Biorelevant dissolution testing

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Artificial stomach-duodenum (ASD) model. • BioGIT. • Gastrointestinal Simulator (GIS). • Tiny-TIM. 17. Biorelevant gastrointestinal transfer (BioGIT) model.
In vitro tools to simulate the regional differences of the human GI tract Mirko Koziolek Department of Biopharmaceutics & Pharmaceutical Technology Center of Drug Absorption and Transport University of Greifswald, Germany

1st all-WG UNGAP meeting 2018 in Leuven “Regional differences along the GI tract”

Simulation of gastrointestinal conditions in dissolution testing Typical test conditions • large media volumes (900-1000 mL) • static pH and temperature • use of buffer systems such as phosphate or acetate • application of high shear rates, but low shear stresses • often non-sink conditions

Does this reflect real-life conditions? 2

Dynamic conditions inside gastrointestinal tract pH value pressure [mbar] Temperature [°C] 14

I. Stomach

600

III. Colon

II. SI

12

500

45 40 35

10

400

8 300

30 25 20

6 200

4 2

100

0

0

15 10 5

0

4

8

12

16

20

24

28

32

0

36

Time [h] Individual profiles of pH, temperature and pressure measured by SmartPill®.

Koziolek et al. J Control Release (2015)

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Biorelevant dissolution testing Broad range of different in vitro tools:

• • • • • • •

Dynamic Gastric Model BioGIT dissolution stress test GastroDuo TNO TIM-1 and TIM-2 physio-grad …

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Biorelevant in vitro tools static

dynamic

monocompartmental

paddle apparatus

GastroDuo Dynamic Gastric Model

multicompartmental

USP apparatus III

TNO TIM-1

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Biorelevant dissolution media Selection of biorelevant media used to simulate composition of luminal fluids of certain regions of the human GI tract Fasted state

Fed state

Stomach

SGF FaSSGF

FeSSGF Full-fat milk Ensure Plus

Small intestine

FaSSIF FaSSIF-V2

FeSSIF FeSSIF-V2

Colon

FaSSCoF

FeSSCoF

Markopoulos et al. Eur J Pharm Biopharm (2015)

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Biorelevant dissolution media Levels of complexity of biorelevant media

Level 0

Level 1

Level 2

Markopoulos et al. Eur J Pharm Biopharm (2015)

Level 3

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Stomach – Physiological considerations Oral & esophageal transit

Gastric Emptying

Co-ingested food & liquids

Intragastric Dissolution

Gastric secretion

Physicochemical characteristics Absorption

Gastric motility 8

Stomach – Biorelevant in vitro tools • • • • • •

rotating beaker paddle-bead method Antrum model GastroDuo Dynamic Gastric Model TNO TIM-agc

Antrum model (Neumann et al. Int J Pharm 2017)

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GastroDuo Biorelevant simulation of: • gastric emptying kinetics • gastric pH profiles • temperature profiles • motility • dilution of gastric contents

Schematic figure of the experimental setup in the GastroDuo. 10

GastroDuo Test programs – standard program A Temperature / °C

36 32 28 24 20 16 0

5

10

15 20 Time / min

25

30

0

5

10

15 20 Time / min

25

30

7 6 5

pH

4 3 2 1 0

Test program A (standard program for fasted state) with varying pressure, flow and movement conditions in the GastroDuo. Sager et al. PBP World Meeting 2018

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GastroDuo Test programs Description A

standard program

B

no initial pressure event

C

short gastric transit (15 min)

D

long gastric transit (45 min)

E

constant temperature (37°C)

F

constant pH (pH 1.2) Test program A with varying pressure, flow and movement conditions in the GastroDuo.

Sager et al. PBP World Meeting 2018

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GastroDuo Drug release from hard gelatin capsules

Cumulative caffeine release in the acceptor vessel (means, n=6 ± SD). Sager et al. PBP World Meeting 2018

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Small intestine – physiological considerations • • • • •

limited fluid volumes1 formation of micellar structures2 antro-duodenal pH change drug absorption motility

1Schiller

et al. Aliment Pharmacol Ther (2005), 2Porter et al. Nat Rev Drug Discov (2007)

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Small intestine – biorelevant in vitro methods In vitro tools: • Mini paddle dissolution test for the simulation of the conditions in the ileum • transfer model • Bio-GIT • Gastrointestinal Simulator (GIS) • TNO TIM-1 Biorelevant dissolution media: • Fasted State Simulated Intestinal Fluid (FaSSIF) • Fed State Simulated Intestinal Fluid (FeSSIF) • enhanced versions of FaSSIF/FeSSIF 15

Changes during antro-duodenal transit

GE

8 7 pH value

6 5 4 3 2 1 0 3.0

3.2 3.1 time / h

3.3

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Simulation of antro-duodenal transfer • • • •

Artificial stomach-duodenum (ASD) model BioGIT Gastrointestinal Simulator (GIS) Tiny-TIM

Biorelevant gastrointestinal transfer (BioGIT) model

Kourentas et al. Eur J Pharm Sci (2016)

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Small intestine – Simulation of drug absorption  either separate absorption modules or integrated into dissolution test • cell and tissue based models  monolayers of Caco-2 cells or MDCK cells  porcine intestinal mucosa or rat intestine

• models based on artificial membranes or filters  µFlux (PVDF membrane)  MacroFlux  permeation bag  dialysis cells

• biphasic dissolution tests • ... 18

Colon – physiological considerations • • • •

variable pH values limited amount of fluid variable transit times complex microbiom

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Colon – Biorelevant in vitro methods In vitro tools:  typically used for metabolization studies • batch fermenters (static or semi-dynamic) • MimiCol • TNO TIM-2

Biorelevant media: • FaSSCoF/FeSSCoF • addition of specific enzymes (e.g. pectinase, amylases) • addition of rat caecal contents or human fecal slurrry 20

Simulation of GI transit of dosage forms

Dissolution Stress Test Apparatus • • • •

alternating phases of stress and rest high pressure events and high velocities hydrodynamics inhomogenous fluid distribution

Garbacz et al. Eur J Pharm Biopharm (2008)

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B

Applied Test Algorithms Stomach

A 0

1

Small Intestine

B time (h)

Colon Colon

A

A

A

A

5

7

9

11

High stress phase 3 Pressure waves of 300 mBar per 6 s, (duty cycle 50%) + 1 min rotation at 100 rpm

A

Mild intestinal transit B

Every 10 min: 0,5 min rotation at 10 rpm

Garbacz et al. AAPS PharmSciTech 2014

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Dissolution Stress Test Drug release from quetiapine 50 mg ER tablets Ileocaecal valve

50

drug dissolved (mg)

40

Pylorus

30 20 Stress Test PP pH 6.8 USP II PP pH 6.8

10 0 0

4

8

12

16

20

24

time (h) Garbacz et al. AAPS PharmSciTech 2014

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Simulation of GI pH profiles How can we simulate dynamic pH profiles?

subject 1-3

Koziolek et al. J Pharm Sci 2014.

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Simulation of GI pH profiles Semi-dynamic simulation of gastrointestinal pH values in USP apparatus III

Tablets Klein S et al. J Pharm Pharmacol (2005), Klein S. Pharmazie (2015)

Pellets 27

Simulation of pH profiles

N2

CO2

Intestinal media based on physiological buffers - in vitro setup

pH electrode gas diffusor

pH 6.80 pH ysio-grad® 3/2 way solenoid valve

Garbacz G et al. Eur J Pharm Sci (2014)

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Simulation of pH profiles Fasted GI passages in individual patients

Karkossa & Klein J Pharm Sci (2018)

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Simulation of pH profiles Tablets versus pellets – Mesalazine MR

Karkossa & Klein J Pharm Sci (2018)

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Complex simulation of human GI physiology - TNO TIM-1 Simulation of: • body temperature • peristalsis • gastrointestinal pH profiles • GI transit times • secretion of gastric acid and salivary/gastric enzymes • secretion of bile and pancreatic juice • drug absorption

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Biorelevant in vitro tools Which aspects need further consideration? • certain physicochemical parameters of luminal fluids (e.g. viscosity) • digestive processes (e.g. human gastric lipase) in stomach and small intestine • simulation of absorption • simulation of the action of colonic microbiota

 need for in vivo data of high quality

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Implementation of in vivo data Simulation of human gastric motility

pH value pressure [mbar] Temperature [°C] 14

600

12

500

45 40 35

10

400

8 300

30 25 20

6 200

4 2

100

0

0

15 10 5

0

4

8

12

16

20

24

28

32

0

36

Time [h]

SmartPill data

GastroDuo

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Implementation of realistic motility scenarios In vivo data

In vitro simulation

Schneider et al. Eur J Pharm Sci (2017)

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Physiologically relevant models used in Food Science and Technology • • • •

Digestive Cell (U Leeds) Human Gastric Simulator (UC Davis) SHIME Dynamic Duodenal Model (U Birmingham)

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Thank you for your attention! Acknowledgement University of Greifswald Werner Weitschies Michael Grimm Felix Schneider Philipp Jedamzik Maximilian Sager Regine Beeck Gunnar Glöckl

Center of Drug Absorption and Transport, Greifswald

Sandra Klein Frank Karkossa Physiolution GmbH Grzegorz Garbacz

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