Monash.edu Reducing variability in drug absorption from oral dosage forms Colin W Pouton Monash...

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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

http://www.lfcsconsortium.org/


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


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


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


% non-precipitated dose

< 40% 40-70% >70%

Does SRMAX predict the likelihood of drug precipitation ?

7.5

2.5

SRMAX


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



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



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.


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


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


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

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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


LC-SEDDS: SBO/Maisine/Crem EL/EtOH

15/15/60/10

MC-SEDDS:MCT/Capmul/Crem EL/EtOH,

15/15/60/10

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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)


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.

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In situ rat loop model combined with in vitro digestion testing better IVIVC

Matt Crum

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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

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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

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