1. Reducing variability in drug absorption from oral dosage forms
Khartoum meeting, November 2015
Reducing variability in drug absorption from oral dosage forms
Colin W Pouton
Monash Institute of Pharmaceutical Sciences

2. Reducing variability in drug absorption from oral dosage forms
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

3. 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

4. Changes in log P and MW for 592 oral drugs
Leeson and Springthorpe, Nature Reviews Drug Discovery, 6: (2007)

5. 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: (2013)

6. Amorphous solid dosage forms offer advantages due to temporary supersaturation
Dissolution
Sustained supersaturation
Precipitation towards intrinsic crystalline solubility

7. Lipid Based Drug Delivery Systems – basic conceptsDs
Dppt
fast
Ddisp
digestion
bile D
slow
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

8. Digestion and solubilization of dietary oils
Christopher J. H. Porter et al. , Nature Reviews | Drug Discovery, Vol. 6, March 2007,

9. Important to consider [drug] vs
Important to consider [drug] vs. solubility (in the digested lipid formulation)
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 D
absorption
digestion D
[D]colloid
[D]free
(fast) D
(fast)
Intestinal wall

10. Supersaturation generated by digestion can increase drug absorption
Intestinal wall
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. D
absorption
digestion D
[D]colloid
[D]free
(fast) D
(fast)
Intestinal wall

11. However, supersaturation generated by digestion
can also decrease drug absorption
High degrees of supersaturation can also drive precipitation, which will in turn decrease drug absorption. D
absorption
digestion D
[D]colloid
[D]free
(fast) D
(fast)
precipitation
precipitation
[D]solid
Intestinal wall

12. How do lipid systems enhance bioavailability?
Lipid systems can present the drug in solution which avoids slow dissolution
- but be aware of the possibility of precipitation
A rapidly dispersing lipid system is likely to empty into the small intestine quickly
- be aware that his may lead to rapid onset and high Cmax
Interaction of drug with bile salt-lipid mixed micelles is usually the mechanisms for enhanced bioavailability after a fatty meal
Even a small dose of lipid in capsule form can stimulate bile flow and turnover of endogenous lipid

13. How much advantage can we expect from lipid systems?
Lipid systems can often achieve the same gains in bioavailability as a fatty meal – but are unlikely to do better
The main benefit of lipid systems is the opportunity to formulate the drug such that absorption rate and bioavailability are unaffected by food
With the above comes reduced variability from day- to-day and patient-to-patient

14. Halofantrine: fed/fasted vs lipid formulation effect
tablet fed
Lipidic formulation fasted
fed
fasted
tablet fasted
Healthy volunteers, oral administration of 250 mg Hf HCl as a simple tablet formulation (n = 6)
(Milton et al. Br. J. Clin. Pharmacol. 1989; 28:71-7.)
Beagle dogs, 250 mg of Hf HCl as a simple tablet formulation fasted and fed or molar equivalent of Hf base in a self-emulsifying formulation (peanut oil, Tagat TO)
(Humberstone et al J. Pharm. Sci. 1996; 85:525-9)

15. Danazol: fed/fasted vs lipid formulation effect
Lipidic formulation fasted
fed
Powder fed
fasted
Powder fasted
Healthy volunteers (n=12), oral administration, commercial 100 mg danazol capsule
(Charman et al. J. Clin. Pharmacol. 1993; 33:381-6)
Beagle dogs (n=4), 15 mg of danazol,
powder-in-capsule formulation, fasted and fed; Self-microemulsifying formulation (SBO, Maisine, Cremophor)
(Porter et al. Pharm. Res. 2004; 21: )

16. Generation of supersaturation during digestion and dispersion in the gastrointestinal tract
Although the digestion of formulations and interaction with bile can provide a matrix for solubilization of drug, in practice many formulations can lead to drug precipitation.
Precipitation can take place during dispersion or digestion
Supersaturation will drive more rapid absorption as well. If this happens before precipitation then it may be a benefit.

17. NON IONIC SURFACTANT(S)
What do lipid formulations consist of?
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.
Further reading:
Pouton and Porter 2008 Advanced Drug Delivery Reviews 60,

18. 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
<20 -
Water insoluble surfactant
20-60
0-20
Water soluble surfactant
20-50
30-80
Cosolvent
0-40
0-50
Pouton, Eur J Pharm Sci 29: (2006)

19. Lessons learned from digestion testing
The Lipid Formulation Classification System (LFCS) Consortium was formed in 2010 (
During the Consortium funded studies on dispersion and digestion testing and performed some IVIVC studies in dogs which have advanced our understanding
- but there is a lot more research to be done

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 (
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

21. The 8 lipid formulations investigated by the LFCS
Type I Type II Type IIIA Type IIIB Type IV
Lipids:
Long-chain: Corn oil and MaisineTM 35-1 (in a 1:1 ratio)
Medium-chain : Captex® 300 and Capmul® MCM EP (in a 1:1 ratio)
Lipophilic surfactant: Tween® 85
Moving on to the core of the LFCS and day-to-day operation, we have been scrutinizing the performance of 8 lipid formulations shown above.
You will see that we have deliberately selected a wide range of formulations, showing variability in a range of properties so that LFCS guidelines and performance criteria are applicable to all types of lipid formulations
Hydrophilic surfactant: Cremophor® EL
Cosolvent: Transcutol HP
Variation in :
Composition Drug Loading Capacity Dispersibility Digestibility

22. Metrohm® titration apparatus for in vitro digestion testing
Dosing units
Overhead stirrer
This slide essentially captures the set-up used both at Monash and Copenhagen to perform in vitro digestion tests, where are using the Metrohm pH-stat apparatus for continous monitoring of pH during the digestion tests, with the actual digestions performed within a Metrohm stirrer-vessel assembly.
pH probe
pH-stat titrator to maintain constant pH during digestion.
Rate and total titrant added informs of LBF digestibility.
Reaction vessel

23. Drug load (saturation) very important for medium chain lipids
Type II-MC
Solubilised drug (aqueous phase)
Precipitated drug 20 40 60 80 90
Drug loading (% sat sol in formulation)
Increasing drug load from 20-90% of saturated solubility in formulation, significantly decreases % solubilised post digestion
Williams et al Mol Pharmaceutics (2012)

24. Drug load (saturation) very important for medium chain lipids
Type II-MC
Type IIIA-MC
Type IIIB-MC
Type IV
Solubilised drug (aqueous phase)
Precipitated drug 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90
Drug loading (% sat sol in formulation)
Degree of precipitation most significant in least lipophilic formulations (ie more cosolvent, more hydrophilic surfactants)
Williams et al Mol Pharmaceutics (2012)

25. Drug load (saturation) less critical in LC formulations
Type II-MC
Type IIIA-MC
Type IIIB-MC
Type IV
Type IIIA-LC
Drug loading (% sat sol in formulation) 20 40 60 80 90
Long chain lipid containing formulations resist ppt more favourably and are less sensitive to drug load
Note: Type IIIA-LC formulations are incompletely digested in the fixed volume available (low density oil phase is shown in yellow)
Williams et al Mol Pharmaceutics (2012)

26. Drug load (saturation) less critical in LC formulations
Type II-MC
Type IIIA-MC
Type IIIB-MC
Type IV
Type IIIA-LC
Drug loading (% sat sol in formulation) 20 40 60 80 90
Why do LC formulations resist ppt more effectively?
- Generate intestinal colloids with intrinsically higher drug solubility?
- Stabilise supersaturated drug concentrations?
Williams et al Mol Pharmaceutics (2012)

27. Grading (/) based on level of drug precipitation
Towards a classification based on performance
A-type
B-type
C-type
D-type
Performance test
Dispersion  
Digestion (fasted)
Digestion (stressed)
A traditional “Type IIIA-MC” formulation might be classified B-type at high
drug loading but demonstrate A-type performance at low drug loading.
Sub-classification of the A-type might be required e.g. LBFs showing A-type
properties across a wide-range of drug loadings might be called a “A*-type”
Grading (/) based on level of drug precipitation
Decreasing performance

28. Supersaturation Effect
LBDDS often result in supersaturation
Supersaturated LBDDS
Supersaturation Effect
Drug solubility in GIT fluids plus (digested) lipids, surfactants in LBDDS
Dispersed and digested LBDDS
Solubilisation Effect
Drug solubility in GIT fluids
Conventional IR solid dose form

29. In vitro digestion testing – fenofibrate formulations
Time (min)
Fenofibrate solubilized (mg/ml)
IIIA-LC
IIIA-MC IV
IIIB-MC
In vitro digestion data at a fixed 125 mg fenofibrate dose

30. Quantifying supersaturation in lipid based formulations
Maximum [drug]aq (100% solubilised)
[drug]aq
[drug]aq
= Maximum supersaturation ratio (SRmax)
Supersaturation ratio at time, t
Equilibrium drug solubility in drug-free APDIGEST t
time
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?

31. Does SRMAX predict the likelihood of drug precipitation ?
7.5
2.5
SRMAX
% non-precipitated dose
< 40% % >70%

32. Saturation study: the trends based on supersaturation
High BS
Fasted
Highly diluted
Min
40%
60%
80%
20%
II-MC 30
3.1
4.7
6.2
1.5
4.6
7.6
11.5
15.3 60
IIIA-MC
2.7
4.0
5.3
1.4
2.8
4.3
5.7
5.0
10.1
IIIB-MC
4.5
6.8
9.1
2.0
3.9
5.9
7.8
3.6
6.0
8.0 IV
7.5
11.2
15.0
2.9
8.6
8.5
11.4
% non-precipitated dose
< 40% % >70%

33. Saturation study: the trends based on supersaturation
High BS
Fasted
Highly diluted
Min
40%
60%
80%
20%
II-MC 30
3.1
4.7
6.2
1.5
4.6
7.6
11.5
15.3 60
IIIA-MC
2.7
4.0
5.3
1.4
2.8
4.3
5.7
5.0
10.1
IIIB-MC
4.5
6.8
9.1
2.0
3.9
5.9
7.8
3.6
6.0
8.0 IV
7.5
11.2
15.0
2.9
8.6
8.5
11.4
% non-precipitated dose
Low SRMAX = Green (good solubilisation)
High SRMAX = Red (precipitation)
< 40% % >70%

34. SRM ‘predicts’ drug fate during in vitro digestion of LBFs:
danazol
fenofibrate
Threshold SRM ~2.5
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.
tolfenamic acid
Threshold SRM ~3.0
Williams et al Mol Pharmaceutics (2012)

35. 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.

36. Effect of HPMC on precipitation of danazol during digestion
No polymer
HPMC effectively reduced ppt from MC SEDDS in conc dependent manner

37. Captex®/Capmul®/Cremophor® EL/EtOH
Polymer precipitation inhibitors have the greatest effect close to the SRM threshold
Formulations:
Captex®/Capmul®/Cremophor® EL/EtOH
% danazol solubilized
add HPMC to the LBF SM
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
Anby et al Mol. Pharm. (2012) 9,

38. Profiling danazol precipitation during in vitro digestion
Initiation of digestion
Oil F1 Aq F2 F3
Pellet F4
Cremophor EL
SBO/maisine
Ethanol 1 2 3 4
On digestion, solubilising capacity lost to varying degrees
Cuine et al, Pharm Res 24, , 2007

39. in vitro – in vivo correlation with danazol
In vitro dispersion and digestion
In vivo bioavailability in beagle dogs F1 F1 F2 F3 F4 F4 F2 F3
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
Cuine et al, Pharm Res 24, , 2007

40. Calculate AUC and plot vs. in vivo AUC
Poor in vitro – in vivo correlation with fenofibrate
In vitro summary:
Time (min)
Fenofibrate solubilized (mg/ml)
IIIA-LC
IIIA-MC IV
IIIB-MC
IIIA-LC IV
Calculate AUC and plot vs. in vivo AUC
IIIA-MC
IIIB-MC
In vitro performance data at a fixed 125 mg fenofibrate dose
Differences in in vivo exposure were comparatively small compared to differences in vitro

41. In vivo results summary
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
Decreasing
AUC
no significant differences were observed across the four LFCS formulation types

42. Future perspectives
For weak electrolyte drugs the production of novel salts in the form ionic liquids is an interesting new option

43. Example Ionic liquid forms of CIN
CIN decylsulphate
Viscous liquid at RT
CIN octadecylsulphate
Tm 78-81ºC
CIN oleate
Tm 93-98ºC
CIN triflimide
Tm 38-43ºC
CIN free base Tm ºC
Sahbaz et al Mol Pharm (2015) 12,

44. Solubility of CIN ionic liquids in two lipid formulations
Ionic liquid forms of CIN
>300 mg/g
LC-SEDDS:
SBO/Maisine/Crem EL/EtOH
15/15/60/10
MC-SEDDS:
MCT/Capmul/Crem EL/EtOH,
Solubility of CIN.IL forms substantially higher (up to 10-fold), some (decyl sulphate and triflimide) essentially miscible
Sahbaz et al Mol Pharm (2015) 12,

45. In vivo performance of CIN.DS containing lipid formulations
CIN.DS, LC SEDDS (125 mg/kg)
CIN free base, LC SEDDS (35 mg/kg)
CIN free base, aq. suspension (125 mg/kg)
CIN.DS IL allowed >3.5 increase in CIN dose
Despite increased CIN/formulation ratio, absorption maintained
Sahbaz et al Mol Pharm (2015) 12,

46. 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.

47. In situ rat loop model combined with in vitro digestion testing better IVIVC
Matt Crum

48. The LFCS Consortium Industrial Full Members Associate Members Capsugel
Sanofi Aventis
Associate Members
Actelion
BMS
Gattefossé
Merck-Serono
NicOx
Roche
Academic Members
Monash University
University of Copenhagen
University of Marseille

49. Acknowledgements University of Bath (1982-2001) Mark Wakerly
Debbie Challis
Linda Solomon
Naser Hasan
Rajaa Al Sukhun
Monash University (2001-present)
Jean Cuine Prof Chris Porter
Kazi Mohsin Prof Bill Charman
Mette Anby Dallas Warren
Ravi Devraj Hywel Williams
Orlagh Feeney
Matt Crum
R P Scherer Ltd (collaboration on digestion experiments )
Cardinal Health (support for molecular dynamics modeling )
Abbott Laboratories (lipid formulations )
Michelle Long
Capsugel (lipid formulations, LFCS and IVIVC 2003-present)
Hassan Benameur, Jan Vertommen, Keith Hutchison, Hywel Williams