aaps, october 2015 enabling lipid formulations that ... enabling lipid formulations that harness...

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Enabling Lipid Formulations That Harness Supersaturation and Drug Absorption in the GI Tract

Colin W Pouton Monash Institute of Pharmaceutical Sciences [email protected]

AAPS, October 2015

• Generation of supersaturation during digestion and dispersion

• Lessons learned from digestion testing

• Polymeric precipitation inhibitors

• Future perspectives

Enabling Lipid Formulations That Harness Supersaturation and Drug Absorption in the GI Tract

2

3

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

slow fast

Lipid Based Drug Delivery Systems – basic concepts

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.

4

Conventional IR solid dose form

Solubilisation Effect

Drug solubility in GIT fluids

LBDDS May Also Promote Supersaturation

Drug solubility in GIT fluids plus (digested) lipids, surfactants in LBDDS

Supersaturated LBDDS

Supersaturation Effect

Dispersed and digested LBDDS

5

Lessons learned from digestion testing

• The Lipid Formulation Classification System (LFCS) Consortium was formed in 2010 (www.lfcsconsortium.org)

• During 2011-2014 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

6

www.lfcsconsortium.org 7

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) The Consortium is in its third year of operation

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/

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.

8

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) 9


The 8 lipid formulations investigated by the LFCS

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

Hydrophilic surfactant: Cremophor® EL

Cosolvent: Transcutol HP

Variation in :

Composition Drug Loading Capacity Dispersibility Digestibility

Type I Type II Type IIIA Type IIIB Type IV


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

anazol

0

25

50

75

100

Drug load (saturation) very important for MC

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

anazol

0

25

50

75

100

Drug load (saturation) very important for MC

Degree of precipitation most significant in least lipophilic formulations (ie more cosolvent, more hydrophilic surfactants)


Type II-MC Type IIIA-MC Type IV


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) less critical in LC formulations

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)


% d

anazol

0

25

50

75

100

Type II-MC Type IIIA-MC Type IV Type IIIA-LC


20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90

Type IIIB-MC


Drug load (saturation) less critical in LC formulations

Why do LC formulations resist ppt more effectively?

- Generate intestinal colloids with intrinsically higher drug solubility?

- Stabilise supersaturated drug concentrations?


% d

anazol

0

25

50

75

100

Type II-MC Type IIIA-MC Type IV Type IIIA-LC


20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90 20 40 60 80 90

Type IIIB-MC


Towards a classification based on performance

• 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”

A-type B-type C-type D-type

Performance test

Dispersion

Digestion (fasted)

Digestion (stressed)

Decreasing performance

Grading (/) based on level of

drug precipitation

16

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


In vitro digestion testing

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)

Fenofib

rate

solu

bili

zed (

mg/m

l)

IIIA-LC

IIIA-MC

IV

IIIB-MC


% 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 15

0

25

50

75

100

SRM

Tolf. acid

so

lubiliz

ed in t

he

aque

ous p

hase

(%

)

SRM

0 5 10 150

25

50

75

100

Fen

ofibra

te s

olu

biliz

ed in

the a

queou

s p

hase (

%)

SRM

0 5 10

0

25

50

75

100

Dana

zol solu

biliz

ed in

the a

qu

eous 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) in press

Profiling danazol precipitation during in vitro digestion

Time (min)

0 10 20 30 40 50 60

% D

rug in

aqu

eo

us p

hase

0

20

40

60

80

100

120

On digestion, solubilising capacity lost to varying degrees

Cremophor EL

SBO/maisine Ethanol

1

2 3 4

Initiation of digestion

Oil

Aq

Pellet

F4

F3

F2

F1

Cuine et al, Pharm Res 24, 748-757, 2007 23

Comparison of in vitro digestion vs in vivo exposure

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

azo

l p

lasm

a c

once

ntr

atio

n (

ng

/mL)

0

20

40

60

80

100

120

140

Time (min)

0 10 20 30 40 50 60

% D

rug in a

queous p

hase

0

20

40

60

80

100

120

F4

F3

F2

F1

F4

F3 F2

F1

Cuine et al, Pharm Res 24, 748-757, 2007 24


In vivo results summary

Time [h]

0 2 4 6 8

Feno

fibric a

cid

Pla

sm

a C

onc.

[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

De

cre

asin

g

AU

C

no significant differences were observed across the four LFCS

formulation types


R² = 0.9182

0

10

20

30

40

50

0 50 100 150 200 250 300

In v

ivo

AU

C (

µg

*h/m

l)

In vitro AUC (mg*min/ml)

In vitro-in vivo correlations

• 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

ilized (

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

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.

27

28

Effect of HPMC on precipitation of danazol during digestion

• HPMC effectively reduced ppt from MC SEDDS in conc dependent manner

• Conc required ~ 10 fold higher than in screening assay

Time [min]

-20 0 20 40 60

Da

na

zo

l in

AP

[u

g/m

L]

0

100

200

300

400

500

600

No polymer

0.0125% HPMC

0.025% HPMC

0.125% HPMC

29

SFmax

0 2 4 6 8 10

% S

olu

bili

se

d

0

20

40

60

80

100

It is at the SRM threshold when:

Polymer precipitation inhibitors have the greatest effect:

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

anazol solu

bili

zed

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

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.

30

31

Example Ionic liquid forms of CIN

CIN octadecylsulphate

Tm 78-81ºC

CIN triflimide

Tm 38-43ºC

CIN oleate

Tm 93-98ºC

CIN decylsulphate

Viscous liquid at RT

Sahbaz et al Mol Pharm (2015) 12, 1980-1991

CIN free base Tm 118-120ºC

32

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

0

50

100

150

200

250

300

350

400

CIN Cin OS Cin ST Cin OL CIN DS Cin LS Cin TF

CIN

so

lub

ility

, m

g/g

–

(fre

e b

ase

eq

uiv

ale

nt)

LC-SEDDS

MC-SEDDS

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

33

T im e (h )

Cin

na

riz

ine

pla

sm

a c

on

ce

ntr

ati

on

(n

g/m

l)

0 5 1 0 1 5 2 0 2 5

0

1 0 0 0

2 0 0 0

3 0 0 0

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.FB, LC SEDDS (35 mg/kg)

CIN.FB, aq. suspension (125 mg/kg)


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

36

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 1991-1994) Cardinal Health (support for molecular dynamics modeling 2002-2004) Abbott Laboratories (lipid formulations 2002-2007) Michelle Long Capsugel (lipid formulations, LFCS and IVIVC 2003-present) Hassan Benameur, Jan Vertommen, Keith Hutchison, Hywel Williams

aaps, october 2015 enabling lipid formulations that ... enabling lipid formulations that harness...

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