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Fine Chemicals Division
Human Nutrition
Helping Make Products More
NutritiousNano-scale Formulations ofNano-scale Formulations ofHealth IngredientsHealth Ingredients
Dr. Lutz End
Fine Chemicals DivisionR&D Formulation
Bethesda, October 10, 2006
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 2
Health Ingredients andNano-Formulations
Nano-formulations are used for
Fat-soluble vitamins (A, E, D, K)
Carotenoids PUFAs Co-Enzyme Q10
Phytosterols Minerals Extracts (e.g.polyphenols, curcumin) There are few only for water-soluble vitamins.
(taste masking, antioxidants).
Subject of this presentation:BASF Products
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 3
Nanoparticulate Formulations of Health IngredientsThe result of continuous development
Health Ingredient
Main Reason for Formulation
Nanopartikel Marketed since
CarotenoidsBioavailability
Color StrengthSolid Sixties
Co-Enzyme Q10
Bioavailability Solid Nineties
Vitamin AStability through encapsulation
Droplet Sixties
Vitamin ECompressibility, use in tablets
Droplet Sixties
Vitamin D, KStability through encapsulation
Droplet Sixties
PUFAsStability through encapsulation
Droplet Nineties
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 4
Nano-FormulationsDistinction between Food and Pharma
A large part of nano-formulations is not relevant for application in food.
Reason:Lack of formulation auxiliaries registered for use in food.
Drug Targeting:Invasive – Vehicel is resorbed.No chance for food approval.
Solubilisate(Micelles)
Emulsions, Suspensionsencapsulated
E.g. loaded silica spheres
ResorptionDrug TargetingNanotubes
Co-Azervates
Reactive-encapsulation
ColloidalCoating
PersistentCoating
PersistentCoating+ Targeting
Food
10 100 1000 [nm]
ExclusivelyPharma
Range of Particle Sizes
Old Definition Nanoparticels
New Definition
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 5
Nanoparticulate Formulations Dissolution and Release in Water
Powder particles dissolve in water and release nanoparticles.
Re-dissolution and release is the reversal of the manufacturing process.Comparable: Dissolution of instant milk powder – reconstituted milk.
0.3 Millimeter*(300,000 Nanometer)
300 Nanometer*(0.0003 Millimeter)
* Size indicated: typical values
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 6
Nanoparticles: Vitamins and CarotenoidsPrinciples
Free nanoparticles of these compounds cannot exist in air. Instantaneous oxidation occurs and spontaneous ignition is possible.
Nanoparticles are always embedded in a matrix and incorporated into macroscopic powder particles.
Powder Particle, 0.3 mmThought experiment:Extracting nanoparticles into air
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 7
Nanoparticulate FormulationsStructure of Nanoparticles
250 nm250 nm
Example: Electron microscopy: Nanoparticles -Carotene in Water
Contrasting the Cores Contrasting the Colloid
The structure and properties of nanoparticles are well understood based on comprehensive investigations.
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 8
Fruits Rich in CarotenoidsStorage: In Nano-Crystallites
Carotenoid nanoparticles mimic nature.
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 9
Liver
Lipoproteins(LDL, VLDL)
Micelles from bile acidtransport fats and carotenoids as individual molecules
Chylomicrons
Other Tissues
Digestion
IntestinalWall
Size ratio nanoparticle to micelle only indicatory. [after Chow et al. 2004]
Fine Chemicals Division
Bioavailability Principles: Resorption of Lipids
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 10
Average change from initial value (n=12)
*P < 0.001
*
LycoVit® 10% Tomato based Placebo
1.0
0.8
0.6
0.4
0.2
0
Ser
um
Lyc
op
ene
[µ
mo
l/l]
Observation:
Bioavailability of synthetic product is similar to that found for formulated tomato extract (extracted lycopene).
Bioavailability of lycopene from fresh, non-processed tomatoes is poor.
Nanoparticulate Formulation: LycopeneConfirmation of bioavailability in humans
Continuous intake, 15mg/day over 28 days
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 11
Size Comparison NanoformulationsSolubilizates vs. Nanoparticles
20 nmMicelle loaded withHealth Ingredient
300 nmTypical Nanoparticle
Solubilizate micelles, the smallest nanoparticles.
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 12
Formulations:
A: SoluTM Q10 5% - a solubilizateB: CoQ10 crist. PowderC: CoQ10 Oil dispersion 1D: CoQ10 Solubilizate (Market Leader)E: CoQ10 Oil dispersion 2
Single dose, 60 mgPlasma-Values (AUC), 0-4 hours
Improvement by Solubilization:
• 80 % improvement over mean value.
• Factor 3-4 compared to fine crystals.
Bioavailability of NanoformulationsCo-Enzyme Q10 – Market Products – Human Study
0.0
0.4
0.3
0.2
0.1
A B C D E
Formulations
AU
C0-
4h [
µm
ol/
mm
ol*
h]
Mean Value
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 13
Nanoformulations of Health IngredientsToxicology
Carotenoid Formulations – Solid Nanoparticles Safety studies, esp. oral toxicity studies, are performed with formulations
as marketed. Nanoformulation of fat-soluble nutrients is a prerequisite for a meaningful
resorption. BASF GRAS notification on synthetic lycopene is based on toxicological
evaluation made with commercial products (LycoVit 10% DC,10 CWD). Very high tolerance levels were observed for carotenoids.
Fat-soluble Vitamins – Spray Dried Emulsions No evidence for adverse effects resulting from this long used technology.
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 14
The label “Nano” is often marketed as if it were a value as such.
Great differences between different countries – more aggressive marketing in the USA than in Europe.
However, often something long known is simply renamed.
Stark imbalance between realistic potential and fantasy.
Nanoformulations of Health IngredientsCurrent Market Observations
Fine Chemicals Division
Nanotagung Zürich 2006 Final 210806 – 15
Nanoformulations of Health IngredientsConclusion
Standard Formulations of Fat-Soluble Health Ingredients
Without nanoformulations only insufficient resorption of e.g. carotenoids and coenzyme Q10.
Nanoformulations with particle sizes between 200 and 1000 nm.
Products and technologies on the market for over 30 years.
Nanoformulation is the enabling technology to make Health Ingredients like -carotene applicable in foods and beverages – resorption, color, stability
Smallest Nanoformulations: Solubilizates
Highly suitable products for selected applications.
Bioavailability is increased by a factor of approximately 2.
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