Biorelevant dissolution Sandra Klein · PDF fileBiorelevant Dissolution ... Troglitazone 2 µg/ml pKa 6.1 100 ... Aqueous solubility and D/S ratio of BCS class II and IV drugs,

Biorelevant Dissolution

- Concepts and Application -

Prof. Dr. Sandra Klein

Center of Drug Absorption and Transport

Institute of Biopharmacy and Pharmaceutical Technology

Ernst Moritz Arndt University Greifswald, Germany

AAPS Webinar • Physical Pharmacy and Biopharmaceutics Section • December 01 • 2011

2

What is dissolution testing?

• dissolution testing is a standardized method for measuring the rate and extent of drug release from a dosage form

• dissolution testing is the primary quality control test to determine whether a drug product can release the active in a timely manner

• dissolution is an important tool in the development of new drug products and can be a key tool in the approval of new (multisource) drug products

3

Absorption

Tablet Granules Powder / fine particles

Dissolved drug

Complexation, drug binding in the GIT

Blood

Plasma

Metabolites, Urine

Site of action

Dissolution

Gastrointestinal tract First pass effect

Dissolution and oral drug delivery

Disintegration Disintegration Systemic

circulation

4

What is dissolution testing?

• dissolution testing is a standardized method for measuring the rate and extent of drug release from a dosage form

• dissolution testing is the primary quality control test to determine whether a drug product can release its active pharmaceutical ingredient(s) in a timely manner

• optimization of therapeutic effectiveness during product development

• assessment of bioequivalence

• prediction of in vivo bioavailability

What can dissolution testing be used for?

5

Factors influencing dissolution

• properties of the API

• quality and design of the drug product

• conditions under which the test is run

6

Biopharmaceutics Classification Scheme

criteria can be very helpful to predict the bioavailability of a drug

Rate and extent of drug absorption from „Immediate Release“ (IR)dosage forms depends on:

1. solubility 2. permeability of the API3. dissolution of the pharmaceutical product

7

Guidance for Industry: Immediate release solid oral dosage forms, FDA, 1995

Biopharmaceutics Classification Scheme

CLASS 1 CLASS 2

highly soluble poorly soluble

highly permeable highly permeable

CLASS 3 CLASS 4

highly soluble poorly soluble

poorly permeable poorly permeable

8

Selection of test conditions

• classify the drug substance according to the BCS

characterize the drug solubilityover the pH range 1.2 to 6.8 (7.5)(BCS classification)

a highly soluble substance has a dose:solubility ratioD:S < 250 mL over a pH-range of 1-6.8 (7.5)

a D:S > 250 mL indicates that dissolution in the GI tract may not occur under sink conditions

9

NCEs and formulation development

Top 200 marketed products (US)

New chemical entities

BCS I35%

BCS II30%

BCS III25%

BCS IV10%

BCS I5%

BCS II70%

BCS III5%

BCS IV20%

Benet LZ (2006), Bulletin technique. Gattefossé 99: 9-16

10

Pharmacopoeial methods

• primarily use of apparatus I (Basket) and II (Paddle)

• simple dissolution media

In vitro characterization of oral dosage forms

11

Pharmacopoeial methods

useful for quality control

not useful for examining biopharmaceutical properties

often not predictive for the in vivo performance


12

Is it possible to predict the in vivo behavior of a drug or a dosage form using simple in vitro tests ?

Prerequisite: solubility / drug release rate is the rate limiting stepin drug absorption (BCS class II drugs & MR formulations)

biorelevant solubility tests

biorelevant dissolution tests

simulation of conditions in the human gastrointestinal tractthat may affect the dissolution process


13

Predictive test methods

Biorelevant dissolution tests

• simulating residence / passage of the dosage form in / through

relevant segments of the gastrointestinal tract

• prediction of in vivo absorption using in vitro data

How to select adequate test conditions?

How to simulate a gastrointestinal passage?

14

GI passage

Stomach pH: 1-3 / 3-7 residence

fasted: 0.5-2hfed: several hrs

15

GI passage


fasted: 0.5-2hfed: several hrsDuodenum

pH: 4-6

16

GI passage



pH: 4-6

Jejunum pH: 6-7

Ileum pH: 7-7.5

Small intestine residence

3-5 hrs influence of food intake

often disregarded

17

GI passage



pH: 4-6

Jejunum pH: 6-7

Ileum pH: 7-7.5

Colon pH: 5-7 great number and

variety of bacteria individual passage times

differ largelyfew hours – 1/2/3 days

18

Immediate release (IR) formulations

• intended to release drugs before reaching or at the site of absorption

• drug release in the upper gastrointestinal (GI) tract

• release drug over a relatively short time period 1 – 4 hrs

poorly soluble APIs

insufficient drug solubility

19

Test setup

• Paddle apparatus• 500 ml medium• SIFsp or IP Phosphate buffer pH 6.8• 75 rpm• 37°C• sampling after 30 min

Specification

• > 85 % release within 30 min (class I) and 15 min (class III)

Proposed simplified test method for IR dosage forms with highly soluble drugs

http://whqlibdoc.who.int/trs/WHO_TRS_937_eng.pdf

20

Developing dissolution tests for poorlysoluble drugs (Class II and Class IV)Weak acids D/S LITERS !

Troglitazone 2 µg/ml pKa 6.1 100Glyburide < 0.1 µg/ml pKa 5.3 >> 36Phenytoin 27 µg/ml pKa 8.3 3.7

Neutral substancesDanazol 0.5 µg/ml 200Atovaquone 0.1 µg/ml (pKa 9) 1,785Felodipine 1 µg/ml 10Griseofulvin 15 µg/ml 16.6

Weak basesKetoconazole 4.7 µg/ml pKa 2.9; 6.5 44.4Itraconazole < 0.001 µg/ml pKa 3.7 >> 100,000Tamoxifen 3.3 µg/ml pKa 8.8 12

Aqueous solubility and D/S ratio of BCS class II and IV drugs, partly adapted from J. Dressman

21

• solubility of lipophilic compounds (typically logP > 2) is better in

presence of bile salt / lecithin micelles

• solubility of weak bases is often best in the stomach, that of

weak acids in the small intestine

• solubilities in the GI tract may far exceed the aqueous solubility

dissolution is often better in vivo !!!

Solubility in the GI tract comparedto aqueous solubility

partly adapted from J. Dressman

22

Proposed test methods for IR dosage forms with poorly soluble drugs

• screen solubility in compendial and biorelevant media

• perform dissolution tests in biorelevant media • Paddle for final dosage forms• Mini Paddle for preformulations

• compare in vitro data with in vivo data

• determine critical parameters for the in vivo performance

• develop a discriminative QC method


23

Media to simulate upper GI contents

Biorelevant dissolution media

Location pre-/postprandial Medium

Stomach preprandial FaSSGF

Stomach postprandial Ensure® Plus, Milk, FeSSGF

Small intestine preprandial FaSSIF, FaSSIF V-2

Small intestine postprandial FeSSIF, FeSSIF V-2

Overview of the respective original references in: S Klein. The AAPS Journal (Review article). 12(3) : 397-406 (2010)

24

Fasted State Simulated Gastric Fluid

„Biorelevant“ conditions in the fasted stomach

Na taurocholate 80 µmol/LLecithin 20 µmol/LPepsin 0.1 mg/mLNaCl 34.2 mmol/LHCl conc. ad pH 1.6Demineralized water ad 1000 mL

pH 1.6Surface tension 42.6 mN/mOsmolality 121 mOsm/kg

M Vertzoni et al. Eur J Pharm Biopharm. 60:413-417 (2005)

25

Milk

Objective: Simulation of the initial gastric conditions after a light breakfast

Whole milk, 3,5 % fat(per 100 g)

269 kJ64 kcal3,5 g fat

3,3 g proteins4,7 g carbohydrates

Ref.: CMA (www.cma.de)

P. Macheras et al. Int. J. Pharm. 33: 125-136 (1986)S. Klein et al. J. Pharm. Pharmacol. 56: 605-610 (2004)

26

Ensure® Plus

Objective: Simulation of the initial gastric conditions after a standardized (FDA) high fat breakfast

Standard Breakfast FDA Division of Biopharmaceutics

2 slices of toasted white bread with butter2 eggs fried in butter2 slices of bacon2 ounces of hash-browned ( fried shradded ) potatoes = 56,7 g8 ounces of whole milk

Carbohydrate: 58g, 232 kcal, 972 kJ, 24 %Protein: 33g, 132 kcal, 552 kJ, 14 %Fat: 67 g, 603 kcal, 2533 kJ, 62 %

S. Klein et al. J. Pharm. Pharmacol. 56: 605-610 (2004)

27

Fed State Simulated Gastric Fluid

„Biorelevant“ conditions in the fed stomach some time after a meal

NaCl 237.02 mmol/LAcetic acid 17.12 mmol/L

Sodium acetate 29.75 mmol/L

Demineralized water ad 1000 mL

Milk:acetate buffer 1:1

HCl conc. ad pH 5.0

pH 5.0Osmolality 400 mOsm/kgBuffer capacity 25 mEq/L/pH

E Jantratid et al. Pharm Res. 25(7):1663–76 (2008)

28

Fasted State Simulated Intestinal Fluid

„Biorelevant“ conditions in the fasted small intestine

NaH2PO4 1.977 gNa taurocholat 3 mmol/L

Lecithin 0.75 mmol/L

NaCl 3.093 g

NaOH ad pH 6.5

Demineralized water ad 500 ml

pH 6.5Osmolality 270 + 10 mOsm/kgBuffer capacity 10 + 2 mEq/L/pH

29

Fed State Simulated Intestinal Fluid

„Biorelevant“ conditions in the fed small intestine

Glacial acetic acid 8.65 gNa taurocholate 15 mmol/L

Lecithin 3.75 mmol/L

NaCl 11.874 g

NaOH ad pH 5.0

Demineralized water ad 1 Liter

pH 5.0Osmolality 635 + 10 mOsm/kgBuffer capacity 76 + 2 mEq/L/pH

30

Case example: Danazol (neutral compound, BCS Class II)

Aqueous solubility: 1µg/ml D:S = 200 litres H20Dose: 200 mg 20 litres FaSSIFpKa: neutral 6 litres FeSSIFlogP: 4.53

Can a meal increase the API bioavailability?

31

Danazol dissolution profiles in various media

postprandial

preprandial

compendial

32 Charman et al., J. Clin. Pharm. 33: 1207-1213 (1993)

Food effects on bioavailability of danazol

preprandial

postprandial

33

Official test method

Danazol Capsules (USP)

Medium: 0.75 % sodium lauryl sulfate solution, 900 mL

Apparatus 2: 75 rpm

Time: 30 minutes

Procedure: measure UV absorbance at 286 nm in comparisonwith a standard solution having a known concentrationof USP danazol

Tolerance: n.l.t. 75% (Q) of the labeled amount of danazol isdissolved in 30 minutes

34

0,001

0,01

0,1

1

10

100

1 2 3 4 5 6 7 8 9 10

pH

Solu

bilit

y [µ

g/m

l]

Free Acid Free Base

pH/solubility profile of weak acids/bases

35

• dissolution in the stomach is likely to be poor due to the low pHand likely to begin in the more neutral small intestine

• the pH of the medium should be pH >> pKa where possible if applicable, conditions of the upper or mid small intestine

should be used (pH 5-7)

a typical pH would be pH 6.8

• if the compound is lipophilic, bile components may boost thesolubility in vivo

Dissolution of poorly soluble weak acids


36

• to characterize the compound, perform solubility- / dissolutiontests in biorelevant media

the pH will be most favourable in the fasting stomach, but (iflipophilic) the bile salts may also contribute to solubilization

• in the fasted state the primary site of dissolution is usually thestomach, but caution: many patients are also receiving protonpump inhibitors or H2 receptor antagonists

• in the postprandial state, the greater concentration of bile in theGI tract can compensate for the initial higher gastric pH

Dissolution of poorly soluble weak bases


37

Case example: Tamoxifen (BCS Class II)

Aqueous solubility: 3.3 µg/mlDose: max. 40 mg (anticancer)pKa: 8.8logP: 7.1

Is it possible to predict the plasmaprofile of weak bases?

38

Test medium pH D:S [mL] Tamoxifen

D:S [mL] Tam-HBenBCD

Water 12288 26SGFsp 1,2 2.644 27

SGFsp mod. 1,8 1.991 132Acetate buffer 5,0 638 30

FaSSIF 6,5 188 48FeSSIF 5,0 44 6

Blank FaSSIF 6,5 10490 201Blank FeSSIF 5,0 6404 200Acetate buffer 4,5 10598 60

SIFsp 6,8 8724 43

Tamoxifen D:S ratio in different test media

39

Dissolution profiles of tamoxifen in thefasted and the fed state

Tamoxifen (base) pure drug

0

20

40

60

80

100

0 30 60 90 120 150 180 210 240

Time (min)

% R

elea

se

Blank FaSSIF pH 6.5

FaSSIF pH 6.5

Blank FeSSIF pH 5.0

FeSSIF pH 5.0

40

Dissolution profiles of tamoxifen in thefasted and the fed state

Tamoxifen-HBen--Cyclodextrin complex

0

20

40

60

80

100

120

0 30 60 90 120 150 180 210 240

Time (min)

% R

elea

se

Blank FaSSIF pH 6.5

FaSSIF pH 6.5

Blank FeSSIF pH 5.0

FeSSIF pH 5.0

41

Precipitation in the small intestine?

Miniaturized transfer model

The use of Hydroxybutenyl--Cyclodextrin for dissolution rate improvement of poorly soluble weak bases: preparation and in vitro studies of a tamoxifen -complex, S. Klein et al. 7th World Meeting on Pharmaceutics and Biopharmaceutics, Barcelona (2008)

42


0,000

0,005

0,010

0,015

0,020

0,025

0,030

0,035

0,040

0 30 60 90 120 150 180 210 240

Time (min)

drug

in s

olut

ion

(mg/

ml)

Tamoxifen:HBenBCDtransfer into FaSSIF,2 ml/min

Tamoxifen:HBenBCDtransfer into FeSSIF,2 ml/min

Theoreticalconcentration oftamoxifen

Tamoxifen:HBenBCDtransfer into FaSSIF,at once

Tamoxifen:HBenBCDtransfer into FaSSIF,at once

No !!!No !!!

43

Case example: Itraconazole (BCS Class II)

Aqueous Solubility: 0.001 µg/mlDose: 200 mgpKa: 3.7logP: 6.5

Is it possible to predict the plasma profile of weak bases?

44

Test medium pH D:S [mL] Itraconazole

D:S [mL] Itra-HBenBCD

Water n.m. 112SGFsp 1,2 925.925 24

SGFsp mod. 1,8 2.083.333 40Acetate buffer 5,0 n.m. 2.050

FaSSIF 6,5 n.m. 2.957FeSSIF 5,0 n.m. 3.237

Blank FaSSIF 6,5 n.m. 4.300Blank FeSSIF 5,0 n.m. 5.106Acetate buffer 4,5 n.m. 3.479

SIFsp 6,8 n.m. 4.314

Itraconazole D:S ratio in different test media

45

Dissolution profiles of itraconazole in compendial and biorelevant test media

0

20

40

60

80

100

0 30 60 90 120 150 180 210 240

Time (min)

% R

elea

se

SGFsp pH 1.2

SGFsp mod. pH 1.8

SGFsp mod. pH 2.0

Acetate buffer pH 4.5

Acetate buffer pH 5.0

SIFsp pH 6.8

Blank FaSSIF pH 6.5

FaSSIF pH 6.5

Blank FeSSIF pH 5.0

FeSSIF pH 5.0

Itraconazole-HBen--CD complex drug in various dissolution media

CM Buchanan et al. J Pharm Sci 96 (11):3100-16 (2007)

46

0

20

40

60

80

100

0 30 60 90 120 150 180 210 240

Time [min]

% in

sol

utio

n

Mean (n=3)X29841-1-1transfer intoFaSSIF pH 7.5 atonce

Mean (n=3)X29841-1-1transfer intoFeSSIF pH 5.0 atonce


CM Buchanan et al. J Pharm Sci 96 (11):3100-16 (2007)

Sporanox®

no significant food effect expected

47

Conclusion

• solubility and dissolution rate of a drug can be linked to bioavailability in many cases, but ….

… to achieve physiologically relevant results, it is necessary touse well designed test setups

48

Modified release (MR) formulations

• intended to release drugs in a controlled and pre-determined fashion and/or to target to selective sites in the gastrointestinal (GI) tract

• release drug over a long time period (12 hrs, 24 hrs, ..)

• typically contain much higher doses than IR formulations

• give release patterns which in turn can offer a lot of benefits

dose dumping

insufficient drug release

49

Typical MR formulations

Coated dosage forms

1. Delayed release formulations

2. Extended Release Formulations

Matrix systems

Extended Release Formulations erodible or non-erodible matrices

Osmotic systems

monolithic dosage forms vs. multiparticulates

50

Possible release profiles

time [h]

% R

elea

se

51

Criteria for dissolution test design

Media to simulate gastrointestinal passage• pH-value / pH profiles• volume• composition

Dissolution equipment• apparatus• hydrodynamic conditions

Passage times• multiple units single unit dosage form

Food effects• fasted fed state conditions

52

Compendial dissolution equipment

Reciprocating cylinderBioDis

Flow through cell

53

Dissolution media

Compendial media

• changing pH-values

Biorelevant media

• various aspects of the intraluminal composition pH

buffer capacity

osmolality / ionic strength

ionic composition

surfactants

food & digestive products

54

Media to simulate a gastrointestinal passage

Biorelevant dissolution media

Location pre-/postprandial Medium

Stomach preprandial FaSSGF, SGFplusStomach postprandial Ensure® Plus,

Milk, FeSSGFSmall intestine preprandial FaSSIF, FaSSIF V-2Small intestine postprandial FeSSIF, FeSSIF V-2Colon preprandial SCoF, FaSSCoFColon postprandial SCoF, FeSSCoF

Overview of the respective original references in: S Klein. The AAPS Journal (Review article). 12(3) : 397-406 (2010)

55

Simulated Colonic Fluid

Simulation of the pH-values and ions in the proximal colon

1 molar acetic acid solution 170 ml

1 molar NaOH solution 157 ml

Demineralized water ad 1 Liter

pH 5.8

Osmolality 295 mOsm/kg

Buffer capacity 29 mEq/L/pH

N. Fotaki et al , Eur. J. Pharm. Sci. 24 : 115-122, 2005

56

„Delayed release“ formulations – QC method

0

20

40

60

80

100

0 60 120 180 240 300Time [min]

Rel

ease

[%]

Claversal 500 mg

Salofalk 500 mg

Asacolitin 400 mg

0

20

40

60

80

100

0 60 120 180 240 300Time [min]

Rel

ease

[%]

Claversal 500 mg

Salofalk 500 mg

Asacolitin 400 mg

pH 6.8 pH 7.5

S. Klein et al., J. Pharm. Pharmacol. 2005: 57 (6) 709-720

57

Biorelevant pH-gradient „fasted“


GI segment pH Mediumtablets pellets

Stomach 1.8 SGF plus 60 min 30 min

Proximal Jejunum 6.5 FaSSIF 15 min 45 min

Distal Jejunum 6.8 FaSSIFa,b 15 min 45 min

Proximal Ileum 7.2 FaSSIFa,b 30 min 45 min

Distal Ileum 7.5 Blank FaSSIFa 120 min 45 min

Proximal Colon 6.5 Blank FaSSIF 360 min 360 min

Proximal Colon 6.5 Blank FaSSIF 240 min 240 min

Distal Colon 6.8 Blank FaSSIFa 360 min 360 min

Distal Colon 6.8 Blank FaSSIFa 240 min 270 min

a pH-modified, b concentration of bile components modified

Transit time

58

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rel

ease

[%]

Claversal 500 mg

Salofalk 500 mg

Asacolitin 400 mg



59

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rel

ease

[%]

Claversal 500 mg

Salofalk 500 mg

Asacolitin 400 mg

Prototyp


e

S. Klein et al., J. Contr. Rel. 2008, 130: 216-219

fraction released

in vitro

60

Plasma profile “fraction absorbed”

0

1

2

3

4

5

6

7

8

9

0 2 4 6 8 10 12 14 16 18 20 22 24

Zeit [h]

Plas

mak

onze

ntra

tion

[µm

ol/L

]

0

20

40

60

80

100

0 120 240 360 480

Zeit [min]

Frac

tion

abso

rbed

[%]

Calculation


fraction absorbed

in vivo

61

Biorelevant pH-gradient „fasted“ LEVY-Plot

• prospective IVIVC predictive in-vitro method

y = 0,6104x + 1,4488R2 = 0,9948

0

20

40

60

80

100

0 20 40 60 80 100

fraction re leased [%]

frac

tion

abso

rbed

[%]


in vivo

in vitro

62

„Extended release“ formulationsSalbutamol OROS – fraction releasedBioDis

1. SGF2. FaSSIF3. SCoF

Flow-though cell1. SGF2. FaSSIF3. SCoF

N. Fotaki et al., Eur J Pharm Biopharm. 2009, 73: 115-120

1

1

2

2

3

3

63

Salbutamol OROS – fabs & frel

BioDis

Flow-through cell


upper profile

lower profile

upper profile

lower profile

64

Salbutamol OROS – plasma profiles

In vivo plasma profiles & predicted upper and lower plasma profiles


65

„Extended release“ formulations

Theophylline treatment of chronic asthma narrow therapeutic index

Therapeutic requirements plasma levels in the therapeutic range reduce serum level fluctuations avoid toxic plasma levels avoid subtherapeutic levels

Is there a risk for dose dumping?

66

Theophylline ER formulations

Medium-fat breakfast High-fat breakfast

A. Karim et al., Clin. Pharmacol. Ther. 38, 642-647 (1985)

67

Compendial method: Paddle – SIF pH 6.8

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rele

ase

[%]

Contiphyllin 300 mg

Tromphyllin 300 mg

68

1. Compendial buffer gradient simulation of the pH conditions in the GI tract

2. Biorelevant media gradient simulation of the physiological GI milieu

fasted state

fed state

Dissolution media

Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009

69

Compendial and biorelevant media gradients

GI-sectionCompendial media pH Biorelevant media pH Tablets Pellets

Stomach Acetate buffer / SGFsp*5.0 / 2.0 Ensure Plus (Milk)® 6.5 (120/120) 240 120

Proximal Jejunum Blank FeSSIF 5.0 FeSSIF 5.0 45 45

Distal Jejunum Blank FaSSIF 6.5 FeSSIF* 6.5 45 45

Proximal Ileum Blank FaSSIF 6.5 FeSSIF*/** 6.5 45 45

Distal Ileum Blank FaSSIF* 7.5 Blank FaSSIF* 7.5 45 45

Proximal Colon SCoF 5.8 SCoF 5.8 --- 240* pH modified, ** Concentration of bile components modified

Passage time [min]Media and pH-values postprandial pH-Gradient

GI-sectionCompendial media pH Biorelevant media pH Tablets Pellets

Stomach SGFsp* 1.8 FaSSGF 1.8 60 30

Proximal Jejunum Blank FaSSIF 6.5 FaSSIF 6.5 15 45

Distal Jejunum Blank FaSSIF 6.8 FaSSIF* 6.5 15 45

Proximal Ileum Blank FaSSIF 7.2 FaSSIF*/** 7.2 30 45

Distal Ileum Blank FaSSIF* 7.5 Blank FaSSIF* 7.5 120 45

Proximal Colon SCoF 5.8 SCoF 5.8 240 240* pH modified, ** Concentration of bile components modified

Passage time [min]Media and pH-values preprandial pH-Gradient


70

Contiphyllin 300 mg tablets

Preprandial pH profile: = compendial buffers, = biorelevant mediaPostprandial pH profile: = compendial buffers, = biorelevant media

biorelevant media

compendialmedia

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rele

ase

[%]


71

Contiphyllin 300 mg tablets


biorelevant media

compendialmedia

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rele

ase

[%]


72

Tromphyllin 300 mg tablets


biorelevant media

compendialmedia

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rele

ase

[%] ?


73

Tromphyllin 300 mg tablets


biorelevant media

compendialmedia

0

20

40

60

80

100

0 60 120 180 240 300 360 420 480

Time [min]

Rele

ase

[%] ?


74


Predicting the bioavailability of diclofenac sodium• non-steroidal anti-inflammatory drug• here: model compound• capsules containing MR pellets consisting of 100 mg API per

dosage and Eudragit® RL as a release-modifying agent

in vitro study - apparatus• Basket• Paddle• Reciprocating cylinder / BioDis• Flow through cell

Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009

75


in vitro study – biorelevant pH-gradient


76

Media composition


77

Compendial method: Paddle / Basket900 ml phosphate buffer pH 6.8


78

Biorelevant pH-gradient method


79

Biorelevant pH-gradient method


80

“fraction dissolved” vs. “fraction released”

fasted state fed state


81

Importance of biorelevant test conditions

• pH-gradient and biorelevant pH-gradient methods allow a better prediction of the potential in-vivo behaviour of MR dosage forms

• pH values and passage times can be easily adapted to different patient subgroups or a best / worst case scenario

• composition of media can be even better adapted to physiological conditions

• methods can be adapted to check for alcohol-dependentdose dumping

• hydrodynamic conditions ???

82

Gastrointestinal fluid volumes & stress

83

Gastrointestinal stress

from: SmartPill GI-Monitoring System Brochure

84

Gastrointestinal fluid volumes

Schiller C. et al. Aliment Pharmacol Ther. 22:971-979 (2005)

fasted 1 hr after meal intake

85

Dynamic dissolution testing

Dynamic gastric model TIM-1 gastrointestinal model

Courtesy of Institute of Food Research,Colney, Norwich, UK

Courtesy of TNO, Zeist, The Netherlands

86

Mechanical forces acting on the dosage forms during GI transit

Pressure waves ≤ 300 mbar• critical GI-sections:

pylorus und ileocecal junction

Transport events ≤ 50 cm/s• relatively long phases of rest • spiked by short transport events

Interrupted contact of the dosage forms with GI liquids

discontinuous GI transit conditions

shortacting

Garbacz G, Klein S, Weitschies W. Expert Opin Drug Deliv. 7 (2010) 1251-61

87

Biorelevant dissolution stress tester

88 www.physiolution.eu


89 www.physiolution.eu


90

Diclofenac retard 100 mg

Mean plasma profiles after fasted administration of Voltarenretard 100 mg, 24 subjects

0 2 4 6 8 10 12 14 16 18 20 22 24t (h)

0

100

200

300

400

500

c (n

g / m

l)

Water (100-200 ml)Meal (Lunch, Snack, Dinner)

91


Individual plasma profiles after fasted administration of Voltarenretard 100 mg , 24 subjects

0 2 4 6 8 10 12 14 16 18 20 22 24t (h )

0

200

400

600

800

1000

1200

c (n

g / m

l)

Water (100-200 ml)Meal (Lunch, Snack, Dinner)

Pyloricpassage?

Ileocecal passage?

92


In vitro dissolution profiles of Voltaren retard 100 mg in USP apparatus II

0 2 4 6 8 10 12 14 16 18 20 22 24t (h )

0

20

40

60

80

100

rrel

ease

d di

clof

enac

(mg)

pH 4 .5 , 50 rpmpH 6 .8 , 50 rpmpH 6 .8 , 100 rpm

Garbacz G & Weitschies W, Drug Dev. Ind. Pharm. 36 (2010) 518-530

93


Test program setup

B

B

B

A

0 0. 5

0.05

Program 1

Program 2

time (h)

Program 3

0 1

3 Pressure waves of 300 mBarper 6 s, duty cycle 50% + 1 min rotation at 100 rpm B 0,5 min rotation

at 10 rpm

A

A

A

A

A A

time (h)

time (h)

“Early gastric emptying“ (3 min)

“Regular gastric emptying“ (30 min)

“Late gastric emptying“ (60 min)

5

5

5

94


Stress test: ”Early gastric emptying” (3 min)(phosphate buffer pH 6.8 USP) individual data, n = 6


95


Stress test: “Regular gastric emptying” (30 min)(phosphate buffer pH 6.8 USP) individual data, n = 6


96


Stress test: “Late gastric emptying” (60 min)(phosphate buffer pH 6.8 USP) individual data, n = 6


97


Simulation of plasma profiles

0 42 6 8 10

0

2000

c (n

g/m

l)

t (h)


98


A simulation of the GI passage is an essential steptowards a better prediction of the in vivo behaviour of orallyadministered dosage forms …

… but is only possible with biorelevant baseline data, whichrequire a good characterization of all relevant in vivoparameters that can affect drug release in the human GI tract

99


• simulating pH-changes in the GI tract

• adapting media composition to physiological conditions• pH, surfactants, enzymes, food / digestive products

• simulating relevant GI hydrodynamics / stress for monolithicdosage forms

• adequate simulation of the dosing conditions• fasted vs. fed state dosing• morning, lunchtime, evening, nighttime dosing

100

Acknowledgements

• Prof. Dr. Jennifer Dressman

• Prof. Dr. Christos Reppas

• Dr. Nikoletta Fotaki

• Prof. Dr. Werner Weitschies

• Dr. Grzegorz Garbacz

• Physiolution GmbH

Thank you !!! Sandra Klein

Center of Drug Absorption and Transport

Institute of Biopharmacy and Pharmaceutical Technology

Ernst Moritz Arndt University Greifswald, Germany

Sandra.Klein@uni‐greifswald.de

AAPS • Physical Pharmacy and Biopharmaceutics Section • December 01 • 2011

Documents

Biorelevant dissolution Sandra Klein · PDF fileBiorelevant Dissolution ... Troglitazone 2 µg/ml pKa 6.1 100 ... Aqueous solubility and D/S ratio of BCS class II and IV drugs,