PRACTICAL
GASTROENTEROLOGY
A Peer Review Journal
Supplement to November 1999
A SCINTIGRAPHIC STUDY
TO EVALUATE WHAT HAPPENS
TO PENTASA® AND ASACOL®
IN THE HUMAN GUT
by Ian R. Wilding
PUBLISHER’S NOTE:
The opinions expressed in this publication are those of the author and are not to
be attributed to the sponsor or to the publisher or editorial board of Practical
Gastroenterology.
This research was supported by an
unrestricted grant from Roberts Pharmaceuticals.
A Scintigraphic Study to Evaluate
What Happens to Pentasa®
and Asacol® in the Human Gut
Ian R. Wilding
In order to ensure adequate intra-luminal mesalamine levels at the sites of intestinal
lesion in inflammatory bowel disease, prolonged release (eg Pentasa®) and targeted
release (eg Asacol®) products have been developed. In this study we have used the
imaging technique of gamma scintigraphy to visualize the effect of food on performance of Pentasa® and Asacol® in the human gut in a group of seven healthy volunteers. The research demonstrates that gastrointestinal transit of Pentasa® is largely
unaffected by food providing for uniform mesalamine delivery throughout the
intestines. However, gastric residence of the enteric-coated Asacol® product was influenced by dosing after food. Interestingly, the site of intestinal delivery for Asacol® was
variable in both the fasted and fed condition. Incomplete disintegration was also
observed in one individual. The study highlights the importance of recognizing that our
understanding of intestinal pH over the last few years has advanced significantly, questioning the relevance of using Eudragit® S coated products for colonic delivery of
mesalamine.
INTRODUCTION
lcerative colitis (UC) 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. Crohn’s Dis-
U
Dr. Ian Wilding is with the niche imaging CRO,
Pharmaceutical Profiles, and is also a special lecturer
in the Department of Pharmaceutical Sciences at Nottingham University.
ease is a transmural inflammatory disease which can
affect the small bowel only (30%), the colon only
(25%), or both small bowel and colon at the same time
(40%). Collectively these conditions are often referred
to under the more generic name of inflammatory
bowel disease (IBD).
The use of the anti-inflammatory agent,
mesalamine, to inhibit the effect of inflammatory
mediators is one of the main treatment approaches in
IBD (1). Mesalamine is poorly absorbed from the disPRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
1
tal bowel (2) and high intra-luminal drug concentrations at the site of inflammatory lesions have been
shown to be clinically important. The oral mesalamine
products on the market at the present time are either
prolonged release (eg Pentasa®) or targeted release (eg
Asacol®) formulations.
Pentasa® has been designed as a preparation consisting of a myriad of prolonged release mesalamine
microspheres of circa 1 mm in diameter. Previous
product visualization studies have shown that the
microspheres are dispersed throughout the gastrointestinal tract and drug release occurs uniformly in both
the small and large bowel (3).
Enteric coatings that dissolve at relatively high
pH values (eg Eudragit® S) have been used to target
mesalamine delivery to the colon, eg Asacol® (4).
When these type of systems were first developed, it
was under the original belief that pH increased progressively from the stomach (pH 2–3), small intestine
(pH 6.5-7) to the colon (pH 7–8) (5). However, subsequent studies using modern pH telemetric technology
have demonstrated that the highest pH levels in the gut
(pH 7.5 ± 0.5) are found in the terminal ileum (6). On
entering into the colon in healthy volunteers, the pH
drops to 6.4 ± 0.6 due to the presence of short chain
fatty acids arising from the bacterial fermentation of
polysaccharides in the right colon. Other researchers
(7) have shown that in 25 % of healthy individuals the
pH in the gastrointestinal tract never reaches the
threshold pH of Eudragit® S (pH7). As a consequence
of this new knowledge, a number of researchers have
concluded that a change in luminal pH cannot be used
reliably and routinely as a mechanism to deliver drugs
specifically to the colon (8, 9).
Gamma scintigraphy has been described as an
“elegant technique for phase I investigation of the
locality of in vivo release” (10) and has “become
the method of choice for investigating the fate of pharmaceutical dosage [forms] in the body” (11). The ability to visualize the drug delivery process in a non-invasive manner acts to fill a significant void in current
understanding. In this study, we have used gamma
scintigraphy to visualize the gastrointestinal performance of two mesalamine formulations: Pentasa® and
Asacol®. The objectives of the research were to investigate the effect of food on the transit of both products
2
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
and also to assess the site of tablet disintegration for
the targeted mesalamine product (Asacol®).
MATERIALS AND METHODS
Radiolabelling of Formulations
Asacol® tablets (400 mg mesalamine) were radiolabelled by the insertion of 5 mg of 111In-labelled resin
(1 MBq) into each tablet through a drilled microhole
which was subsequently sealed with a cyanoacrylate
adhesive. In vitro dissolution testing demonstrated that
there was no significant change in the disintegration
properties of the treated versus non-treated tablets.
The Pentasa® capsules (250 mg mesalamine)
were radiolabelled by replacing a small quantity of the
capsule fill weight (circa 5% w/w) with 111In-radiolabelled ethylcellulose coated non-pareil pellets. The
surrogate radiolabelled microspheres were the same
size, diameter and surface coating as the currently
marketed Pentasa® microspheres.
Study Design & Procedures
Seven healthy male and female volunteers provided
written informed consent to participate in the four-way
randomized crossover study. The investigation was
approved by the Quorn Research Review Committee
and the administration of the radiolabelled product was
authorized by the Department of Health.
Subjects were dosed with the radiolabelled formulation on four occasions, a minimum of 72 hours
apart. On two occasions the volunteers received either
the Asacol® or Pentasa® product after a 10-hour
overnight fast. The remaining crossover legs involved
the same product being dosed immediately after the
subjects had consumed a standard breakfast (circa
2500 KJ).
Time lapse photography of the gastrointestinal
performance of the products was obtained via gamma
scintigraphy with images being acquired every 10 minutes for 8 hours post-dose. Subsequently, images were
obtained every 30 minutes until 16 hours post-dose; a
final picture was also obtained at 24 hours post-dose.
The scintigraphic pictures were subsequently analyzed
in accordance with validated procedures (3,11). Standard meals were provided at 4 and 9 hours post-dose.
RESULTS
The individual transit profiles for the Pentasa® microsphere formulation have been characterized by the halflife (T50%) for gastric emptying, small bowel transit
and colon arrival in both the fed and fasted state
(Table 1). Gastrointestinal transit of the radiolabelled
Asacol® product is provided in Table 2 and the disintegration properties are highlighted in Table 3. A
sequence of scintigraphic images showing key stages
of gastrointestinal performance are shown for Asacol®
and Pentasa® in Figures 1 and 2, respectively.
DISCUSSION
a) Gastrointestinal Transit
The major factor influencing the gastric emptying of
oral drug delivery systems is whether they are administered with or without food. In the fasted state, drug
preparations are typically retained in the stomach until
they are removed by the phase III contractions of the
migrating myoelectric complex (MMC). Gastric emptying occurred on average at 0.3 ± 0.1 and 0.9 ± 0.9
hours post-dose for the Pentasa® and Asacol® preparations, respectively. These data demonstrate that the
two formulations were discharged from the stomach
well within the 120–140 minute MMC cycle following
administration in the fasted state.
In the fed state the rate of stomach emptying is
such that the number of calories delivered to the duodenum tends to be constant with time. Therefore, one typically sees less agitation early after high fat dosing
whilst the stomach becomes accustomed to the calorific
content of the ingested meal. Then agitation and mixing
commence with the gradual emptying of material of
appropriate particle size from the stomach. As a consequence it is not surprising that the gastric emptying of
both the Asacol® and Pentasa® formulations was generally slower following post-prandial administration.
However, it is important to distinguish between the
effect of food on the rate of gastric emptying for the
Asacol® and Pentasa® formulations.
Gastric emptying of the Asacol® tablet occurred
on average over 2 hours later when the dosage form
was administered after food, with the gastric residence
time of the formulation ranging from 2.2 to 4.4 hours
post-dose following post-prandial dosing. In comparison, gastric emptying of the Asacol® tablet when
dosed to fasted subjects occurred within 1 hour of dosing in five of the seven volunteers, and the duration of
Table 1.
The Effect of Food on the Gastrointestinal Transit (T50%) of the Labelled Microsphere Formulation (time in hours)
Subject
Number
Fed
01
02
03
04
05
06
07
1.6
1.5
1.8
1.3
1.6
0.9
1.7
Mean
SD
Median
n=
1.5
0.3
1.6
7
Gastric Emptying
Fasted
Small Intestinal Transit
Fed
Fasted
Fed
Colon Arrival
Fasted
0.3
0.3
0.3
0.5
0.2
0.4
0.4
4.2
6.2
*
3.2
3.8
4.8
3.3
4.3
11.1
5.5
3.0
7.2
4.0
6.7
5.8
7.7
*
4.5
5.4
5.7
5.1
4.5
11.4
5.8
3.6
7.4
4.3
7.0
0.3
0.1
0.3
7
4.3
1.1
4.0
6
5.9
2.7
5.5
7
5.7
1.1
5.6
6
6.3
2.7
5.8
7
*T50% colon arrival did not occur during the 16-hour imaging period
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
3
Table 2.
The Effect of Food on the Gastrointestinal Transit of Asacol® (time in hours)
Subject
Number
Fed
01
02
03
04
05
06
07
3.2
3.5
2.5
2.4
2.2
4.4
3.5
Mean
SD
Median
n=
3.1
0.8
3.2
7
Gastric Emptying
Fasted
Small Intestinal Transit
Fed
Fasted
Fed
Colon Arrival
Fasted
0.6
0.4
2.0
0.2
0.7
0.2
2.3
4.1
*
6.3
3.9
2.7
*
3.6
6.4
9.0
4.9
3.2
6.8
3.5
5.5
7.3
*
8.8
6.3
4.9
*
7.1
7.0
9.4
6.9
3.3
7.5
3.6
7.8
0.9
0.9
0.6
7
4.1
1.3
3.9
5
5.6
2.0
5.5
7
6.9
1.4
7.1
5
6.5
2.2
7.0
7
*Tablet disintegration occurred in the small bowel
Table 3.
The Effect of Food on the In Vivo DIsintegration Properties of Asacol® (time in hours)
Fed
Subject
Number
Initial Disintegration
Time
Location
01
02
03
04
05
06
07
7.5
*
6.0
5.4
3.2
5.7
9.2
Mean
SD
Median
n=
6.2
2.1
5.8
6
AC
*
SI
SI
SI
SI
AC
Fasted
Complete Disintegration
Time
Location
Initial Disintegration
Time
Location
8.2
4.8
**
10.9
12.8
6.8
19.9
6.5
3.4
7.4
3.8
12.2
9.6
4.6
HF
SI
**
AC
SF
SI
SF
10.6
5.4
9.6
6
6.8
3.2
6.5
7
*Initial disintegration could not be confirmed
**Complete tablet disintegration did not occur during the study period
SI = Small intestine, AC = ascending colon, HF = hepatic flexure, TC = transverse colon, SF = splenic flexure
4
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
SI
SI
AC
AC
TC
HF
SI
Complete Disintegration
Time
Location
14.6
9.4
19.9
7.2
14.2
19.6
20.2
15.0
5.3
14.6
7
HF
AC
SF
AC
SF
TC
SF
Figure 1. Gastrointestinal transit of the labelled Asacol® tablet following fed dosing in
subject 3.
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
5
Figure 2. Gastrointestinal transit of the labelled microspheres (Pentasa®) following fed
dosing in subject 3.
6
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
residence ranged from 0.4 to 2.3 hours. Gastric emptying of the Pentasa® formulation (T50%) was slightly
slower following fed dosing. However, the overall rate
of gastric emptying in the presence of food was generally faster than that seen for the Asacol® tablet, with
gastric emptying (T50%) of the Pentasa® formulation
occurring within 2 hours of dosing on all except one
occasion following fed dosing. This suggests that
although the presence of food may have delayed the
onset of gastric emptying for the Pentasa® product, the
overall rate of gastric emptying remained rapid following post-prandial administration of the dosage
form.
Small intestinal transit data for the two formulations in either the fed or fasted state were, broadly
speaking, comparable; circa 5 hours. Previous studies
have shown that the small bowel transit of pharmaceutical products ranging from pellets to tablets is not
affected by the ingestion of food (12).
The Pentasa® microspheres were observed to
disperse fully within the colon in the majority of individuals (Figure 2). This finding is in good agreement
with previous scintigraphic studies on the Pentasa®
tablet preparations (3,13). These studies showed drug
release from the Pentasa® formulation occurred
throughout the gastrointestinal tract allowing for topical delivery of mesalamine to a range of inflammatory
lesions in the bowel.
b) Pentasa® Capsule Disintegration
The hard gelatin capsule containing the labelled
microspheres rapidly disintegrated in the stomach
releasing the prolonged release multiple dose units.
Previous studies have shown that mesalamine release
for the product is essentially complete during total GI
transit time (14). Therefore any microspheres found in
the stools on defecation will have released most of
their available drug.
c) Asacol® Tablet Disintegration
Initial tablet disintegration occurred, on average, 6
hours post-dose following fasted and fed dosing. However, in the fasted state, onset of disintegration typi-
cally occurred more distally in the intestine, eg n = 4
in the colon, whereby following post-prandial administration start of break-up occurred in the upper bowel
in four individuals.
Complete disintegration occurred more rapidly
following fed administration; 10.5 ± 5 hours post-dose,
compared to 15.0 ± 5.3 hours following fasted dosing.
The site of complete disintegration also varied
between regimens, with complete disintegration occurring in the colon following all seven administrations in
the fasted state. However, in comparison, only six of
the seven tablets dosed following fed administration
completely disintegrated; the tablet for Subject 3 did
not completely disintegrate during the 24 hour imaging
period (Figure 1). Complete disintegration occurred in
the small intestine in two subjects and the colon in the
remaining four subjects receiving this regimen.
It is therefore clear from these findings that the
site of intestinal mesalamine delivery for the Eudragit®
S coated Asacol® product is variable. In some individuals complete drug release occurred in the small bowel
(eg Subjects 2 and 6 in the fed state) whilst in Subject
5, in the fasted state, drug release only started in the
transverse colon. In addition, incomplete release of
drug in Subject 3 following post-prandial dosing supports the anecdotal reporting of intact Asacol® tablets
being observed in the stools of some patients (15). Previous scintigraphic studies have also demonstrated
highly variable in vivo release properties for Eudragit®
S coated tablets (16). Variation in intestinal pH is the
logical explanation for the poor targeting specificity of
Eudragit® S coated products in these healthy volunteers studies (6).
However, it is also important to recognize that
there is now a growing body of evidence to suggest that
in patients with active UC there is the potential for intraluminal pH levels to be lowered considerably. Intraluminal gastrointestinal pH was assessed by Fallingborg
et al, in patients with active UC (17). In half the individuals, very low pH levels (pH 2–3) were recorded in the
proximal colon. In the research by Raimundo et al, the
right sided luminal colonic pH in acute UC and UC in
remission was found to be significantly lower than in
healthy volunteers (18). Examination of the individual
small intestinal pH findings in UC patients showed that
in 24% of individuals a luminal pH of 7.0 or greater was
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999
7
sustained for less than 30 minutes. The authors speculate
that suboptimal mesalamine release from Asacol® may
occur in a small proportion of UC patients. The results of
our scintigraphic findings are in good accord with their
concern about the variability of Asacol® ’s disintegration
properties.
CONCLUSION
In summary, the transit results of this study indicate that administration of Asacol® following a meal
can lead to increased gastric residence which ultimately
delays arrival of the product at the target area for drug
action. However, in comparison, the gastrointestinal
transit of the multiparticulate Pentasa® formulation was
less affected by the presence of food which correlates
with previous food effect studies on pellet preparations.
In addition, the disintegration of the Asacol®
preparation was variable with complete break up of the
tablet occurring in many different parts of the gut ranging from small intestine to splenic flexure. The results
of the study are therefore consistent with previous
research which has suggested that the Eudragit® S
coating should not be used to reliably deliver drugs
specifically to the colon.
Pentasa®, on the other hand, performed much
more consistently. Disintegration of the capsule
occurred in the stomach. The microspheres then dispersed throughout the entire gastrointestinal tract from
the small intestine through the distal colon in both the
fasted or fed conditions. ■
References
1. Khan AZ, Piris J, Truelove SC: An experiment to determine the
active therapeutic moiety of sulphasalazine. Lancet 1977;ii:892895.
8
PRACTICAL GASTROENTEROLOGY • NOVEMBER 1999