emulsion-based delivery systems -...
TRANSCRIPT
Emulsion-based Delivery Systems:Novel or Improved Performance through
Emulsion Technology
D.J. McClements
Department of Food Science
University of Massachusetts , Amherst
Conventional Emulsions
Oil
Water
HomogenizationEmulsion
Droplet
+ Emulsifier
Interfacial
Layer
Limitations of Conventional
Emulsions
• Limited robustness to environmental stress:
– pH, ionic strength, thermal processing, chilling,
freezing, drying, ingredient compatibility
• Limited ability to create novel product
performance or functionality:
– Ingredient protection systems, controlled release,
site-specific release, triggered release
Structured Emulsions: Encapsulation & Delivery Systems
Structured Particle
Filler
Air bubbles
Water droplets
Lipid droplets
Fat crystals
Micelles
Microemulsions
Core
Air
Oil
Fat crystals
Water
Ice
Hydrogel
Surfactants
Shell
Biopolymers
Surfactants
Lipid droplets
Fat crystals
Solid particles
Multilayers
Structured Emulsion Systems: Encapsulation & Delivery Systems
Particle Properties• Dimensions
• Diameter
• Thickness
• Charge
• Sign
• Magnitude
• Permeability
• Diffusion
• Selectivity
• Partitioning
• Polarity
• Volume Fraction
• Responsiveness
Functional Performance• Ingredient loading capacity
• Ingredient protection capacity
• Release rate
• c versus t
• Release trigger
• pH, I, T
• Matrix compatibility
• pH, I, T, Ingredients
0
0.2
0.4
0.6
0.8
1
0 100 200 300
Time (s)
Fra
cti
on
Re
lea
se
d
δ
d
Structured Emulsions: Emulsion-based Delivery Systems
Structural
Design
Lipid
DropletsFilled Lipid
Droplets
Solid Lipid
Nanoparticles
Filled
Liposomes
Filled
Hydrogel Beads
LiposomesHydrogel
Beads
Multilayer
Droplets
Colloidomes
Nano-emulsions
Structured Emulsion Delivery
Systems: Performance Parameters
Matrix
Compatibility- Optical
- Rheological
- Stability
- Flavor
Processing - Heating
- Cooling
- Drying
- Shearing
Storage- Temperature
- Mechanical stress
- Light
- Oxygen
- Time
Consumption- Appearance
- Texture
- Taste and Aroma
- Convenience
Ingestion- Digestion
- Absorption
DELIVERY SYSTEM CRITERIA:
• Fabricated from food grade ingredients using economic processing operations.
• Designed to function over wide range of conditions in food product and human body.
• Sensory acceptance
Stable Unstable
Understanding Lipid Digestion & Absorption
in the Human Digestive SystemMouth
• pH 5-7
• Enzymes
• Salts
• Biopolymers
• 5 – 60 s
Stomach
• pH 1-3
• Enzymes
• Salts
• Biopolymers
• Agitation
• 30 min – 4 hours
Small Intestine
• pH 6-7.5
• Enzymes
• Salts, Bile
• Biopolymers
• Agitation
• 1 – 2 hours
0
0.2
0.4
0.6
0.8
1
0 100 200 300
Time (s)
Fra
cti
on
Re
lea
se
dFood Matrix
Disruption
Droplet Formation
& Disruption
Breakup
Coalescence
Competitive Adsorption
& Displacement
Enzyme Adsorption
& Activity
Solubilization &
Transport
Transport
Solubilization
Binding &
Interactions
Accumulation
at site of action
Controlled Self-
Assembly
Nanoemulsions
A nanoemulsion consists of two immiscible liquids
(usually oil and water), with one liquid being dispersed
as very small spherical droplets in the other liquid.
Characteristics:• Thermodynamically unstable
• Particle Diameter (10 to 100 nm)
• Optically Transparent
• Low Surfactant-to-Oil ratio (≈≈≈≈ 1:1)
• High Surface Area (30 m2/g)
(Wooster TJ et al, Langmuir 2008)
Applications:• Fortified beverages
• Increasing bioavailablity
Nanoemulsion Formation:Influence of Homogenizer Type
Oil
Water
Premix
http://www.microfluidicscorp.com
0
1
2
3
4
0 10 20
Effective Energy Input
Mea
n R
ad
ius
MF
HSM
Nanoemulsion Formation:Influence of Surfactant Characteristics
50
70
90
110
130
150
170
190
0 1 2 3 4 5 6
Surfactant (wt%)
Dia
met
er (
nm
)
Alkane
Low ηηηη
TAG
High ηηηη
Surfactant Properties• Concentration – sufficient to cover all
droplet interfaces formed
• Kinetics – sufficiently fast to prevent re-
coalescence due to collisions
• Protection – sufficient to protect
against droplet coalescence
• Surface Pressure – sufficiently low to
facilitate breakup
dc
φΓ=
6
(Wooster TJ et al, Langmuir 2008)
Nanoemulsion Formation:Influence of Component Rheology
0
2
4
6
8
10
0.001 0.01 0.1 1 10
ηηηηd/ηηηηc
Dro
ple
t D
iam
ete
r
20
40
60
80
100
120
0 10 20
ηηηηd/ηηηηc
Dro
ple
t D
iam
eter
(n
m)
(Wooster TJ et al, Langmuir 2008)
Increasing Cosolvent Concentration
Ratio of viscosities of disperse to continuous phases plays a crucial role in
nanoemulsion formation
Nanoemulsions:Potential Applications
(Wooster TJ et al, Langmuir 2008)
Increased bioavailablity of nutraceuticals
(20 × more effective than conventional)Optically transparent – fortified beverages
(Tagne JB et al, Mol. Pharmaceutics, 2007)
Multilayer Emulsions
A multilayer emulsion consists of lipid droplets
surrounded by nanolaminated biopolymer layers.
Synthetic polymer shells
Wolfgang Meier, 2000
Nano-laminated
Biopolymer coating
Lipid
Droplet
• Protection of labile ingredients
• Increased environmental stability
• Controlled release
Multilayer Emulsions:Formation using LbL Method
Add Emulsifier
Separate Oil
& Water Phases
Single-Layer
Primary
Emulsion
AddBiopolymer 1
Two Layers
Secondary
Emulsion
Add Biopolymer 2
Three Layers
Tertiary
Emulsion
Repeat n times
++++ −−−−++++
Advantages of Multilayer Approach
• Control of Interfacial Properties– Charge Sign & Density
– Thickness
– Packing
– Selective Permeability
– Rheology
– Responsiveness
• Improvement of Emulsion Properties– Increase Shelf-Life
– Controlled Release
– Triggered Release
-
-
-
-
-
+
+
+
+
+
+
+
-
-
-
-
+
+
+
+
+
+
+
+
+
-
-
-
-
-
+
+
+
+
+
+
+
+
-
-
-
-
+
+
+
+
+
++
+
Optimization of Preparation Conditions:Establishment of Adsorption Conditions
-80-60-40
-200
2040
6080
3 4 5 6 7
pHζζ ζζ
-Po
ten
tia
l (m
V) 1º
2º
ζζζζ-Potential Measurements Show Where Adsorption Occurs
-30-20-10
0102030405060
0 0.02 0.04 0.06 0.08 0.1
Pectin (wt%)
ζζ ζζ-P
ote
nti
al
(mV
)
cSatAdsorption
pH 3.5
1º 2º
ΓΓΓΓSat = 1.6 mg m-2
Droplet Concentration: 1 wt%
0% 0.01 wt% 0.04 wt% 0.5 wt%
Multilayer Emulsion Formation:
Bridging & Depletion (pH 3.5)
Bridging
Flocculation
Depletion
Flocculation
Pectin Concentration
cDepcSat Laminated
Droplets
Coating Properties:• Surface load (Γ)
• Thickness (δ)
• Permeability
• Responsiveness
0
0.05
0.1
0.15
0.2
0 0.05 0.1 0.15 0.2
φφφφ
C (
kg
/m3)
CSat
CDep
Bridging
CAds
Depletion
Theoretical Stability MapEffect of Droplet & Polymer Concentration
Reversible
Bridging
For stable system: CAds< C < CDep
Stable
Optimum Multilayer Preparation
Conditions
CSat < C < CDep
Acid
Polymer +
Emulsion
Stirrer
(I). Initially pH > pI
(II). Adjust pH < pI
High wMax (Uncoated)
High wMax (Coated)
Further work:• Molecular weight
• Charge density
• Conformation
• Flexibility
• etc
Application of Technology:Improving Emulsion Stability
Motivation
• Multilayer technology could be used to
improve the stability of many food emulsions
to environmental stresses
Environmental Stresses
• pH, Ionic Strength
• Thermal processing, Chilling, Freezing
• Dehydration
Multilayer Emulsion Properties:Extension of pH Range
1º ββββ-Lg
2º Pectin
100
1000
10000
3 4 5 6 7
pH
Dia
met
er (
nm
)-80-60-40
-200
2040
6080
3 4 5 6 7
pH
ζζ ζζ-P
ote
nti
al
(mV
) 1º
2º
Adsorption
Primary
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
Secondary
3.0 3.5 4.0 4.5 5.0 5.5 6.0 6.5 7.0
Multilayer Emulsion Properties:Extension of NaCl Stability Range
1º ββββ-Lg
2º Pectin
0
2000
4000
6000
8000
0 100 200 300
NaCl (mM)
Dia
met
er (
nm
)
1º
2º
pH 3.5
Primary w/ NaCl
0 50 100 150 200 250 300
mM
Secondary w/ NaCl
0 50 100 150 200 250 300
mM
Primary w/ NaCl
0 50 100 150 200 250 300
mM
Primary w/ NaCl
0 50 100 150 200 250 300
mM
Secondary w/ NaCl
0 50 100 150 200 250 300
mM
Secondary w/ NaCl
0 50 100 150 200 250 300
mM
Multilayer Emulsion Properties:Improvement of Freeze-Thaw Stability
1º ββββ-Lg
2º Carrageenan
3 º Gelatin
0.1
1
10
100
1000
0 1 2 3
Freeze-Thaw Cycles
Dia
met
er (
µµ µµm
)
1°
2°
3°
0% Sucrose
Thick
Layer
Multilayer Emulsion Properties:Improvement of Dehydration Stability
1º 2º
PrimarySecondary
Multilayer Emulsion Properties:Improvement of Oxidative Stability
0
200
400
600
800
1000
1200
1400
3 4 5 6 7 8
Time (Days)
TB
AR
S (
mM
) 1º
2º3º
1º 2º 3º
Fe2+
−−−− −−−−++++
Applications of Multilayer Emulsions
Controlled or Triggered Release
(pH, I, T, enzymes)
Membrane
Porosity
Detachment
-50
-45
-40
-35
-30
-25
-20
30 40 50 60 70 80 90
Temperature (ºC)
ζζ ζζ-P
ote
nti
al
(mV
) 1º
2º
pH 6, 150 mM NaCl
1º ββββ-Lg
2º ιιιι−−−−Carrageenan
Current Status of Multilayer Emulsions
• Emulsions containing lipid droplets coated by nano-laminated layers can be prepared by a simple cost effective method using food ingredients
• These emulsions have improved stability to environmental stresses, such as heating, freezing, drying, pH extremes, and high mineral contents
• Future studies are needed to determine their suitability for use in real foods (encapsulation, controlled release, triggered release)
+
+
++
++
+
+ +
+Wesfolk – licensed this technology
Colloidosomes: Preparation
−−−−−−−−
+ Increasing Small Droplet Concentration
Dinsmore et al
Emulsion 1
Bridging DepletionStable
-40
-30
-20
-10
0
10
20
30
0 0.5 1Small Particle
Concentration (wt%)
ζζ ζζ-P
ote
nti
al
(mV
)
+
++
++
+ +
+
+
++
Colloidosomes:Potential Advantages
Sintering
• Control Particle Properties
– Density, optical properties, permeability
• Protection of Reactive Substances
– Reactive substances can be trapped within
a protective shell
• Controlled Release
– Release trapped component in response to
trigger by disrupting/melting shell
Primary
Homogen.
W/O/W
Emulsion
Oil
Water
W/O
Emulsion
Secondary
Homogen.
Oil-soluble
emulsifier
Water
Water-soluble
emulsifier
Multiple Emulsions:Preparation
W/O/W
Emulsion
Multiple Emulsions:Potential Advantages
• Reduced Fat Products
– Some oil can be replaced by water while maintaining quality attributes
• Protection of Reactive Substances
– Reactive water-soluble substances can be compartmentalized in internal & external aqueous phases
• Controlled Release
– Release component at specific site
Internal
Coalescence
Internal
Flocculation
Water
Droplet
Expulsion
Water Diffusion
(Out)
Water
Diffusion
(In)
Multiple Emulsions:Instability Mechanisms
• Gel W2 particles
• Crystallize oil
• Emulsifier choice
• Crystallize oil
• Emulsifier choice
• Balance ΠΠΠΠ
• Balance ΠΠΠΠ
• Crystallize oil
• Emulsifier choice
Multiple Emulsions:Protective Strategies
• Careful emulsifier selection
• Balance osmotic gradients (concentrations)
• Crystallize oil phase
• Gel aqueous phase
Current Status of Multiple Emulsions
• Multiple emulsions of the W/O/W type have been formulated in the laboratory using simple cost effectivemethods and food ingredients
• These systems have many potential applications for reduced fat products, protection of labile components, or for controlled release applications
• There are few successful examples of multiple emulsions being used in food products due to problems in cost-effectively making stable systems.
• Future studies are needed to improve their robustness for application in real foods
Protein
Solution
Polysaccharide
Solution
Transition (pH, I)
Coacervate
or Precipitate
Soluble
Complex
CosolubilityIncompatibility
+
Low CHigh CComplexation
2-Phase1-Phase 2-Phase 1-Phase
ATTRACTIVE
INTERACTION
REPULSIVE
INTERACTION
Hydrogel ParticlesPhase Separated Biopolymer Solutions
+−−−− −−−−
−−−−
Two-Phase
Incompatibility
Biopolymer A
Biopolymer B
STIR &
GEL
W/W
Emulsion
Figure 2Preparation of Biopolymer ParticlesWater-in-Water (W/W) Emulsions
Filled Biopolymer ParticlesPhase Separated Biopolymer Solutions
MIXSTIR &
GEL
Phase Separated
Biopolymer Mixture
Oil-in-Water
Emulsion
O/W/W
Emulsion
Filled Biopolymer ParticlesSegregative Separation
Optical Microscopy Image of O/W1/W2 Emulsion. This emulsion
consists of fish oil (O) droplets contained within a whey protein aqueous
phase (W1) that is contained within a HM-pectin aqueous phase W2 (pH 7).
Filled Biopolymer ParticlesAggregative Separation
Yeo et al J. Agric. Food Chem., Vol. 53, No. 19, 2005
Orange oil encapsulated in Gum-Arabic/Gelatin Coacervates.
Microcapsules observed by a bright-field microscope: (A)
homogenization at 3000 rpm, 2% polymer concentration (All
scale bars 100 µm).
Applications of Filled Hydrogel
Particles: Controlled Flavor Release
• Release rate can be controlled by creation of novel microstructures
Faster
ReleaseSlower
Release
Filled Hydrogel
Particles
0
20
40
60
0 20 40 60
Time (s)
Fla
vo
r I
nte
snit
y
0%
1%
5%
15%
30%
Conventional
Emulsion
Current Status of Filled Hydrogel
Particles
• Filled hydrogel particles containing lipid droplets embedded in microscopic hydrogel beads can be prepared by a simple cost effective method using food ingredients
• These systems may be useful for protection of labile components or for controlled release applications
• Future studies are needed to determine their suitability for use in real foods
Solid Lipid Nanoparticles (SLN)
• High melting point lipid
• Glycerides or waxes
• Size: 50 - 1000 nm
• Crystal structure can be controlled
• Decreased molecular diffusion
• Less chemical degradation
• Controlled Release
EmulsionLiquid
lipid
Lipophilic
compound
ExchangeDegradation
• Liquid lipid
• Glycerides
• Size: 50 - 1000 nm
• High chemical degradation
SLN
lipophilic
compound
Solid
lipid
No exchangeLess degradation
Formation of Tripalmitin Solid Lipid Nanoparticles (SLN)
Formation of Tripalmitin Solid Formation of Tripalmitin Solid
Lipid Nanoparticles (SLN)Lipid Nanoparticles (SLN)
Hot Melt
Homogenization
Emulsion
preparation
75 ºC
°°°°
SLN
Oil, water &
emulsifier
Controlled
Cooling
5 ºC
Liquid core Solid core
Conclusions
• Structural design principles can be used to create a wide variety of different delivery systems
• These systems can often be designed from food grade ingredients using simple processing operations.
• The novel functionality and robustness of these systems still needs to be tested in food applications
• The economics of formulation and production needs to be assessed
Structural
Design