TM

The BV Droplets Down Under: From Model Emulsions to Drug Delivery

Clive Prestidge

Ian Wark Research Institute,The ARC Special Research Centre for Particle and Material Interfaces,

University of South Australia,

Windsurfing in the Bristol Channel

Definitely not the Bristol Channel!

Memories of those good old days at Bristol in the late 80’s with Brian as your supervisor

Civilised with a high level of decorum

The BV Birthday – Always a Special Day……..

Kick a few students into a Mini Bus

Treat him like a King and make him the centre of attention

Feed him a nice big cake

Respect from your Supervisor????But some students just got a bit too friendly!!

BV’s Balls

Non-Cross linked Droplets:Viscous & deformable

(η < 5 mNm-2s)

NH3 NH3

OEtEtO

CH3

Si

CH3

Cross linked droplets Deformability control:viscous to viscoelastic

OEtEtO

OEt

Si

CH3

- Highly monodispersed (~1μm in diameter)

- Emulsifier free, negatively charged with IEP ≈ pH 2.5

T. M. Obey & B. Vincent, J. Colloid Interface Sci., 163 (1994) 454.M. I. Goller et al., Colloids Surf. A:, 123-124 (1997) 183.

T. M. Obey & B. Vincent, J. Colloid Interface Sci., 163 (1994) 454.M. I. Goller et al., Colloids Surf. A:, 123-124 (1997) 183.

BV’s PDMS Droplets

The BV Droplets – an excellent model colloid with controllable deformability

Interaction forces of the BV droplets

Rheological studies on concentrated emulsions of the BV droplets

Block copolymers at the BV droplet - water interface

Nanoparticles at the BV droplet - water interface

Molecular transport across the BV droplet - water interface.

Do the BV Balls Squash?Deformable BV droplets are more colloidally stable

0

50

100

150

200

250

300

4 6 8 10pH

ccc

(mM

)

Cross-linked droplets

Liquid droplets

Potential from PDPotential from PD

Deflection of cantileverDeflection of cantilever

Interdroplet forcesInterdroplet forces

F = – kc xF = – kc xkc: spring constant of cantileverkc: spring constant of cantileverx : deflection of cantileverx : deflection of cantilever

Hooke’s LawHooke’s Law

PhotodiodePhotodiode

CantileverCantileverProbeProbe

TargetTarget

LaserLaser

Interaction forces on the BV droplets determined using colloid probe atomic force

microscopy (AFM)

00Forc

eFo

rce

Drive distanceDrive distanceAABBCCDD

AA BB CC DD AA BB CC DD

DeformableDeformable

NondeformableNondeformable

(Def

lect

ion)

(Def

lect

ion)

Approach Rate DependenceApproach Rate Dependence

Low rateLow rate

Forc

eFo

rce

Drive distanceDrive distance

High rateHigh rate

Forc

eFo

rce

Drive distanceDrive distance

-12

-10

-8

-6

0 50 100 150 200 250

Arbitrary Separation (nm)

ln (F

orce

/2πR

)

-12-11-10

-9-8

200 210 220 230 240

50% ( ), 45% (▲), 40% (■), 35% (▲), 30% (•).

Interaction Forces between BV Droplets and AFM colloid probe Interaction Forces between BV Droplets and AFM colloid probe

Gillies and Prestidge, Langmuir, 21, 12342-12347, 2005

-0.5

0

0.5

1

1.5

2

2.5

3

-150 -100 -50 0 50

Nominal Separation (nm)

Forc

e/2 π

R (m

N/m

)

50% ( ), 45% (▲), 40% (■), 35% (▲), 30% (•).

Deformation & Deformation & HysteresisHysteresis-- influence of crossinfluence of cross--linking:linking:

Gillies and Prestidge, Langmuir, 21, 12342-12347, 2005

0

0.01

0.02

0.03

0.04

0.05

-100 -50 0 50

Nominal Separation (nm)

Forc

e/2 π

R (m

N/m

)Liquid-like BV Droplets:

Influence of Surfactant (SDS)( ) No SDS ( )10-4M ( )10-3M ( )10-2M

RPDMS = 10 μm

GS Gillies, CA Prestidge, Adv. Colloid Interface Sci, 108-109, 197-205, 2004.

Spring constant controlled by interfacial tension

0123456789

0 5 10 15 20

Interfacial Tension (mN/m)

Sprin

g C

onst

ant (

mN

/m) No SDS

10 -4M SDS

10 -2M SDS

10 -3M SDS

RPDMS = 10 μm

GS Gillies, CA Prestidge, Adv. Colloid Interface Sci, 108-109, 197-205, 2004.

Laplace pressure controls spring constant

0

10

20

30

40

50

0 0.5 1 1.5 21/Radius (μm-1)

Sprin

g C

onst

ant (

mN

/m)

Liquid-like BV Droplets: Influence of size

GS Gillies, CA Prestidge, Adv. Colloid Interface Sci, 108-109, 197-205, 2004.

-0.50

0.5

1.5

2.5

3.5

-70 -50 -30 -10 10 30 50Nominal Separation (nm)

Forc

e/2π

R (m

N/m

)

Cross-linked BV Droplets: Approach Rate Dependence

Slow (0.25 μm/s)

Fast (4 μm/s)

Gillies and Prestidge, Langmuir, 21, 12342-12347, 2005

Cross-linked BV Droplets: Load Dependence

-1

1

3

5

7

-90 -40 10

Nominal Separation (nm)

Forc

e/2 π

R (m

N/m

)

Approach rate = 1 μm/s

Nano-Rheology of a BV Droplet

ViscoelasticityViscoelasticity of a Sphere (Attard, of a Sphere (Attard, Phys. Rev. E,Phys. Rev. E, 2001)2001)

( )τ/

0

011 teEE

EEEtE

−

∞

∞

∞

−+=

E0 = 1.2 MPa, E∞ = 0.8 MPa and τ = 0.12 s

-0.5

0.5

1.5

2.5

3.5

-100 -50 0 50Nominal Separation (nm)

Forc

e/2 π

R (m

N/m

)

0.25 0.25 μμm/sm/s

1 1 μμm/sm/s

1 1 μμm/s (low load)m/s (low load)

Gillies and Prestidge, Langmuir, 21, 12342-12347, 2005

Rheological studies on concentrated emulsions of the BV droplets

Shear RateShear Rate

Shea

r Vis

cosi

tySh

ear V

isco

sity

3D Network3D Network

LayersLayers

CompressionCompression

“Order-Disorder”Transition

“Order-Disorder”Transition

ClustersClustersSuspensionsSuspensions

EmulsionsEmulsions

1

10

100

1000

0 10 20 30 40 50 60 70 80

Viscosity versus volume fractionViscosity versus volume fraction

Volume Fraction / %Volume Fraction / %

Rel

ativ

e V

isco

sity

Rel

ativ

e V

isco

sity

SilicaSilicaBV droplets (cross linked)BV droplets (cross linked)BV droplets (liquid)BV droplets (liquid)

Krieger-DoughertyHard spheresKrieger-DoughertyHard spheres

Saiki, Prestidge and Horn, Colloids and Surfaces A, 299, 65-72, 2006.

PEO-PPO-PEO Copolymers at the BV droplet - water interface

PEO

PPO

0.00.51.01.52.02.53.03.54.0

0 20 40 60 80 100Ceq (ppm)

Ads

orbe

d Amt (m

g m

-2)

0.00.51.01.52.02.53.03.54.0

0 20 40 60 80 100Ceq (ppm)

Ads

orbe

d Amt (m

g m

-2)

0.00.51.01.52.02.53.03.54.0

0 20 40 60 80 100Ceq (ppm)

Ads

orbe

d Amt (m

g m

-2)

0.00.51.01.52.02.53.03.54.0

0 20 40 60 80 100Ceq (ppm)

Ads

orbe

d Amt (m

g m

-2)

Adsorbed Amount of F108

Silica

Polystyrene latex

Cross-linked droplets

Liquid droplets

Prestidge, Barnes and Simovic, Adv. Colloid Interface Sci , 108-109, 105-118, 2004.

0

5

10

15

20

25

0 20 40 60 80 100Concentration (ppm)

Thickn

ess (nm)

0

5

10

15

20

25

0 20 40 60 80 100Concentration (ppm)

Thickn

ess (nm)

0

5

10

15

20

25

0 20 40 60 80 100Concentration (ppm)

Thickn

ess (nm)

0

5

10

15

20

25

0 20 40 60 80 100Concentration (ppm)

Thickn

ess (nm)

Adsorbed Layer Thickness of F108

Silica

Polystyrene latex

Cross-linked droplets

Liquid droplets

Prestidge, Barnes and Simovic, Adv. Colloid Interface Sci , 108-109, 105-118, 2004.

PEO-PPO-PEO Copolymers

Liquid PDMS droplet

δ

Cross-linked PDMS droplet

Silica Polystyrene latex

0

100

200

300

400

500

0 0.5 1Surface Coverage

ccc

(mM

)

0

100

200

300

400

500

0 0.5 1Surface Coverage

ccc

(mM

)

Hydrophilic

Hydrophobic

Nanoparticles at the BV droplet - water interface

Simovic and Prestidge, Langmuir, 20, 8357-8365, 2004.

Adsorption of hydrophilic silica nanoparticles to Droplets

Simovic & Prestidge, Langmuir 19 (2003) 3785-3790

0

50

100

150

200

250

0 0.2 0.4 0.6Equilibrium concentration (wt%)

Ads

orbe

d a

mou

nt

(mgm

-2)

♦10-3 M NaCl; ■ 10-2 M NaCl; ▲10-1 M NaCl

h = a (1/θ1/2 –1) h- lateral separationa-particle diameterθ-plateau fraction

coverage

Simovic & Prestidge, Langmuir 19 (2003) 8364-8370

Adsorption of hydrophobic silica nanoparticles (10-4 M NaCl)pH: ♦ 9; ▲ 7; ■ 5; ● 4

0

200

400

600

800

1000

1200

0 0.1 0.2 0.3 0.4 0.5Equilibrium concentration (wt%)

Ads

orbe

d am

ount

(mgm

-2)

050

100150200250

0 0.1 0.2

Liquid BV Droplets Cross-linked BV Droplets

Multilayer adsorptionStrong pH dependencyAdsorption affinity is greater for liquid droplets

Simovic & Prestidge, Langmuir 19 (2003) 8364-8370

Adsorption of hydrophobic silica nanoparticles (10-4 M NaCl)pH: ♦ 9; ▲ 7; ■ 5; ● 4

0

200

400

600

800

1000

1200

0 0.1 0.2 0.3 0.4 0.5Equilibrium concentration (wt%)

Ads

orbe

d am

ount

(mgm

-2)

050

100150200250

0 0.1 0.2

0

100

200

300

400

500

0 0.1 0.2 0.3 0.4 0.5Equilibrium concentration (wt%)

Adso

rbed

am

ount

(mgm

-2)

0

50

100

0 0.1 0.2

Dibutyl phthlate (DBP)

USP rotating paddle method+ ultracentrifugation + HPLC analysis

Molecular transport across the BV Molecular transport across the BV dropletdroplet--water interfacewater interface

DBL release from BV Droplets: low loading levels – 0.28mg/100ml

0

0.05

0.1

0.15

0.2

0.25

0.3

0 2000 4000

Time (min.)

DB

P re

leas

ed (m

g/10

0ml) bare PDMS droplets

hydrophobic nanoparticle coatings

~580 kJmol-1

Activation Energy

Pluronic F-68 Activation energy for release = 52.8 kJmol-1

Washington et al. J. Controlled Release 33 (1995) 383-390

Prestidge & Simovic: Int. J. Pharmaceutics, 324, 92-100, 2006.European J. of Pharmaceutics and Biopharmaceutics, 66, 39-47 2007

bare BV Droplets

hydrophilic

Nanoparticle coatings:

DBL release from BV Droplets: high loading levels – 2.8mg/100ml

0

0.5

1

1.52

2.5

3

3.5

0 2 4 6 8

Time (h)

Amou

nt re

leas

ed (m

g/10

0ml)

Prestidge & Simovic: Int. J. Pharmaceutics, 324, 92-100, 2006.European J. of Pharmaceutics and Biopharmaceutics, 66, 39-47 2007

hydrophobic

1. Drug incorporation into lipid vehicle

Vehicle (oil droplet)

2. Vehicle encapsulation by nanoparticles

Wet coated droplet

3. Vehicle drying

4. Vehicle redispersion Dry coated

droplets (for storage)

Hydrophilic silica Hydrophilic silica nanoparticlesnanoparticles

(~ 50 nm)(~ 50 nm)

Lipophilicdrug

DermalDelivery

OralDelivery

Towards Drug DeliveryTowards Drug Delivery

Improved Photo-stability of Vitamin A in Nanoparticle Coated Emulsions

26.220.18Nanoparticlecoating B

5.270.91Nanoparticlecoating A

0.3713.10Control Emulsion

t1/2 (day)k, min -1(×104)Formulation

All-trans Vitamin A 9-cis Vitamin A(Biopotency: 100%) (Biopotency: 24% )

UV lightIsomerisation

N. Ghouchi Eskandar, S. Simovic and C. A. Prestidge, Phys ChemChem Phys, 9 (48), 6426-6434, 2007.

Delivery to the skin

Schematic of a Static Franz Diffusion Cell

Nanoparticle coated droplets improve the skin penetration of Vitamin A

Dry capsules for oral delivery:

Spray dryingFreeze-dryingPhase coacervation

Drying method + formulation composition controls:

StructureStabilityDelivery characteristics

Internal structure of capsules is controllable and facilitates capsule performance

In vivo studies:

Increased bioavailability

Faster action

improved oral delivery of poorly soluble drugs,

e.g.indomethicin

0

2

4

6

8

10

12

14

0 5 10 15 20Time(h)

Con

.C(u

g/m

l) Lipoceramic capsule

Drug suspension

COOHCH2

Me O

Me

Cl

O

N

In vivo Bioavailability of Celecoxib

Emulsion 2Emulsion 1

Miglyol Oil

Aq susp.

Capsule 2Capsule 3

Capsule 1

Celebrex

In-vitro / In-vivo Correlation

0

20

40

60

80

100

120

0 20 40 60 80 100

% of dissolved drug after 15 min.

Bioa

vaila

bilit

y (%

)

Celecoxib

Celebrex

Lipoceramic Capsules

Concluding Remarks

BVBV’’s s monodispersedmonodispersed silicone emulsions are an excellent silicone emulsions are an excellent model colloidmodel colloid

Investigations of the BV droplets have improved Investigations of the BV droplets have improved understanding of emulsion interfacesunderstanding of emulsion interfaces

The BV droplets have inspired the development of new drug delivery systems based on emulsions and nanoparticles

Dr Graeme Gillies (AFM studies)Dr Graeme Gillies (AFM studies)

Dr Yasushi Saiki (rheology Dr Yasushi Saiki (rheology studies)studies)

Dr Tim Barnes (polymer Dr Tim Barnes (polymer interaction)interaction)

Dr Spomenka Simovic Dr Spomenka Simovic ((nanoparticlenanoparticle interaction)interaction)

Angel Tan (oral delivery)Angel Tan (oral delivery)

Nasrin Eskandar (dermal Nasrin Eskandar (dermal delivery)delivery)

AcknowledgementsAcknowledgements

Nano-structured Drug Delivery Systems at the Wark

Liposomes

Emulsions + Micro/NanoCapsules

Nanoparticles

MesoporousParticles

DNA-lipids

Dendrimers

Drug encapsulation

Formulation stability

Controlled release

Improving bioavailability

Controlled circulation

Targeted delivery

Functional Nanoparticle Research at the WarkTM: Towards a new generation of diagnostic and

therapeutic nanomaterials.

Initial interfacial coverage in the range 0.7 and 0.9: chain structures

45 min. 2h

Hydrophobic nanoparticles: restricted (limited) coalescence

Initial interfacial coverage of hydrophobic nanoparticlesof ~0.6: dendritic structures

Simovic & Prestidge: Langmuir 20, 8357, 2004

log (time)

E(t)

Data Analysis: Nano-RheologyViscoelasticityViscoelasticity of a Sphere (Attard, of a Sphere (Attard, Phys. Rev. E,Phys. Rev. E, 2001)2001)

Long time-scale Modulus E∞

Short time-scale Modulus E0

( )τ/

0

011 teEE

EEEtE

−

∞

∞

∞

−+=

τ

Bioavailability

L-Maltodex.

L-bare droplets

Pure celecoxib

susp.

CELEBREXOil disp.

50

60

70

80

90

100

110

120

Celecoxib formulations

Absolute F (%)

Bare liquid systems Redispersed dry capsules

(n ≥ 3; One-way ANOVA: p < 0.1 )

®

L-S(aq)L-S(aq,oil)

Cmax (μg/ml) Tmax (min)

Oil disp.

CELEBREX

Pure celecoxib

susp.

L-bare droplets

L-Maltodex.

L-Si(aq)

L-Si(aq+oil)

0.0

0.2

0.4

0.6

0.8

1.0

1.2

Celecoxib formulations

L-Si(aq+oil)

L-Si(aq)L-Maltodex.

L-bare droplets

Pure celecoxib

susp.

CELEBREX

Oil disp.

0

60

120

180

240

300

360

420

Celecoxib formulations

p<0.01 p<0.05

Model Drug: Celecoxib (BCS Class II drug)

Indications: Anti-inflammatory drug

primarily for rheumatoid arthritis & osteoarthritis

Difficult processing into solid dosage forms (tablets)

► Cohesiveness; Low bulk density & compressibility; Poor flow properties

Slow onset of action (pain relieving)► High Tmax (3 h)

Incomplete & variable absorption; Excessive dose-dumping; No liquid formulation exists

► Hydrophobic (log P ≈ 3.5)► Low solubility (7 µg/ml)

Pharmaceutical limitationsCelecoxib properties

Subject: fasted male Sprague-Dawley rats

Capsule B

Capsule C

Capsule A

Celecoxib Pharmacokinetics: Bioavailability in Orally Dosed Rats

Ex-vivo delivery of Vitamin A to abdominal pig skin:Nanoparticle coatings facilitate better skin delivery from emulsions

-10

-9

-8

-7

-6

-5

0 20 40 60 80 100

Arbitrary Separation (nm)

Ln

(For

ce/2π R

)

CrosslinkedCrosslinked BV Droplets and a Silica SphereBV Droplets and a Silica Sphere

hard spherehard spherebehaviourbehaviour

P(h)=P0e-κh

h

Δh

∼Δh

Nanoparticle coated emulsions facilitate better skin retention and less penetration of vitamin A in comparison with commercial products.

Topical delivery of vitamin A to upper layers of skin with minimum transport across the skin and minimal systemic exposure.

Skin layers