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

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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

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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.

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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.