Download realistic simulation of human gastric motility, pressure forces

integration of drug products and subsequently the release and solubility of the active
redient, the advanced gastric compartment (AGC) was developed as part of the dynamic
Realistic simulation of human gastric motility, pressure forces, digestive enzymes and liquid/solid
vitro gastrointestinal emptying
model TIM (Minekus
et
al.,
1995).
To
ensure
physiological
relevance
in
the
advanced
gastric
compartment
of
the
in
vitro
dynamic
gastrointestinal
model
TIM
R6308
simulated parameters, we here describe the TIM-AGC in terms of Schilderink,
gastric motility,
R., Bellmann, S., Lelieveld J, Verwei, M, Minekus M.
TNO Triskelion, Zeist, The Netherlands
ssure forces, gastric secretions and gastric emptying.
INTRODUCTION
thods
Gastric motility and pressure forces
Due to its ease of administration, a large percentage of pharmaceutical
drug products are administered orally. Oral drug product performance
already starts in the stomach. Gastric parameters impact the behavior of
pharmaceutical formulations consumed with water (fasted conditions) or
a solid / liquid meal (fed conditions). To more accurately study the disintegration of drug products and subsequently the release and solubility of
the active ingredient, the advanced gastric compartment (AGC) was
developed as part of the dynamic in vitro gastrointestinal model TIM
(Minekus et al., 1995). To ensure physiological relevance of simulated
parameters, we here describe the TIM-AGC in terms of gastric motility,
pressure forces, gastric secretions and gastric emptying.
The three phases of gastric mixing, namely propulsion, emptying and
mixing and retropulsion are enabled through computer-controlled and
synchronized
movements
Gastric
motility and pressure
forcesof the contractile proximal and terminal antrum
and the pylorus. This results in motility patterns and pressure forces.
The three phases of gastric mixing, propulsion, emptying and mixing and retropulsion are
Similar
enabled through computer-controlled and synchronized movements of the contractile
patterns
were
observed
as compared
withpatterns
published
data of
Gastric
motility
and pressure
proximal
and terminal
antrumforces
andin
theTIM-AGC
pylorus. This
results in motility
and pressure
theSimilar
human
stomach.
Figure 2inshows
theascomparison
pressure
profiles
forces.
patterns
were observed
TIM-AGC
compared withofpublished
data
of the
The three phases of gastric mixing, propulsion, emptying and mixing and retropulsion are
®3
human
stomach
. Figure
2 shows
the comparison
of pressure
over time
and Figure
over
time and
Figure
3 shows
an example
of theprofiles
Migrating
Motor
enabled through computer-controlled and synchronized movements of the contractile
shows
an example
of the
Motorthe
Complex
(MMC or also
called
housekeeper
Complex
(MMC
orMigrating
also
called
housekeeper
wave)
as the
observed
in vivo
proximal
and terminal
antrum
and
the pylorus.
This results in motility
patterns
and pressure
wave) as observed in vivo and in the TIM-AGC.
andSimilar
in the
TIM-AGC.
forces.
patterns
were observed in TIM-AGC as compared with published data of the
Figure 4. Theoretical (solid line) and measured (markers) pepsin concentration References
during gastric passage of a formula milk (Nutrilon®), compared to the gastric M., m
Marteau,
pepsin concentration in vivo (dashed line) with Ensure p lus ® Minekus,
as a meal atrix. P., Havenaar, R. and Huis in ‘t Veld, J.H.J.
(1995). A multi compartmental dynamic computer-controlled model
simulating the stomach and small intestine. Alternatives to Laboratory
Animals, 23, 197-209.
lowing the design and development of the TIM-AGC, experiments for technical validation
re performed. The validation experiments were designed and performed based on
Kalantzi, L., Gounas, K., Kalioras, V., Abrahamsson, B., Dressmann, J.B.,
rature with relevant data on the human stomach. The gastric motility patterns and
Reppas, C. (2006). Characterization of the upper gastrointestinal contents under conditions simulating bioavailability/bioequivalence studies.
ssure values were measured with the Smartpill® technology. For this, the Smartpill
Gastric emptying
Pharmaceutical Research, 23, 165-176.
orded pressure values over time after introduction
into the TIM-AGC. Dynamic secretionsFigure 4. Theoretical (solid line) and measured (markers) pepsin concentration Moore, J., Christian, B., Coleman, R. (1981). Gastric emptying of varying
human stomach . Figure 2 shows the comparison of pressure profiles over time and Figure 3
during gastric passage of a fingested
ormula milk (Nutrilon®), compared to the gastric and phase separation occurs. Solids
In the human
stomach
the
meal
disintegrates
shows an example of the Migrating Motor Complex (MMC or also called the housekeeper
meal weight and composition in man, evaluation by dual liquid- and solid
Figure 4. Theoretical (green line) and measured (red markers) pepsin
digestive enzymes (lipase, pepsin, (swallowed)
pepsin concentration in vivo (dashed line) with Ensure p lus ® as a meal matrix. wave) salivary
as observed in vivoamylase)
and in the TIM-AGC. and HCl were set with
phase isotopic method. Digestive Diseases and Sciences, 26, 16-22.
concentration during gastric passage of a formula milk (Nutrilon®), comfollow a linear
emptying
manner,
while
the
liquid
phase
would
empty
with
an
exponential
Methods
pared to the gastric pepsin concentration in vivo (blue line) with Ensure
ard to flow rates and postprandial concentrations. Luminal enzyme activity
plus ®clear
as a meal
matrix.
pattern. This
difference
as shown in vivo by Moore et al. (1981), was reproduced in the
Following the design and development of the TIM-AGC, experiments for
asurements
and
digestion
experiments
were
performed
to
confirm
the
settings.
Mixing
of
TIM-AGC Gastric
(Figure 5).
This indicates realistic mixing, sieving characteristics and gastric
technical validation were performed. The validation experiments were
emptying
Gastric emptying
designed and performed based on literature with relevant data on the
waterhuman
andstomach.
meals
in
the
body
and
antrum
parts
was
monitored
as
well
as
emptying
of
the
emptying
of the in vitro system.
The gastric motility patterns and pressure values were
In the
human
stomach
the
ingested
meal
disintegrates
and phase separation occurs. Solids
Figure
2.
Pressure
profiles
obtained
from
the
Smartpill®
in
the
human
In
the
human
stomach
the
ingested
meal
disintegrates
and
phase
measured
with
the
Smartpill®
technology.
For
this,
the
Smartpill®
recoruids and
solids
over
time
in
the
experiments
with
relevant
liquid
and
solid
meals
in
ded pressure values over time after introduction into the TIM-AGC.
separation
Solidsmanner,
follow a linear
manner,
while
the empty with an exponential
stomach (left) and in TIM-AGC (right).
follow
a linearoccurs.
emptying
whileemptying
the liquid
phase
would
Dynamic
secretions
of
digestive
enzymes
(lipase,
pepsin,
(swallowed)
liquidThis
phase
woulddifference
empty with as
an shown
exponential
pattern.
clearet al. (1981), was reproduced in the
pattern.
clear
in vivo
by This
Moore
mbination
with
water.
difference as shown in vivo by Moore et al. (1981), was reproduced in
salivary amylase) and HCl were set with regard to flow rates and post-
sults
Figure 2. Pressure p rofiles obtained from the smartpill® in the human stomach (left) and in TIM-­‐AGC (right).
Figure 2. Pressure p rofiles obtained from the smartpill® in the human stomach (left) and in TIM-­‐AGC (right).
prandial concentrations. Luminal enzyme activity measurements and
digestion experiments were performed to confirm the settings. Mixing of
the water and meals in the body and antrum parts was monitored as
well as emptying of the liquids and solids over time in the experiments
with relevant liquid and solid meals in combination with water.
sign and construction
Results
TIM-AGC
(Figure
5).
This
indicates
realistic
mixing,
sieving
characteristics
and
gastric
the TIM-AGC (Figure 5). This indicates realistic mixing, sieving
emptying
of the inand
vitro
system.
characteristics
gastric
emptying of the in vitro system.
Figure 3. Pressure p eak obtained from the smartpill® during MMC in the human stomach (left) and in TIM-­‐AGC (right). Figure 3. Pressure p eak obtained from the smartpill® during MMC in the human stomach (left) and in TIM-­‐AGC (right). Secretions
Figure
3.body
Pressure peak
obtained
from the 1A)
Smartpill®
during
MMC in
ke the human stomach, the TIM-AGC consists
of
a
part
(Figure
that
gradually
First,the
measurements
of luminal
enzyme
during ingestion of a meal were in
human stomach
(left)
andconcentrations
in TIM-AGC (right).
Design and construction
line with in vivo observed concentrations. Figure 4 exemplarily shows the comparison of
Secretions
ntracts to simulate gastric tone and consequent
reduction
gastric
volume
during
pepsin
concentrations in vivo of
(Kalantzi
et al., 2006) and
in the TIM-AGC.
Second, measured
digestion
correlated well with that measured in humans. The realistic digestibility of
Secretions
First,
measurements
of luminal enzyme concentrations during ingestion of a meal were in
Alike
the
human
stomach,
the
TIM-AGC
consists
of
a
body
part
(Figure
macronutrients
of a high fat meal
was 64.6%,
94.8% and 90.7%
for moved
fats, proteins andin
ptying.1A)The
antrum
part
features
a
flexible
bottom
(Figure
1B)
that
be
line with in vivo
observed concentrations.
Figure 4 can
exemplarily
shows
the comparison of
that gradually contracts to simulate gastric tone and consequent
carbohydrates, respectively.
pepsin concentrations in vivo (Kalantzi et al., 2006) and in the TIM-AGC. Second, measured
First,correlated
measurements
of luminal
enzyme
concentrations
during ingestion
reduction
of gastric
volume contractions
during emptying. The antrum
part features
a digestion
njunction
with
antral
(Figure
1C).
well with that
measured
in humans.
The realistic digestibility
of
flexible bottom (Figure 1B) that can be moved in conjunction with antral
contractions (Figure 1C).
of a mealofwere
line
with
vivo observed
Figure
macronutrients
a highinfat
meal
wasin64.6%,
94.8% and concentrations.
90.7% for fats, proteins
and4
carbohydrates,
respectively.
exemplarily
shows the comparison of pepsin concentrations in vivo
(Kalantzi et al., 2006) and in the TIM-AGC. Second, measured digestion
correlated well with that measured in humans. The realistic digestibility
of macronutrients of a high fat meal was 64.6%, 94.8% and 90.7% for
fats, proteins and carbohydrates, respectively.
Figure 1. TIM-­‐AGC, A. body, B. antrum, C. contracting antrum, D. pyloric valve (E, F en G moeten weg)
Figure 5. Solid emptying in TIM-­‐AGC (line, round markers) compared to in vivo (doted-­‐dashed line), and liquid emptying in TIM-­‐AGC (line, square markers) compared to in vivo (dashed line) . The dotted line Figure
5.5Solid
emptying
in TIM-AGC
(line,
round(markers)
compared
to
Figure . S
olid e
mptying i
n T
IM-­‐AGC line, r
ound m
arkers) compared presents the gastric emptying of the total meal. in vivo
and liquid
emptying
in TIM-AGC
(line, square
to in v(doted-dashed
ivo (doted-­‐line),
dashed line), and liquid emptying in TIM-­‐AGC (line, markers) compared to in vivo (dashed line). The dotted line presents the
square markers) compared gastric emptying
of the
total meal. to in vivo (dashed line) . The dotted l ine presents the gastric emptying of the total meal. CONCLUSION
The presented data indicate that the TIM-AGC realistically simulates the
processes in the human stomach, such as motility patterns and pressure values, gastric secretions and the emptying of realistic meals over
time. As a result, the AGC, as part of the TIM system, is an useful tool
to study the gastric behavior of different drug formulations within the
preclinical drug development process.
Figure 1. TIM-AGC, A. body, B. antrum, C. contracting antrum,
D. pyloric valve
Close-up of the TIM-AGC
Close up of the AGC during digestion of a high fat meal