monash.edu reducing variability in drug absorption from oral dosage forms colin w pouton monash...
TRANSCRIPT
monash.edu
Reducing variability in drug absorption from oral dosage formsColin W PoutonMonash Institute of Pharmaceutical [email protected]
Khartoum meeting, November 2015
• Delivery challenges presented by contemporary drugs• Generation of supersaturation during digestion and dispersion• Lipid delivery systems: lessons learned from digestion testing• Polymeric precipitation inhibitors• Future perspectives
Reducing variability in drug absorption from oral dosage forms
2
The changing nature of drug candidates
• The low hanging fruit has been picked• Search for improved selectivity, higher potency, building on hits derived
from library screens - often leads to higher molecular weight drugs with high log P- these drug candidates have low water solubility (BCS Class II) - often low membrane permeability as well (BCS Class IV)
• Traditional tablet formulations do not give adequate control of drug absorption
• The important issue is variability- between patients, on different days etc- administration to fasted versus fed subjects
Changes in log P and MW for 592 oral drugs
Leeson and Springthorpe, Nature Reviews Drug Discovery, 6: 881-890 (2007)
Options for formulation of poorly-water soluble drugs
Nanosuspensions- increase dissolution rate but not drug solubility
Amorphous drug in solid drug dispersions- spray-dried dispersions formed into tablets- melt extrusion technologies
Lipid-based delivery systems- mixed liquids (oils, surfactants, cosolvents) filled into soft or hard capsules
Williams et al, Pharmacol. Rev., 65: 315-499 (2013)
Amorphous solid dosage forms offer advantages due to temporary supersaturation
1. Dissolution2. Sustained supersaturation3. Precipitation towards intrinsic crystalline solubility
7
Aim is to avoid drug precipitation (Dppt) during dispersion and/or digestion
Dissolution rate from crystalline solid drug is likely to be limiting for poorly water-soluble drugs
Porter et al., Adv. Drug. Del. Rev. (2008) 60, 673
Ds
Dppt
fast
Ddisp
± digestion± bile
D
slowfast
Lipid Based Drug Delivery Systems – basic concepts
8
Digestion and solubilization of dietary oils
Christopher J. H. Porter et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007, 231-248
Important to consider [drug] vs. solubility (in the digested lipid formulation)
[D]colloid
D DD
Intestinal wall
digestion[D]free
absorption
(fast)(fast)
D DDD DD
Total solubilized concentration of drug in the digested lipid formulation
Concentration relative to the solubility in the digested formulation will determine whether supersaturation is produced
Intestinal wall
10
[D]colloid
D DD
Intestinal wall
digestion[D]free
absorption
(fast)(fast)
D DDD DD
Supersaturation is generated if this concentration is above the solubility in the digested lipid formulation.
Supersaturation drives absorption via increases in thermodynamic activity in both the colloidal and free fraction.
Supersaturation generated by digestion can increase drug absorption
Intestinal wall
However, supersaturation generated by digestion can also decrease drug absorption
11
[D]colloid
D DD
Intestinal wall
digestion[D]free
absorption
(fast)(fast)
D DDD DD
High degrees of supersaturation can also drive precipitation, which will in turn decrease drug absorption.
[D]solid
precipitationprecipitation
What do lipid formulations consist of?
Further reading: Pouton and Porter 2008 Advanced Drug Delivery Reviews 60, 625-637
LIPIDS/OILS
Soybean oil, corn oil, Miglyol®, MaisineTM 35-1, Capmul®
Include for: - Dissolving highly lipophilic drugs.- Maintaining solubilization post-dispersion.- Harnessing natural digestion, absorption/lymphatic pathways.
NON IONIC SURFACTANT(S)
Tween® 85 (low HLB), Tween® 80, Cremophor® EL (higher HLB)
Include for :- Emulsification of the oil component- Minimizing loss of solubilization on dispersion/digestion
COSOLVENTS
Ethanol, PEG 400, propylene glycol etc.
Include for: - Higher drug loading capacity - Better dispersibility
Drug is usually dissolved, and therefore, ‘molecularly dispersed’ in the formulation. Commercial examples: Neoral®, Agenerase®, Fortovase® etc.
17
Current Lipid Formulation Classification System
Formulations classified according to composition
Type I Type II Type IIIA
Type IIIB
Type IV
Typical composition (%)
Triglycerides or mixture of glycerides
100 40-80 40-80 <20 -
Water insoluble surfactant
- 20-60 - - 0-20
Water soluble surfactant
- - 20-60 20-50 30-80
Cosolvent - - 0-40 20-50 0-50
Pouton, Eur J Pharm Sci 29: 278-287 (2006) 18
www.lfcsconsortium.org 20
Introducing the LFCS Consortium
A non-profit organization that sponsors and conducts research on lipid-based drug delivery systems (LBDDS) for the oral administration of poorly soluble drugs (www.lfcsconsortium.org)
Industrial Full Members• Capsugel• Sanofi Aventis
Associate Members• Actelion• BMS• Gattefossé• Merck-Serono• NicOx• Roche
Academic Members• Monash University • University of Copenhagen• University of Marseille
www.lfcsconsortium.org 22
Metrohm® titration apparatus for in vitro digestion testing
Reaction vessel
Dosing units
Overhead stirrer
pH probe• pH-stat titrator to maintain
constant pH during digestion.
• Rate and total titrant added informs of LBF digestibility.
% d
anaz
ol
0
25
50
75
100
Drug load (saturation) very important for medium chain lipids
Increasing drug load from 20-90% of saturated solubility in formulation, significantly decreases % solubilised post digestion
www.lfcsconsortium.org
20 40 60 80 90
Type II-MC
Precipitated drug
Solubilised drug (aqueous phase)
Drug loading (% sat sol in formulation)
Williams et al Mol Pharmaceutics (2012)
% d
anaz
ol
0
25
50
75
100
Degree of precipitation most significant in least lipophilic formulations (ie more cosolvent, more hydrophilic surfactants)
www.lfcsconsortium.org
Type II-MC Type IIIA-MC Type IV
Drug loading (% sat sol in formulation)
20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90
Solubilised drug (aqueous phase)
Precipitated drug
Type IIIB-MC
Williams et al Mol Pharmaceutics (2012)
Drug load (saturation) very important for medium chain lipids
Conventional IR solid dose form
Solubilisation Effect
Drug solubility in GIT fluids
LBDDS often result in supersaturation
Drug solubility in GIT fluids plus (digested) lipids, surfactants in LBDDS
Supersaturated LBDDS
Supersaturation Effect
Dispersed and digested LBDDS
28
www.lfcsconsortium.org 29
In vitro digestion testing – fenofibrate formulations
In vitro digestion data at a fixed 125 mg fenofibrate dose
0 20 40 600.0
1.0
2.0
3.0
4.0Disp Digestion
Time (min)
Fen
ofib
rate
sol
ubili
zed
(mg/
ml)
IIIA-LC
IIIA-MC
IV
IIIB-MC
Quantifying supersaturation in lipid based formulations
time
[drug]aq
Equilibrium drug solubility in drug-free APDIGEST
Maximum [drug]aq (100% solubilised)
= Maximum supersaturation ratio (SRmax)
Supersaturation ratio at time, t
t
The greater the maximum supersaturation ratio, the greater the driving force to precipitation dependent on drug loading (ie saturation level)
Does maximum (initial) supersaturation ‘pressure’ dictate precipitation profiles?
[dru
g] a
q
www.lfcsconsortium.org 31
% non-precipitated dose
< 40% 40-70% >70%
Does SRMAX predict the likelihood of drug precipitation ?
7.5
2.5
SRMAX
www.lfcsconsortium.org 32
Saturation study: the trends based on supersaturation
< 40% 40-70% >70%
High BS Fasted Highly diluted
Min 40% 60% 80% 20% 40% 60% 80% 40% 60% 80%
II-MC 30 3.1 4.7 6.2 1.5 3.1 4.6 6.2 7.6 11.5 15.3
60 3.1 4.7 6.2 1.5 3.1 4.6 6.2 7.6 11.5 15.3
IIIA-MC 30 2.7 4.0 5.3 1.4 2.8 4.3 5.7 5.0 7.6 10.1
60 2.7 4.0 5.3 1.4 2.8 4.3 5.7 5.0 7.6 10.1
IIIB-MC 30 4.5 6.8 9.1 2.0 3.9 5.9 7.8 3.6 6.0 8.0
60 4.5 6.8 9.1 2.0 3.9 5.9 7.8 3.6 6.0 8.0
IV 30 7.5 11.2 15.0 2.9 5.7 8.6 11.5 5.7 8.5 11.4
60 7.5 11.2 15.0 2.9 5.7 8.6 11.5 5.7 8.5 11.4
% non-precipitated dose
www.lfcsconsortium.org 33
Saturation study: the trends based on supersaturation
< 40% 40-70% >70%
- Low SRMAX = Green (good solubilisation)- High SRMAX = Red (precipitation)
High BS Fasted Highly diluted
Min 40% 60% 80% 20% 40% 60% 80% 40% 60% 80%
II-MC 30 3.1 4.7 6.2 1.5 3.1 4.6 6.2 7.6 11.5 15.3
60 3.1 4.7 6.2 1.5 3.1 4.6 6.2 7.6 11.5 15.3
IIIA-MC 30 2.7 4.0 5.3 1.4 2.8 4.3 5.7 5.0 7.6 10.1
60 2.7 4.0 5.3 1.4 2.8 4.3 5.7 5.0 7.6 10.1
IIIB-MC 30 4.5 6.8 9.1 2.0 3.9 5.9 7.8 3.6 6.0 8.0
60 4.5 6.8 9.1 2.0 3.9 5.9 7.8 3.6 6.0 8.0
IV 30 7.5 11.2 15.0 2.9 5.7 8.6 11.5 5.7 8.5 11.4
60 7.5 11.2 15.0 2.9 5.7 8.6 11.5 5.7 8.5 11.4
% non-precipitated dose
www.lfcsconsortium.org 34
SRM ‘predicts’ drug fate during in vitro digestion of LBFs:
0 5 10 150
25
50
75
100
SRM
Tol
f. ac
id s
olu
biliz
ed in
the
aque
ous
pha
se (
%)
SRM
0 5 10 150
25
50
75
100
Fen
ofib
rate
so
lubi
lized
inth
e aq
ueou
s ph
ase
(%)
SRM
0 5 100
25
50
75
100
Dan
azo
l sol
ubili
zed
inth
e aq
ueo
us p
hase
(%
)
danazol fenofibrate
tolfenamic acid
Threshold SRM ~2.5
Threshold SRM ~3.0
Threshold SRM ~3.0
(increasing supersaturation pressure) • ‘SRM threshold identified in each case.
• Above this supersaturation threshold, formulation performance is variable/poorer due to precipitation.
Williams et al Mol Pharmaceutics (2012)
Polymeric precipitation inhibitors
• HPMC and HPMC-AS are polymeric excipients that have been used to produce amorphous spray-dried dispersion formulations of drugs.
• These polymers inhibit the precipitation of some drugs after dissolution of the formulations
• In recent years similar approaches to precipitation inhibition have been explored with lipid systems – but this research is in its infancy.
35
36
Effect of HPMC on precipitation of danazol during digestion
• HPMC effectively reduced ppt from MC SEDDS in conc dependent manner
Time [min]
-20 0 20 40 60
Da
naz
ol i
n A
P [u
g/m
L]
0
100
200
300
400
500
600
No polymer
0.0125% HPMC
0.025% HPMC
0.125% HPMC
37
SFmax
0 2 4 6 8 10
% S
olub
ilise
d
0
20
40
60
80
100
Polymer precipitation inhibitors have the greatest effect close to the SRM threshold
HPMC inhibits precipitation at the threshold, but exhibits a lower utility at high supersaturations (i.e., >5).
SM is shown during dispersion (triangles) or digestion (circles) from formulations containing danazol at either 40% (orange) or 80% (black) solubility in formulation. Purple formulations are identical but also contain 5% HPMC
SM
% d
anaz
ol s
olub
ilize
d
SFmax
0 2 4 6 8 10
% S
olu
bili
sed
0
20
40
60
80
100
add HPMC to the LBF
Formulations: Captex®/Capmul®/
Cremophor® EL/EtOH
Anby et al Mol. Pharm. (2012) 9, 2063-2079
in vitro – in vivo correlation with danazol
In vitro dispersion and digestion
In vivo exposure after oral administration to beagle dogs
Lack of in vitro precipitation correlated well with enhanced in vivo exposure
Use of digestion tests increasingly popular…but some variation in methods across laboratories
In vivo bioavailability in beagle dogs
Time (hr)
0 2 4 6 8 10
Dan
azol
pla
sma
conc
entr
atio
n (n
g/m
L)
0
20
40
60
80
100
120
140
Time (min)
0 10 20 30 40 50 60
% D
rug
in a
queo
us p
hase
0
20
40
60
80
100
120
F4F3
F2
F1
F4F3
F2
F1
Cuine et al, Pharm Res 24, 748-757, 2007 39
www.lfcsconsortium.org 40
0 50 100 150 200 250 3000
10
20
30
40
R² = 0.918179370547117
In vitro AUC (mg*min/ml)
In v
ivo
AU
C (
µg
*h/m
l)• In vitro performance data
at a fixed 125 mg fenofibrate dose
0 20 40 600.0
1.0
2.0
3.0
4.0Disp Digestion
Time (min)
Fen
ofib
rate
so
lub
ilize
d (
mg
/ml)
IIIA-LC
IIIA-MC
IV
IIIB-MC
In vitro summary:
IIIA-LC
IIIA-MC
IV
IIIB-MC
Calculate AUC and plot vs. in
vivo AUC
• Differences in in vivo exposure were comparatively small compared to differences in vitro
Poor in vitro – in vivo correlation with fenofibrate
www.lfcsconsortium.org 41
In vivo results summary
Time [h]
0 2 4 6 8
Fen
ofib
ric a
cid
Pla
sma
Con
c. [
ng/m
L]
0
2000
4000
6000
8000
10000
12000
Cmax (µg/ml)
AUC0-∞
(µg.h/ml)Tmax
(hours)
Type IIIA-LC 7.4 ± 1.6 34.0 ± 4.4 1.3 ± 0.3
Type IIIA-MC 4.8 ± 1.0 29.1 ± 2.9 1.4 ± 0.5
Type IV 6.8 ± 3.4 26.1 ± 6.6 0.9 ± 0.1
Type IIIB-MC 5.9 ± 1.3 25.3 ± 3.2 1.4 ± 0.3
Dec
reas
ing
AU
C
no significant differences were observed across the four LFCS formulation types
Future perspectives
• For weak electrolyte drugs the production of novel salts in the form ionic liquids is an interesting new option
42
43
Example Ionic liquid forms of CIN
CIN octadecylsulphateTm 78-81ºC
CIN triflimideTm 38-43ºC
CIN oleateTm 93-98ºC
CIN decylsulphateViscous liquid at RT
Sahbaz et al Mol Pharm (2015) 12, 1980-1991
CIN free base Tm 118-120ºC
44
Solubility of CIN ionic liquids in two lipid formulations
• Solubility of CIN.IL forms substantially higher (up to 10-fold), some (decyl sulphate and triflimide) essentially miscible
CIN Cin OS Cin ST Cin OL CIN DS Cin LS Cin TF0
50
100
150
200
250
300
350
LC-SEDDS
MC-SEDDS
CIN
so
lub
ility
, mg
/g –
(fr
ee
ba
se e
qu
iva
len
t)
Ionic liquid forms of CIN
>300 mg/g >300 mg/g
Sahbaz et al Mol Pharm (2015) 12, 1980-1991
LC-SEDDS: SBO/Maisine/Crem EL/EtOH
15/15/60/10
MC-SEDDS:MCT/Capmul/Crem EL/EtOH,
15/15/60/10
45
Time (h)
Cin
nariz
ine
plas
ma
conc
entr
atio
n (n
g/m
l)
0 5 10 15 20 250
1000
2000
3000
In vivo performance of CIN.DS containing lipid formulations
CIN.DS, LC SEDDS (125 mg/kg)
• CIN.DS IL allowed >3.5 increase in CIN dose
• Despite increased CIN/formulation ratio, absorption maintained
CIN free base, LC SEDDS (35 mg/kg)
CIN free base, aq. suspension (125 mg/kg)
Sahbaz et al Mol Pharm (2015) 12, 1980-1991
Future perspectives
• For weak electrolyte drugs the production of novel salts in the form ionic liquids is an interesting new option
• We need to develop a better understanding of the consequences of supersaturation in the gastrointestinal tract. This will require laboratory models that incorporate absorption.
• In the long-term IVIVC studies with a range of drugs will be required to build a database to help formulators predict in vivo performance.
46
In situ rat loop model combined with in vitro digestion testing better IVIVC
Matt Crum
47
The LFCS Consortium
Industrial Full Members• Capsugel• Sanofi Aventis
Associate Members• Actelion• BMS• Gattefossé• Merck-Serono• NicOx• Roche Academic Members
• Monash University • University of Copenhagen• University of Marseille
49
AcknowledgementsUniversity of Bath (1982-2001)Mark Wakerly Debbie ChallisLinda SolomonNaser HasanRajaa Al Sukhun
Monash University (2001-present)Jean Cuine Prof Chris PorterKazi Mohsin Prof Bill CharmanMette Anby Dallas Warren Ravi Devraj Hywel WilliamsOrlagh FeeneyMatt Crum
R P Scherer Ltd (collaboration on digestion experiments 1991-1994)Cardinal Health (support for molecular dynamics modeling 2002-2004)Abbott Laboratories (lipid formulations 2002-2007)Michelle LongCapsugel (lipid formulations, LFCS and IVIVC 2003-present)Hassan Benameur, Jan Vertommen, Keith Hutchison, Hywel Williams