oral formulations for poorly water soluble compounds schwerloesliche wirkstoffe.pdf · oral...
TRANSCRIPT
Oral Formulations for Poorly Water Soluble Compounds
SAQ - Fachgruppe Pharma & ChemieOskar Kalb, Novartis Pharma AG BaselOlten, 23. June 2009
2 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Oral Delivery of Poorly Water Soluble Compounds
For systemic activity of an API molecule after oral administration it must be absorbed from the intestine and reach the bloodstream / the site of action
from. P. D. Ward et.al. Pharmaceutical Sciences and Technology Today Vol. 3, No.10 Oct. 2000
Passive diffusion is the most dominant mechanism of drug absorption from the intestinal lumen (GIT)
3 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Oral Delivery of Poorly Water Soluble Compounds
With a few exceptions, molecular dispersion of a drug is a prerequisite for its absorption across biological membrans
Tablet Powder Solution
Systemic circulation
Disintegration Dissolution Absorption
This implies that the dissolution of a poorly water soluble drug can become the rate limiting step for the onset of drug levels in the blood (if absorption is reasonable fast) Negative impact on Oral Bioavailability
This dictates that after oral administration the drug has to dissolve in the gastrointestinal fluid before partitioning into and across the enterocyte
4 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Drug Dissolution – Noyes Whitney
dx/dt Dissolution rateA Interfacial surface areaD Diffusion coefficienth Thickness of diffusion layerXd Amount of drug dissolvedCs Saturation solubilityV Volume of dissolution medium
Key parameter that influence dissolution rate• Solubility of the API
- Polymorph, pKa, Gastro-intestinal pH, Buffer Capacity of the GIT
• Surface area (A)- Particle size, wetting properties
Physico-chemical properties of the API AND the physiological state of the GIT can have a significant impact on the in-vivo dissolution of the drug
5 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Dose and Dose number (D0)
Solubility and Dose always have to be considered together
Do = Mo/VoCs
Mo = dose administered (mg)Vo = 250 ml (reference volume of human stomach, FDA-approach)Cs = solubility (mg/ml)
Remarks:• Do = > 20 at pharmacological doses -> already critical• In practice, Do values often between 20 and 100 for pharmacological and human doses.
• For TOX doses, Do up to 1000 and more are frequent …!
6 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Absolute bioavailability vs. variability
From Hellriegel E.T et al. Clin. Phamacol. Ther. 1996; 60: 601-607.
Inverse relationship between the absolute bioavailability (F) of an oral dosage form and it‘s total intersubject variability (CV).
To lower the variability means for a formulation scientist in To lower the variability means for a formulation scientist in most cases to improve the bioavailability in the fasted statemost cases to improve the bioavailability in the fasted state
7 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Biopharmaceutical Classification Scheme
Class IILow solubHigh perm
Class IHigh solubHigh perm
Class IIIHigh solubLow perm
Class IVLow solubLow perm
Class II Class I
Class IIIClass IV
Formulation
Limited formulation influence
Solubility and Permeability are key determinant of oral bioavailability Biopharmaceutical Classification System
8 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Use of Drug Delivery Systems in Major Pharmaceutical Companies
47%
18% 16%11%
8%0%
10%
20%
30%
40%
50%
Ora
l
Pare
nter
al
Inha
latio
n
Tran
sder
mal
Oth
er
Source: Kermani, F., et.al., Drug Delivery Technology, Oct. 2001
Dis
tribu
tion
with
rega
rd to
ro
ute
of a
dmin
istra
tion
9 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Approaches to improve Solubility, Dissolution of poorly water soluble APIs and decrease Variability
1. Physical modifications• Particle size reduction
(Nanosuspensions, micronization)• Dispersion of drug in a polymer matrix
(Solid Dispersions, solid solutions)• Polymorphs / Pseudopolymorphs• Complexation / Solubilization
2. Lipid-based systems• e.g. Microemulsions (SMEDDS)
10 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Examples
Impact of a particle size reduction on dissolution and oral bioavailability of a poorly water soluble drug
Nanosuspenions
11 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
I. Nanosuspensions
Technology• Downstream Process (e.g. Milling)• Up-stream Process (e.g. Precipitation)• Drying of nanosuspension Solid Dosage Form
Working principleIncreased dissolution rate by reducing particle size to the nanometer range (and thereby increasing the surface area)
Noyes Whitney (modified)
12 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
I. Nanosuspensions
Nanosizing• Most prominent manufacturing technology
(e.g. NanoCrystal® wet milling technology by Elan)
Ref. E. Merisko-Liversidge et.al. Eur. J. Pharm.Sci. 18 (2003), 113-120
Particle size distribution of Naproxen crystals before milling (triangle, mean 24.2 um) and after milling (circle 0.147 um)
• Addition of stabilizers (polymers, surfactants) to prevent agglomeration of nanosized particles
13 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
I. NanosuspensionsImpact of particle size reduction on dissolution rate
Example: Cilostazol (BCS II)
Particle size (median)- Hammer-milled (□) 13 μm- Jet-milled (◊) 2.4 μm- NanoCrystal (∆) 0.2 μm
Dissolution rate testing- water 37°C, 900ml- 50rpm, USP apparatus 2- 5 mg cilostazol
Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64
Dissolution rate of Cilostazol from a suspension is clearly increased by a reduction of the drug substance particle size
14 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
I. NanosuspensionsPharmacokinetic of Cilostazol suspensions in fasted and fed beagle dogs
Major increase in bioavailability with minimal food effect observed for the Cilostazol nanosuspension (NanoCrystal®)
D
Ref. Jinno J. J. Contr. Rel. 2006; 111:56-64
Serum concentration vs. time after oral administration of cilostazol suspensions (100mg/body) in fasted (open) and fed (closed) beagle dogs (n=4) (mean; SD)
(C) Hammer-milled (□)
(B) Jet-milled (◊)
(A) NanoCrystal (∆)
15 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Examples
Impact of a formulation parameter on oral bioavailability of a poorly soluble compound
Solid dispersion
16 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
II. Solid Dispersions
DefinitionA poorly water soluble drug that is highly dispersed and stabilized in a hydrophilic carrier
Working principle• „Ultimate“ particle size reduction • No crystal structure• Hydrophilic carrier
improved wetting of the drugimproved wetting of the druginhibits recrystalization/precipitationinhibits recrystalization/precipitation of supersaturated solutionof supersaturated solution
• Surfactant (optional)increase solubilization of the drugincrease solubilization of the drug
17 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Solvent evaporation
Melting
II. Solid DispersionsOral Absorption of Poorly Water Soluble Drugs
Solid Dispersions
Melt-extrusion
NOT bioavailable
Organic Solution
Bioavailable
18 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
II. Solid Dispersions In-vitro dissolution rate and in-vivo pharmacokinetic data of NVS02 (BCSII)
Dissolution rateWater, 0.1% SDS(20mg NVS02)
- Crystaline drug - Amorphous drug- Solid Dispersion- Solid Dispersion with 10% SDS
Same rank order of tested formulations in in-vitro dissolution rate and in-vivo plasma level curves
Fasted dogs, 20mg/animal (n=8)
19 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
II. Solid Dispersions Impact of surfactant on pharmacokinetic of NVS02 (BCSII)
30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)
Who
le blo
od co
ncen
tratio
n (ng
/mL)
-10
0
10
20
30
40
50
60
70
80
90
100
Time post-dose (h)0 12 24 36 48 60 72
SD with 10% surfactantSD without surfactant
30 mg ASM981 (MF, fasted, 2 x 15 mg)30 mg ASM981 (FMI, fasted, 1 x 30 mg)
Who
le blo
od co
ncen
tratio
n (ng
/mL)
-10
0
10
20
30
40
50
60
70
80
90
100
Time post-dose (h)0 12 24 36 48 60 72
SD with 10% surfactantSD without surfactant
The formulation containing a surfactant showed a higher and less variable absorption of the drug from the GIT
47
51
CV %CV %
1.0
1.5
ttmaxmax
23
36
CV %CV %
72 (16)296 (130)+10% Polox.
28 (9)214 (97)- Polox.
CCmaxmaxAUC AUC 00--∞∞[ng h/ml][ng h/ml]
SolidSolidDispersionDispersion
Arithmetic mean ± SD whole blood concentration of NVS02 following administration of 30 mg tablets in healthy volunteers (n=18)
20 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
II. Solid Dispersions Physical and chemical stability
time (years)
0
20
40
60
80
100
0 1 2 3 4
%
chemical degradation
physical stability of amorphous state
time (years)
0
20
40
60
80
100
0 1 2 3 4
%
chemical degradation
physical stability of amorphous state
0
20
40
60
80
100
0 1 2 3 4
%
chemical degradation
physical stability of amorphous state
RISK: Recrystalization of amorphous drug during storage
21 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
II. Solid DispersionsPharmacokinetics of NVS02 solid dispersions (with diff. % of crystalline DS)
Data indicate that exposure is significantly reduced when drug Data indicate that exposure is significantly reduced when drug crystalizes out during storage of the solid dispersioncrystalizes out during storage of the solid dispersion
0
2
4
6
8
1 0
1 2
1 4
0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )
NK
P608
pla
sma
conc
entr
atio
n in
ng/m
LH HG GE E
SD-tablet, 100% amorphous drugSD-tablet, 70% amorphous drugSD-tablet, 50% amorphous drug
NVS
02 p
lasm
a co
ncen
trat
ion
in
ng/m
l
0
2
4
6
8
1 0
1 2
1 4
0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )
NK
P608
pla
sma
conc
entr
atio
n in
ng/m
LH HG GE E
SD-tablet, 100% amorphous drugSD-tablet, 70% amorphous drugSD-tablet, 50% amorphous drug
0
2
4
6
8
1 0
1 2
1 4
0 1 0 2 0 3 0 4 0 5 0T im e (h o u rs )
NK
P608
pla
sma
conc
entr
atio
n in
ng/m
LH HG GE E
SD-tablet, 100% amorphous drugSD-tablet, 70% amorphous drugSD-tablet, 50% amorphous drug
NVS
02 p
lasm
a co
ncen
trat
ion
in
ng/m
l
Single dose, 3-arms, crossover study in fasted dogs (n=9)
Physical stability can cause significant variability in pharmacoPhysical stability can cause significant variability in pharmacokinetics kinetics of solid dispersionsof solid dispersions
22 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Example
Formulation approach for a lipophilic, poorly water soluble drug
Microemulsion
23 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsEnhancement of oral absorption of poorly water soluble drugs (PWSD)
Fig from Porter CJH et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007, 231-248
3. Interacting with enterocyte-based transport and metabolic processes
2. Affecting absorption pathway of drug transport to the systemic circulation
1. Increasing solubilizationand drug disposition in the intestinal lumen
SOLUBILIZATION
permeation
24 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsIncreasing solubilization and drug disposition in the intestinal lumen
Fig from Porter CJH et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007, 231-248
Increase solubilization capacity for lipid digestion products and drugs in the small intestine
Formation of colloidal structures with endogenous bilary lipids
Digestion of exogenous lipidsby pancreatic enzymes (lipase, co-lipase) TG DG MG + FA
25 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsIn-vivo performance
Fig from Porter CJH et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007, 231-248
Risk: Precipitation on Dispersion of the formulation
Risk: Precipitation on Digestion of the formulation
Lipid-based formulations must maintain drug in solution in the GIT
to enhance oral bioavailability
26 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based systems Micellular systems, Microemulsions, Emulsions
20 – 150 nm(< 200 nm)
Up to a few µm
Micelle (o/w) Microemulsion (o/w):
Thermodynamically stable
Translucent, isotropic
Emulsion (o/w):
Thermodynamically unstable
Milky apperance
27 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based systems: Microemulsions: Phase diagram screening – Potential formulations
Surfactant
Lipophilicphase
Hydrophilic phase
I00%
90 10
80 20
70 30
60 40
50 50
40 60
30 70
20 80
10 90
I00% 90 80 70 60 50 40 30 20 10I00%
Undiluted Preconcentrate
Diluted
•Clear, homogenousformulation
•No precipitation with a reasonable drug loading
•Self-dispersing•Stable and no precipitationin physiological relevant time frame
28 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Solubilisation
Organic or lipid-based solutions
III. Lipid based SystemsOral Absorption of Poorly Water Soluble Drugs
Microemulsion
Filling
Encapsulation
NOT bioavailable
Bioavailable
29 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
In-situ formation of the microemulsion
Soft gel capsule filledwith microemulsion preconcentrate
Water
III. Lipid based formulationsFrom Preconcentrate to the Microemulsion
30 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid-based formulationsCyclosporine A
Cyclic petide (containing 11 aminoacids)
Lipophilic, low aqueous solubility (< 0.004% w/v)
Higher solubility in lipids (olive oil >4%) and ethanol (~10%)
Cyclosporine A
31 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsCyclosporine vs. Sandimmun ® vs. Sandimmun Neoral ®
Prior to dilution with water
Diluted with water
Cyclosporine drug substance
Sandimmun® SandimmunNeoral®
32 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsSandimmun ® vs. Sandimmune Neoral ® - Pharmacokinetic data
• Sandimmun®: Adsorption is dependent on digestion of the lipid-formulation solubilization depends on individual physiological state in the GIT (e.g. food
intake, bile flow) high inter- and intra-subject variability
Concentration-time profiles following single oral administration of 300 mgSandimmun® to 24 volunteers
J.M. Kovarik et al., Journal of Pharmaceutical Sciences, 83 (3), 1994
0
200
400
600
800
1000
1200
1400
1600
0 2 4 6 8Time (h)
Con
cent
ratio
n (n
g/m
l) Sandimmun®
0
200
400
600
800
1000
1200
1400
1600
0.0 2.0 4.0 6.0 8.0Time (h)
Con
cent
ratio
n (n
g/m
l)
Concentration-time profiles following single oral administration of 180 mgSandimmun Neoral® to 24 volunteers
Sandimmun Neoral®
• Sandimmun Neoral®: Spontaneous formation of the microemulsion in the GIT without the need of endogenous compounds like bile salts / phospholipids
significant reduction of dose as well as inter-, and intra-subject variability
33 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsLipid digestion models for in-vitro assessment lipid-based formulations
Sek L et al. , J. Pharm. Pharmacol., 2002, 54:29-41Porter CJH et al. , Nature Reviews | Drug Discovery, 2007, 6:231-248
Undispersed oil phasecontaining drug (D)
Aqueous phasecontaining drug solubilized in micellarand vesicular structures,
Pellet phasecontaining precipitated drug and insoluble (calcium) soaps of FA
34 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
III. Lipid based formulationsIn vitro digestion test to evaluate solubilization pattern after digestion
0
200
400
600
800
1000
1200
1400
1600
0 2 4 6 8Time (h)
Con
cent
ratio
n (n
g/m
l)
0
200
400
600
800
1000
1200
1400
1600
0.0 2.0 4.0 6.0 8.0Time (h)
Con
cent
ratio
n (n
g/m
l)
Sandimmun Neoral®Sandimmun®
0
10
20
30
40
50
60
70
80
90
100
% in aqueous phase % in pellet phase
Digestion phases%
mod
el P
WSD
FastedFed
Digestion phases
0
10
20
30
40
50
60
70
80
90
100
% in undigested phase % in aqueous phase % in pellet phase
% m
odel
PWS
D
FastedFed
Similar solubilization pattern in Similar solubilization pattern in fasted and fed statefasted and fed state
Digestion needed to release and Digestion needed to release and maintain drug in the aequous solutionmaintain drug in the aequous solution
Ref: Taillardat A. et al. Am. Pharm Rev 2007 10(6):40-46
35 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Examples
Improved oral bioavailability of a weakly basic drug
pH-modified Formulations
36 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
IV. pH-modified FormulationsImproved bioavailability of weakly basic drugs by modulating the micro-pH
Gastrointestinal pH is influenced by several factors (e.g. food, age) intra-, intersubject variability
Stomach (fasted): pH 1-2
Intestine (fasted): pH 5-6
pH-modified Formulation: Incorporation of acids to improve dissolution of weakly basic drugs
pH2 3 4 5 6 7 8
Dip
yrid
amol
e so
lubi
lity
[mg/
ml]
0
10
20
30
40N
N
N
NN
N N
N
CH2OH
CH2OH
CH2OH
CH2OH
Dipyridamole:Solubility pH=2.72 36.64 mg/ml
pH=6.80 0.0031 mg/ml
37 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
0 60 120 180 240 300 3600
20
40
60
80
100 FA CA SA AA no acid
Dru
g re
leas
e [%
]
Time [min]
28.611.64.2Ascorbic acid (AA)
7.75.64.2Succinic acid (SA)
59.26.44.83.1Citric acid(CA)
0.614.43.0Fumaric acid (FA)
SolubilitypKa3pKa2pKa1Acid type
28.611.64.2Ascorbic acid (AA)
7.75.64.2Succinic acid (SA)
59.26.44.83.1Citric acid(CA)
0.614.43.0Fumaric acid (FA)
SolubilitypKa3pKa2pKa1Acid type
Acidic strength and solubility of the acids have an impact on drug release
(Ref. Siepe S. et.al. PhD-thesis 2005)
Dissolution in phosphate buffer pH 6.8, SDS 0.1%
IV. pH-modified FormulationsEffect of different pH-modifier (20%) on release rate of Dypyridamol tablets
Fumaric acid selected due to most favourable phys.-chem. properties
38 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Optimal drug to pH-modifier ratio (1:1)
Monolytic tablet (d=10mm) Minitablets (d=2mm)
0 60 120 180 240 300 3600
20
40
60
80
100
Dru
g re
leas
e [%
]
Time [min]
FA 20% FA 40% Without acid
0 30 60 90 120 150 1800
20
40
60
80
100
Dru
g re
leas
e [%
]
Time [min]
Without acid FA 20%
0 1 2 3 4 5 6 70
20
40
60
80
Solu
bilit
y [g
/l]
pH
Solubility profile NVS05
Dissolution rate: minitablets > monolytic tablets
(Ref. Siepe S. et.al. PhD-thesis 2005)
IV. pH-modified FormulationsDissolution rate of NVS05 (20%) pH-modified tablets (monolytic-, mini-tablets)
Dissolution rate in phosphate buffer pH 6.8, SDS 0.1%
39 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
IV. pH modified FormulationsIn-vivo study in fasted, gastric-acidity controlled beagle dogs (n=6)
Plasma level
A A-FA B B-FA0
20
40
60
80
100
CV
[%]
Formulation
Minitab
lets w
ith F
A
Minitab
lets w
ithou
t FA
Table
ts with
FA
Tablet
s with
out F
A
A A-FA B B-FA0
20
40
60
80
100
CV
[%]
Formulation
Minitab
lets w
ith F
A
Minitab
lets w
ithou
t FA
Table
ts with
FA
Tablet
s with
out F
A
AUC0-24h Variability
The incorporation of an acidic ph-modifier improved oral bioavailability of a weakly basic drug (exposure, variability)
0 2 4 6 8 10 12 140
50
100
150
200
250
300
NV
R1
plas
ma
conc
entra
tion
[ng/
ml]
Time [h]
Tablet without FA Tablets with FA Minitablet without FA Minitablet with FA
NV
S5
Intersubject variability of multiparticulates < monolytic tablet
(Ref. Siepe S. et.al. PhD-thesis 2005)
40 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Several formulation approaches are available to improve the dissolution rate of poorly water soluble compoundsTo identify the most appropriate formulation principles the drug substance properties, the pharmacological dose (range) and physiological state have to be considered In-vitro and in-silico tools should be fully utilized to select the most appropriate technology / formulation variantToday in-vivo studies for a final proof of concept are still needed
Summary
41 | Drug Delivery Systems for PWSD | Oskar Kalb | SAQ Conference, Olten, 23. June 2009
Dieter BeckerJean CuineAnke DiederichBruno GalliMichael JuhnkeMartin Mueller-ZsigmondyStefanie SiepeAgnes TaillardatCarsten Timpe
Thanks to