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Gastrointestinal
physiology: effect
on dosage form
performance
Clive Wilson, SIPBS, Glasgow UK
1at MENA Regulatory
Conference on
Bioequivalence, Biowaivers,
Bioanalysis and Dissolution
September 23rd- 24th 2013
v6
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Variability
Diclofenac Ratiopharm ER pellets Gabacz G. et al.,(2008). Eur. J. Pharm. Biopharm. 70: 421-428
3
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Variability – but a pattern
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Variability in performance of oral
pharmaceutical products Solubility and permeability
related to transit
related to type of formulation
related to food and sequence of dosing
Physiological variation
Pharmacogenetics
Disease variation
Ageing
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pH
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CdTe
Memolog
system
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Acid & food reflux can be separate events
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pH profile after a meal
6
4
2
-1 0 1 2 3 4
hours
pH
Stomach Meal pH 6; 460 calories Vol =400 ml
Food causes a temporary buffering in the stomach but stimulates acid secretion, causing the pH to fall
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pH profile after a meal
Meal pH 6; 460 calories Vol =400 ml
In the
duodenum, the
acid secretion
causes an acid
wash and the pH
seen is lowered
7
6
5
0 1 2 3 4
Duodenum
pH
Time (h)
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pH telemetry capsule
SECRETIONS
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Danny’s experiments with the
Merck pH strps
Courtesy D. Bar-Shalom, Copenhagen University
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Danny’s experiments with the
Merck pH strps
Corpus Fundus pH 1.5 pH 3
Courtesy D. Bar-Shalom, Copenhagen University
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pH after a meal – triple
electrode study
G1 Electrode in Fundus
G2 Electrode in mid stomach
G3 Electrode against wall of pylorus
The pH in the stomach varies according to where it is
sampled from.
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Transit
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•Transit of a Tc-99m
labelled perspex capsule.
•Kaus LC, Fell JT, Sharma H,
Taylor DC. The intestinal
transit of a single non-
disintegrating unit. Int J
Pharm 1984;20:315-323.
•Strathopolous
Neurogastroenterol Motil
(2005) 17, 148–154
Measuring intestinal transit time-
scintigraphy/MMI/MRI
Courtesy: Dr D. Taylor
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Development of faster acting dosage
forms
Dramatic difference in in vitro dissolution
Can you see any difference kinetically?
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Comparative curves new vs old
formulation
Standard acetamidophen (2 x 500 mg)
FD-APAP acetamidophen (2 x 500 mg)
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New vs std paracetamol
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Gastric
emptying of a
dispersing
dosage form,
taken with a
meal
The disintegrated
dose form mixes
and is emptied
according to the
calorific density of
the meal
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Gastric Emptying & duodenal transit (MMI courtesy Prof. Dr. W. Weitschies)
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Variation in gastric anatomy -2
Because this subject is
shorter and fatter, the
Stomach is more
horizontal and tablets
exit easier
25
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Magnetic tablet breaking up in body of
stomach (Wilson et al., 2007)
26
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As the stomach empties, separation of
antral and posterior stomach becomes
evident
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Effects of dosage forms on meal emptying
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One scrambled egg labelled
with 99mTc
1 slice of lightly buttered
toast
One cup of decaffeinated tea
or coffee
34
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Gastric Emptying (T50) of a meal given with different
sized dosage forms
28 28
35
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Swollen device in stomach
Acts as a plug.
The emptying of
everything else
swallowed after would
be altered.
There would be a change
in kinetics
36
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Making faster-acting dosage
forms
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Serum Concentration-Time Profile:
Novel Paracetamol Fasted
Paracetamol Absorption Relative to Tablet Disintegration
and Gastric Emptying
0
5
10
15
20
25
30
0 10 20 30 40 50 60
Time (min)
Seru
m C
on
cen
trati
on
( mg/m
l)
Tablet
Disintegration
50% Gastric Emptying
90%
Gastric
Emptying
90%
Gastric
Emptying
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Triggers for gastric emptying
Modulated via the gastroduodenal bulb-pyloric
pressure difference
Receptors:
Acid
Osmolality
Fat
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Mean Gastric emptying profiles Novel
and Standard IR Paracetamol
0
10
20
30
40
50
60
70
80
90
100
0 50 100 150 200 250 300
Novel Fasted
Panadol Fasted
Novel Fed
Panadol Fed
Time (minutes)
% R
em
ain
ing
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Novel Paracetamol Fasted
t = 15 min
t = 5 min t = 10 min
t = 25 min t = 15 min
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Novel Paracetamol Fed
t = 10 min t = 25 min
t = 45 min t = 150 mi
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Helped in the Development of a
Faster-acting analgesic formulation
….but we still didn’t
understand the reason
why the fast-dissolving
formulation worked
faster in the fed state…
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Other techniques MRI
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Stomach is not
homogenous
Sandwich mass is
moulded by antral
contractions to a
separate solid phase
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Novel Paracetamol Fed
t = 10 min t = 25 min
t = 45 min t = 150 mi
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Magenstrasse
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How stable is gastrointestinal transit as a
parameter in populations?
The variability is seen in specific patients…it reflects anatomical differences, fasting blood sugar levels, fasting short chain free fatty acids, posture, time of day, age and disease Stomach and Colon residence are the biggest variables 65
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Gastric emptying of Tc-99m labelled
Clinutren ISO (400 kCal, 400 ml) n=8
0
10
20
30
40
50
60
70
80
90
100
0.0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 3.0
Time (h)
% R
ema
inin
g i
n R
OI
Fasted
3 h post meal
45
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Emptying pattern is stable between
individuals (Goodman et al, Int J Pharm in preparation )
46
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Variable transit
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Variability in Clinical Trials
a subset (20% of the
population) has a
consistently lower
AUC and lower
Cmax of gefantib than
normal?
Why?
© C G Wilson 2012
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G I Transit of labelled Pellets
Christensen et al., 1985
Small intestinal transit
62
© C G Wilson 2012
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Normal
M
M
M
M
M
Dr Abdul Basit’s Favourite colon Picture!
© C G Wilson 2012
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An Abnormal
Normal
M M M
M M M
M M
© C G Wilson 2012
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Small intestinal content of Label
Subjects with
altered profiles
had low small
intestinal
exposure
© C G Wilson 2012
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Prankulust: Evening versus morning dosing…
Brocks et al., Br J Clin Pharmacol 1997; 44: 289–291
Evening
dosing
Morning
dosing
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The colon goes to sleep at night
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Water in the gut
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Attempt to produce more colonic
gas
Feed subjects fermentable substrates and measure short term adaptation (4
days)
Either Orange Tang or Fybogel for 4 days incorporating Gd-DTPA
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Measurement of gas volumes
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Effect of Fybogel
(6 doses starting pm dose) C
olo
nic
Volu
me (m
l)
579 ±
165 m
l PR
E-D
OS
E
612 ±
195 m
l -
FIN
ISH
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Press et al., Aliment. Pharmacol. Ther. 12: 673-678 (1998)
Gut triggers : Is the caecal pH dip
big enough to use?
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Conclusions
For a medium energy, monophase meals gastric emptying rates can be made into a robust parameter
Man was a hunter-gatherer for centuries. We eat a diet that is very different to ancestors
The variable effects that we seein transit are due to the interplay of gastric AND colonic motor/sensory loops
Timing of dose relative to meal, and meal composition affects exposure; metabolic/secretory variables affect dissolution
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Drug absorption
mechanisms
Upper Small intestine ◦ Mixture of Passive … Lipid solubility
pH of medium (therefore pKa)
Concentration gradient (therefore SOLUBILITY)
◦ and Active mechanisms Active transport
Counter transport
Efflux
Food
Effects
Viscosity
Transit
Time
Salt form
Gastric
Emptying
rate
Colon
filling
Bile
Excipient
effects
Formulation
Many potential interactive effects
Other
medication
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My postgraduates,
especially Dr Kirsteen
Goodman and Dr
Bridgitte O’Mahony.
Prof A C Perkins,
Queen’s Medical
Centre , Nottingham.
Dr D Bar-Shalom,
Copenhagen University
BioImages, Glasgow
Colleagues at GSK
Healthcare and Pharma
Prof. Dr Werner
Weitschies
Acknowledgements