were instructed to
`collect all fecal material until all remaining radiola-
`belled preparation had been recovered or for three days
`post-dose, whichever occurred sooner. Any micros-
`pheres or significant tablet fragments present in fecal
`samples were removed and stored at approximately
`—80°C in labeled containers. The recovered micros-
`pheres and fragments were subsequently analyzed for
`mesalamine using a validated high performance liquid
`chromatography with fluorescence detection method.
`This allowed an approximate calculation of the propor-
`tion of mesalamine that had not been released from the
`preparations and was therefore not available to act on
`the intestinal mucosa.
`
`Location of Radioactive Tracer
`The location of the radioactive tracer within the gas-
`trointestinal tract was determined by viewing the
`images on a computer screen. For both formulations
`transit of the radiolabelled tracer was assessed in rela-
`tion to the external radioactive marker.
`
`60 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`For Pentasa®, quantification of the surrogate radi-
`olabelled microsphere distribution was achieved by
`measuring the number of radioactive counts recorded
`within the stomach and colon regions in the scinti-
`graphic images (14). Each value was corrected for
`background radioactivity. The geometric mean of cor-
`responding anterior and posterior counts was then cal-
`culated, corrected for radioactive decay and expressed
`as a percentage of the dose. The transit profile for the
`Pentasa® microspheres was characterized by the half-
`lives (T50%) for gastric emptying, for colon arrival and
`for small intestine transit (the time interval between
`T50% values for gastric emptying and colon arrival).
`For Asacol® a qualitative assessment of transit
`through the gastrointestinal tract was performed. For
`gastric emptying the recorded time of movement of
`the tablet from the stomach to the small intestine was
`taken as the mid-time between the images about the
`transition. The times for colon arrival and for initial
`and complete disintegration were determined in the
`same manner. Small intestinal transit time was calcu-
`lated as the time interval between gastric emptying
`and colon arrival.
`
`RESULTS
`Thirteen patients with active colitis were studied. Two
`patients were diagnosed with proctitis, three with left-
`sided colitis and eight with extensive colitis. The
`demographic characteristics of the two groups are
`detailed in Table 1. There were no significant differ-
`ences in the baseline characteristics of the two groups.
`
`Gastrointestinal Transit
`Gastrointestinal transit data for Pentasa® and Asacol®
`are provided in Tables 2 and 3, respectively. Gastric
`emptying (T50%) of the Pentasa® microspheres
`occurred on average at 0.61 ± 0.33 hours post-dose
`(n = 7). Gastric emptying of the Asacol® tablet
`occurred on average at 0.42 ± 0.28 hours post-dose (n
`= 6). For Pentasa® the mean small intestinal transit
`time (T50%) was 5.68 ± 2.40 hours (n = 7). For
`Asacol® the mean small intestinal transit time was 7.10
`
`(continued on page 62)
`
`SALIXN00012357
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 4
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`A SPECIAL ARTIC
`
`continued from page 60)
`
`Table 2
`Transit Profile (T500 of 250 mg mesalamine microspheres (Pentasa®
`radiolabelled with 1111n in patients with active ulcerative colitis
`T50% Small Intestinal
`Transit (hours)
`5.42
`9.85
`4.38
`4.10
`3.74
`4.07
`8.22
`5.68
`2.40
`4.38
`
`Subject Number
`01
`02
`04
`08
`10
`11
`12
`Mean
`SD
`Median
`n
`
`T50% Gastric Emptying
`(hours post-dose)
`1.08
`0.28
`1.01
`0.46
`0.26
`0.61
`0.56
`0.61
`0.33
`0.56
`
`T50% Colon Arrival
`(hours post-dose)
`6.50
`10.13
`5.39
`4.56
`4.00
`4.68
`8.78
`6.29
`2.33
`5.39
`
`Formulation
`Disintegration
`As would be expected for a
`gelatin capsule, disintegra-
`tion of the Pentasa® capsule
`and release of the micros-
`pheres occurred rapidly in
`all seven patients. The cap-
`sule disintegrated in the
`stomach in six patients and
`in the proximal small
`intestine in one subject.
`Following disintegration
`the released microspheres
`spread throughout the small
`intestine extending into the
`colon (Table 4).
`Disintegration data
`for the Asacol® tablet are provided in Table 5. Initial
`disintegration of the Asacol® tablet occurred in the ter-
`minal ileum in four patients and in the ascending colon
`in one patient. Complete tablet disintegration was
`observed in three of these five patients and occurred in
`the terminal ileum, ascending colon and transverse
`colon, respectively. In the remaining two patients com-
`plete disintegration of Asacol® was not observed; for
`patient 03 the tablet
`core was still visible
`in the final scinti-
`graphic image and
`for patient 07 the
`tablet core was
`located in the trans-
`verse colon at 24
`hours post-dose and
`was not present in
`the final image
`acquired at 36 hours
`post-dose. Following
`tablet disintegration,
`the tablet remnants
`dispersed throughout
`the colon (Table 6).
`In one patient (09),
`no disintegration was
`observed and the
`
`± 2.97 hours (n = 5). Colon arrival (T50%) for the Pen-
`tasa® microspheres occurred on average at 6.29 ± 2.33
`hours post-dose (n = 7). Colon arrival of the Asacol®
`tablet core occurred on average at 7.50 ± 2.77 hours
`post-dose (n = 5). For one patient, small intestinal tran-
`sit and colon arrival of the Asacol® tablet core could
`not be determined because complete disintegration
`occurred in the terminal ileum.
`
`Table 3
`Transit Profile of 400 mg mesalamine tablets (Asacol®) radiolabelled with
`"'In in patients with active ulcerative colitis
`
`Small Intestinal
`Transit (hours)
`9.90
`8.02
`
`Total Transit
`Colon Arrival
`(hours post-dose) Time (hours)
`10.03
`8.18
`
`Gastric Emptying (cid:9)
`Subject
`(hours post-dose) (cid:9)
`Number
`0.13
`03
`0.16
`05
`29.32
`0.56
`06
`29.47
`10.10
`9.69
`0.41
`07
`19.52
`4.51
`4.13
`0.38
`09
`22.93
`4.66
`3.78
`0.88
`13
`25.31
`7.50
`7.10
`0.42
`Mean
`4.92
`2.77
`2.97
`0.28
`SD
`26.13
`8.18
`8.02
`0.40
`Median
`5
`5
`n
`4
`6
`- Complete disintegration occurred in the terminal ileum, therefore, colon arrival and small intestinal transit
`could not be determined
`# No tablet fragments were recovered, therefore, total transit time could not be calculated
`
`62 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`SALIXN00012358
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 5
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`A SPECIAL ARTICLE
`
`Table 4
`Location of 250 mg mesalamine microspheres (Pentasa®) radiolabelled
`with "'in in patients with active ulcerative colitis
`
`Time (hours
`post-dose)
`
`Subject Number
`
`01
`
`02
`
`04
`
`08
`
`10
`
`11
`
`12
`
`S
`S/SI
`S/SI
`S/SI
`S/SI
`SI
`SI-AC
`AC
`AC-TC
`AC-TC
`
`S
`S/SI
`S/SI
`S/SI
`S/SI
`SI
`SI-AC
`SI-AC
`AC-HF
`AC-TC
`AG-SF
`AG-SF
`AC-DC
`
`S
`S
`0
`SI
`S
`S/SI
`0.5
`S
`SI
`S/SI
`SI
`1
`SI
`SI
`S/SI
`SI
`1.5
`SI
`SI
`S/SI
`2
`SI
`SI
`SI
`SI
`3
`SI
`SI-AC
`SI-AC
`SI-AC
`4
`SI
`AC
`AC
`SI-AC
`SI
`6
`AC-DC
`AC
`SI-AC
`SI
`8
`AC-DC
`AC
`AC
`AC
`10
`AC-DC
`AC
`AC
`AC
`12
`AC-DC
`AC-TC
`AG-SF
`AC
`16
`NR
`AC-TC
`AG-SF
`AC
`24
`NR
`AC-DC
`AC-SF
`AC
`36
`* = No radioactivity remaining. S = stomach. SI = small intestine. AC = ascending colon. HF = hepatic
`flexure. IC = transverse colon. SF = splenic flexure. DC = descending colon. NR = not recorded.
`
`S
`SI
`SI
`SI
`SI-AC
`AC-DC
`AC-DC
`
`Table 5
`Disintegration profile of 400 mg mesalamine tablets (Asacol®) radiolabelled
`with "'In in patients with active ulcerative colitis
`
`Initial Disintegration
`(hours post-dose)
`7.15
`7.93
`5.48
`10.10
`
`Site
`ICJ
`DSB
`DSB
`ICJ/ACt
`
`DSB
`
`Complete Disintegration
`(hours post-dose)
`
`A
`15.38
`6.36
`
`Site
`
`A
`TC
`DSB
`
`AC/HF
`
`Subject
`Number
`03
`05
`06
`07
`09
`20.07
`4.15
`13
`13.94
`6.96
`Mean
`6.97
`2.29
`SD
`15.38
`7.15
`Median
`3
`5
`n
`^Complete tablet disintegration not observed; tablet core located in splenic flexure in final scintigraphic
`image.
`*Initial and complete tablet disintegration not observed; tablet defecated intact.
`fThe intact tablet was located in the ICJ in the image immediately prior to initial disintegration. In the next
`image, the tablet core was located in the AC and initial tablet disintegration had occurred.
`§Complete tablet disintegration not observed; tablet core present in transverse colon at 24 hours post-
`dose. No tablet core remaining in final scintigraphic image (36 hours post-dose).
`DSB = distal small bowel. ICJ = ileo-caecal junction. AC = ascending colon. HF = hepatic flexure.
`TC = transverse colon.
`
`tablet was defecated essentially
`intact.
`A sequence of scintigraphic
`images showing key stages of the
`gastrointestinal transit for Pen-
`tasa® and Asacol® are shown in
`Figures 1 and 2, respectively.
`
`Fecal Mesalamine Recovery
`Recovery of mesalamine from
`fecal samples indicates that the
`majority of both the Asacol® and
`Pentasa® formulation was deliv-
`ered to the patients providing dis-
`integration of the formulation had
`occurred (Table 7).
`
`DISCUSSION
`There are very limited previous
`studies in which gastrointestinal
`transit behavior of pharmaceuti-
`cal products has been investigated
`in patients during the active phase
`of ulcerative colitis (15,16). This
`can be partly explained by an
`understandable unwillingness for
`such patients to be involved in a
`clinical investigation when the
`disease is in its active form. As a
`consequence, this is a bench-
`marking investigation comparing
`the gastrointestinal transit profiles
`for multiparticulate (Pentasa®)
`and monolithic (Asacol®) dosage
`forms administered in the fasted
`state to patients with active ulcer-
`ative colitis.
`Gastric emptying of both for-
`mulations was complete within
`two hours of dosing for the
`majority of patients. These data
`correlate well with transit times
`for healthy subjects, indicating
`that the major factor influencing
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`63
`
`SALIXN00012359
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 6
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`Table 6
`Location of 400 mg mesalamine tablets (Asacol®) radiolabelled with
`"'In in patients with active ulcerative colitis
`
`Time (hours
`post-dose)
`
`Subject Number
`7
`
`13
`
`0
`0.5
`1
`1.5
`
`S
`S
`S
`S (cid:9)
`S (cid:9)
`SI
`SI
`SI (cid:9)
`SI (cid:9)
`SI
`SI
`SI
`SI
`SI
`SI (cid:9)
`SI (cid:9)
`SI
`SI
`SI
`SI (cid:9)
`SI (cid:9)
`SI
`SI
`SI (cid:9)
`SI
`SI
`SI
`SI (cid:9)
`SI
`SI
`AC
`SI
`SI (cid:9)
`SI (cid:9)
`SI (cid:9)
`SI
`AC
`SI
`SI
`SI (cid:9)
`SI
`AC
`AC
`SI
`SI (cid:9)
`SI (cid:9)
`AC
`AC
`SI
`SI
`SI (cid:9)
`SI (cid:9)
`AC
`AC
`AC
`AC
`AC (cid:9)
`SI—AC (cid:9)
`10
`AC—TC
`AC
`AC
`AC
`AC—HF AC—SF
`12
`HF—SF AC—HF SF AC—SF
`AC—HF HF—SF
`16
`HF-SF
`AC—SF
`HF—SF
`24 AC-SF (cid:9)
`HF-SF
`AC-SF (cid:9)
`HF—SC
`AC SF
`36
`= initial tablet disintegration occurred. S = Stomach. SI = Small intestine. AC = Ascending
`colon. HF = Hepatic flexure. TC = Transverse colon. SF = Splenic flexure. DC = Descending
`colon. SC = Sigmoid colon. * = No radioactivity remaining.
`
`Owing to the small number of subjects
`studied, it was not possible to achieve a
`completely balanced randomization. Of
`the five subjects concomitantly receiving
`40 mg prednisolone, four were randomized
`to receive Pentasa®. However, there is no
`evidence to suggest that prednisolone has a
`prokinetic effect on gastrointestinal transit
`and, therefore, it is unlikely that the imbal-
`ance has had any impact on the transit data
`reported. In addition, in those patients
`dosed with prednisolone, there remains
`variability in the transit values at the
`extreme(s) of the range.
`Slowing of small intestinal transit in
`ulcerative colitis patients has been reported
`previously (15). The transit of a radiola-
`belled meal through the gastrointestinal
`tract and stool output were measured in 62
`patients in varying disease states and 20
`healthy subjects. Small intestinal transit
`was slower than normal in all patient
`groups. Patients with active colitis also had
`proximal colonic stasis, whereas transit
`through the sigmoid colon/rectum was
`rapid. Overall, total gastrointestinal transit time of the
`ulcerative colitis patients was not reduced. The para-
`doxical slowing of transit in the small intestine and
`proximal colon is consistent with the constipation often
`prominent in patients with active disease. Davis et al
`1991(18) reported that active ulcerative colitis does not
`lead to an accelerated total transit per se of non-disin-
`tegrating tablets of 5mm diameter.
`Pentasa® is designed to release drug throughout
`the gastrointestinal tract. Following disintegration of
`the capsule, the released microspheres dispersed fully
`within the small intestine and colon in the majority of
`patients (Table 5). This is in good agreement with pre-
`vious studies on both tablet (19,20) and capsule (14)
`formulations of Pentasa®. The pharmacokinetic com-
`ponent of these previous studies confirmed that drug
`release commenced when the microspheres were
`located in the small intestine and continued into the
`colon (19,20). Layer et al, 1995 (21) measured the
`
`gastric emptying in fasted active ulcerative colitis
`patients is the timing of dosing vis-à-vis the migrating
`myoelectric complex (MMC). The length of the MMC
`varies among individuals, but on average it cycles
`every two hours. If a dosage form is administered just
`before the phase III ("housekeeper") contractions
`begin, it will be emptied from the stomach very
`quickly. Alternatively, if a dosage form is administered
`just after the phase III contractions, it will not be emp-
`tied from the stomach for a further two hours.
`The small intestinal transit (T50%) of the Pentasa®
`microspheres in ulcerative colitis patients was similar
`to that reported in healthy subjects (14) suggesting that
`transit of the microspheres to the colon is less affected
`by disease state (5.7 hours [patients] vs. 5.9 hours
`[healthy subjects]). However, the small intestinal tran-
`sit time for Asacol® (7.1 hours) was slower than that
`observed in healthy subjects (5.6 hours) and is double
`the traditional average small intestinal transit time for
`pharmaceutical products in healthy subjects of 3 to 4
`hours (17).
`
`64 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`(continued on page 66)
`
`SALIXN00012360
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 7
`
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`(cid:9)
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`continued from page 64)
`
`both the small intestine and
`the colon.
`In contrast, Asacol® is
`designed to target drug deliv-
`ery to the terminal ileum and
`colon by virtue of the pH-
`dependent release mechanism.
`Initial tablet disintegration
`occurred on average at 7.0
`hours post-dose and occurred
`in the terminal ileum or
`beyond in all subjects. On
`average, the time of initial dis-
`integration was comparable to
`the results obtained in the ear-
`lier healthy volunteer study, in
`which disintegration occurred
`on average at 6.8 hours post-
`dose (14). However, in the pre-
`vious volunteer study, it was
`shown that in three of the
`seven subjects dosed, initial
`disintegration was delayed
`until after colon arrival (14).
`The data presented in this cur-
`rent study suggest that the
`slower small intestinal transit
`times observed in ulcerative
`colitis patients result in deliv-
`ery of mesalamine to the ter-
`minal ileum and beyond with
`less variability than was
`observed in healthy volun-
`teers. In the terminal ileum of
`ulcerative colitis patients, pH
`levels of 7.2 (19) and 8.2 (10)
`have been reported. Prolonged
`residence of Asacol® in the
`small intestine for the majority
`of patients could well provide
`sufficient time for dissolution
`of the enteric coating and,
`therefore, facilitate release of mesalamine to the colon.
`However, in one patient (09), Asacol® disintegration
`was not observed and the tablet passed through the gas-
`trointestinal tract intact. Interestingly, transit of this
`
`1.10 hours post-dose
`
`4,38 hours post-dose
`
`7.37 hours post-dose
`
`0.02 hours post-dose
`
`4.05 hours post-dose
`
`5.88 hours post-dose
`
`Figure 1. Gastrointestinal transit of 250 mg mesalamine microspheres (Pentasa®
`radiolabelled with "'In in a patient with active ulcerative colitis.
`
`concentrations of released drug in the small intestine
`following administration of Pentasa® microspheres to
`healthy subjects. The results confirmed that high con-
`centrations of released mesalamine were available in
`
`66 (cid:9)
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003
`
`SALIXN00012361
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 8
`
`

`
`!re
`
`Intestinal Performance of Two Mesalamine Formulations
`
`A SPECIAL ARTICLE
`
`tablet through the small intes-
`tine and colon was rapid in this
`subject which supports the
`results of earlier studies sug-
`gesting that Asacol® delivery
`can be unpredictable if small
`intestine residence time is not
`extended (14). There have been
`previous reports of intact
`Asacol® tablets in the stools of
`some patients (22) and this sug-
`gests that only in patients with
`significant slowing of small
`intestine transit can Asacol® be
`expected to effectively deliver
`drug to the colon. As seen in
`this study, rapid small intestinal
`transit may result in defecation
`of the intact tablet, whilst
`healthy volunteer studies have
`shown that "normal" small
`intestinal transit times can
`result in the tablet being
`located in the colon prior to the
`start of disintegration and
`hence result in reduced oppor-
`tunity for the delivery of the
`medication to the target region.
`Analysis of recovered tab-
`lets and microspheres from the
`patients suggests that the major-
`ity of the drug is delivered to the
`gastrointestinal tract. In the
`majority of patients less than
`4% of the delivered dose of
`mesalamine was recovered in the
`feces. In one patient (04), who
`received Pentasa®, 12% of the
`dose was recovered. However, it
`should be noted that one sample
`(3.55 hours post-dose) was
`recovered before colon arrival of
`the radiolabelled microspheres had occurred. A funda-
`mental part of the experimental design was the co-admin-
`istration of maintenance medication to all patients with
`active ulcerative colitis. This medication was chosen such
`
`0.02 hours post-dose
`
`4.88 hours post-dose
`
`10.97 hours post-dose
`
`1.05 hours post-dose
`
`12A13 hours post-dose
`
`Figure 2. Gastrointestinal transit of 400 mg mesalamine tablet (Asacolo) radiola-
`belled with "'In in a patient with active ulcerative colitis.
`
`that the experimental formulation could be identified as
`microspheres or tablet on recovery. The recovery of free
`mesalamine before colon arrival of the radiolabelled
`dosage form suggests that fragments of the concomitant
`
`PRACTICAL GASTROENTEROLOGY • OCTOBER 2003 67
`
`SALIXN00012362
`
`Dr. Falk Ex. 2031
`GeneriCo v. Dr. Falk IPR2016-00297
`Page 9
`
`

`
`Intestinal Performance of Two Mesalamine Formulations
`
`Table 7
`Determination of mesalamine in excreted microspheres/tablet fragments
`
`Subject
`Number
`
`01
`
`04
`
`08
`
`10
`
`11
`
`12
`
`06
`
`07
`
`09
`
`13
`
`Radiolabelled
`Regimen
`
`Pentasa
`
`Pentasa
`
`Pentasa
`
`Pentasa
`
`Pentasa
`
`Pentasa
`
`Asacol
`
`Asacol
`
`Asacol
`
`Asacol
`
`Time
`hours post-dose
`7.93
`11.65
`
`3.55
`21.97
`22.13
`22.43
`22.50
`28.40
`
`96.33
`97.92
`
`19.70
`43.53
`44.95
`23.45
`58.78
`
`46.97
`
`2.70
`9.70
`12.78
`15.12
`16.45
`
`29.32
`
`29.47
`
`19.52
`
`22.48
`22.93
`
`Mesalamine
`(u9)
`11500.40
`622.80
`
`443.00
`121.00
`12563.20
`6913.00
`1697.60
`9253.80
`
`213.30
`29.50
`
`333.20
`918.00
`96.60
`1070.00
`544.80
`
`6.60
`
`1730.40
`N/A
`2730.60
`2185.00
`117.20
`
`2287.00
`
`7063.80
`
`373876.80
`
`14.80
`15653.20
`
`Total Mesalamine
`(Ng)
`
`% Recovered
`of delivered dose
`
`12123.20
`
`4.8
`
`30991.60
`
`242.80
`
`2962.60
`
`6.60
`
`6763.20
`
`2287.00
`
`7063.80
`
`373876.80
`
`15668.0
`
`12.4
`
`0.1
`
`1.2
`
`<0.1
`
`2.7
`
`0.6
`
`1.8
`
`93.5
`
`3.9
`
`medication were present in the fecal samples resulting in
`an artificially high recovery of drug for this patient. Inter-
`estingly, in two patients administered with Pentasa® in
`whom transit was rapid (01 and 04), the majority of the
`formulation was delivered suggesting that delivery of
`mesalamine from Pentasa® in these patients was not
`a