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

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Magnetic tablet breaking up in body of

stomach (Wilson et al., 2007)

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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

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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

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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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ers

, Bio

an

aly

sis

an

d

Dis

solu

tio

n, A

mm

an

Sep

t 22-2

3, 2

013

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

1at M

EN

A R

egu

lato

ry C

on

fere

nce o

n

Bio

eq

uiv

ale

nce

, Bio

waiv

ers

, Bio

an

aly

sis

an

d

Dis

solu

tio

n, A

mm

an

Sep

t 22-2

3, 2

013

Measurement of gas volumes

1at M

EN

A R

egu

lato

ry C

on

fere

nce o

n

Bio

eq

uiv

ale

nce

, Bio

waiv

ers

, Bio

an

aly

sis

an

d

Dis

solu

tio

n, A

mm

an

Sep

t 22-2

3, 2

013

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

1at M

EN

A R

egu

lato

ry C

on

fere

nce o

n

Bio

eq

uiv

ale

nce

, Bio

waiv

ers

, Bio

an

aly

sis

an

d

Dis

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n, A

mm

an

Sep

t 22-2

3, 2

013

Press et al., Aliment. Pharmacol. Ther. 12: 673-678 (1998)

Gut triggers : Is the caecal pH dip

big enough to use?

1at M

EN

A R

egu

lato

ry C

on

fere

nce o

n

Bio

eq

uiv

ale

nce

, Bio

waiv

ers

, Bio

an

aly

sis

an

d

Dis

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n, A

mm

an

Sep

t 22-2

3, 2

013

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

1at M

EN

A R

egu

lato

ry C

on

fere

nce o

n

Bio

eq

uiv

ale

nce

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ers

, Bio

an

aly

sis

an

d

Dis

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n, A

mm

an

Sep

t 22-2

3, 2

013

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

1at M

EN

A R

egu

lato

ry C

on

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nce o

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eq

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ale

nce

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ers

, Bio

an

aly

sis

an

d

Dis

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tio

n, A

mm

an

Sep

t 22-2

3, 2

013

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