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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
In vitro characterization of oral dosage forms
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
In vitro characterization of oral dosage forms
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
Stomach pH: 1-3 / 3-7 residence
fasted: 0.5-2hfed: several hrsDuodenum
pH: 4-6
16
GI passage
Stomach pH: 1-3 / 3-7 residence
fasted: 0.5-2hfed: several hrsDuodenum
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
Stomach pH: 1-3 / 3-7 residence
fasted: 0.5-2hfed: several hrsDuodenum
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
partly adapted from J. Dressman
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
partly adapted from J. Dressman
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
partly adapted from J. Dressman
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
Precipitation in the small intestine?
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
Precipitation in the small intestine?
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“
S. Klein et al., J. Pharm. Pharmacol. 2005: 57 (6) 709-720
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
Biorelevant pH-gradient „fasted“
S. Klein et al., J. Pharm. Pharmacol. 2005: 57 (6) 709-720
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
Biorelevant pH-gradient „fasted“
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
S. Klein et al., J. Contr. Rel. 2008, 130: 216-219
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
[%]
S. Klein et al., J. Contr. Rel. 2008, 130: 216-219
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
N. Fotaki et al., Eur J Pharm Biopharm. 2009, 73: 115-120
upper profile
lower profile
upper profile
lower profile
64
Salbutamol OROS – plasma profiles
In vivo plasma profiles & predicted upper and lower plasma profiles
N. Fotaki et al., Eur J Pharm Biopharm. 2009, 73: 115-120
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
Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009
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
[%]
Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009
71
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
[%]
Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009
72
Tromphyllin 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
[%] ?
Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009
73
Tromphyllin 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
[%] ?
Klein S. , Dissolution Technologies, 16 (3): 28-40, 2009
74
„Extended release“ formulations
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
„Extended release“ formulations
in vitro study – biorelevant pH-gradient
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
76
Media composition
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
77
Compendial method: Paddle / Basket900 ml phosphate buffer pH 6.8
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
78
Biorelevant pH-gradient method
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
79
Biorelevant pH-gradient method
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
80
“fraction dissolved” vs. “fraction released”
fasted state fed state
Jantratid E. et al , Eur. J. Pharm. Sci. 37 : 434-441, 2009
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
Biorelevant dissolution stress tester
89 www.physiolution.eu
Biorelevant dissolution stress tester
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
Diclofenac retard 100 mg
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
Diclofenac retard 100 mg
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
Diclofenac retard 100 mg
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
Diclofenac retard 100 mg
Stress test: ”Early gastric emptying” (3 min)(phosphate buffer pH 6.8 USP) individual data, n = 6
Garbacz G & Weitschies W, Drug Dev. Ind. Pharm. 36 (2010) 518-530
95
Diclofenac retard 100 mg
Stress test: “Regular gastric emptying” (30 min)(phosphate buffer pH 6.8 USP) individual data, n = 6
Garbacz G & Weitschies W, Drug Dev. Ind. Pharm. 36 (2010) 518-530
96
Diclofenac retard 100 mg
Stress test: “Late gastric emptying” (60 min)(phosphate buffer pH 6.8 USP) individual data, n = 6
Garbacz G & Weitschies W, Drug Dev. Ind. Pharm. 36 (2010) 518-530
97
Diclofenac retard 100 mg
Simulation of plasma profiles
0 42 6 8 10
0
2000
c (n
g/m
l)
t (h)
Garbacz G & Weitschies W, Drug Dev. Ind. Pharm. 36 (2010) 518-530
98
Importance of biorelevant test conditions
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
Importance of biorelevant test conditions
• 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
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