1. Fine Chemicals Division Human Nutrition Helping Make Products More Nutritious Nano-scale Formulations of Health Ingredients Dr. Lutz End Fine Chemicals Division R&D Formulation Bethesda, October 10, 2006

2. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 2 Health Ingredients and Nano-Formulations Nano-formulations are used for Fat-soluble vitamins (A, E, D, K) Carotenoids PUFAs Co-Enzyme Q 10 Phytosterols Minerals Extracts (e.g.polyphenols, curcumin) There are few only for water-soluble vitamins. (taste masking, antioxidants). Subject of this presentation: BASF Products

3. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 3 Nanoparticulate Formulations of Health Ingredients The result of continuous development Health Ingredient Main Reason for Formulation NanopartikelMarketed since Carotenoids Bioavailability Color Strength SolidSixties Co-Enzyme Q 10 BioavailabilitySolidNineties Vitamin A Stability through encapsulation DropletSixties Vitamin E Compressibility, use in tablets DropletSixties Vitamin D, K Stability through encapsulation DropletSixties PUFAs Stability through encapsulation DropletNineties

4. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 4 Nano-Formulations Distinction 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, Suspensions encapsulated E.g. loaded silica spheres Resorption Drug Targeting Nanotubes Co-Azervates Reactive- encapsulation Colloidal Coating Persistent Coating Persistent Coating + Targeting Food 101001000[nm] Exclusively Pharma Range of Particle Sizes Old Definition Nanoparticels New Definition

5. 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

6. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 6 Nanoparticles: Vitamins and Carotenoids Principles 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 mm Thought experiment: Extracting nanoparticles into air

7. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 7 Nanoparticulate Formulations Structure of Nanoparticles 250 nm Example: Electron microscopy: Nanoparticles  -Carotene in Water Contrasting the CoresContrasting the Colloid The structure and properties of nanoparticles are well understood based on comprehensive investigations.

8. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 8 Fruits Rich in Carotenoids Storage: In Nano-Crystallites Carotenoid nanoparticles mimic nature.

9. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 9 Liver Lipoproteins (LDL, VLDL) Micelles from bile acid transport fats and carotenoids as individual molecules Chylomicrons Other Tissues Digestion Intestinal Wall Size ratio nanoparticle to micelle only indicatory. [after Chow et al. 2004] Fine Chemicals Division Bioavailability Principles: Resorption of Lipids

10. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 10 Average change from initial value (n=12) *P < 0.001 * LycoVit ® 10%Tomato basedPlacebo 1.0 0.8 0.6 0.4 0.2 0 Serum Lycopene [µmol/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: Lycopene Confirmation of bioavailability in humans Continuous intake, 15mg/day over 28 days

11. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 11 Size Comparison Nanoformulations Solubilizates vs. Nanoparticles 20 nm Micelle loaded with Health Ingredient 300 nm Typical Nanoparticle Solubilizate micelles, the smallest nanoparticles.

12. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 12 Formulations: A: Solu TM Q10 5% - a solubilizate B: CoQ 10 crist. Powder C: CoQ 10 Oil dispersion 1 D: CoQ 10 Solubilizate (Market Leader) E: CoQ 10 Oil dispersion 2 Single dose, 60 mg Plasma-Values (AUC), 0-4 hours Improvement by Solubilization: 80 % improvement over mean value. Factor 3-4 compared to fine crystals. Bioavailability of Nanoformulations Co-Enzyme Q10 – Market Products – Human Study 0.0 0.4 0.3 0.2 0.1 ABCDE Formulations AUC 0-4h [µmol/mmol*h] Mean Value

13. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 13 Nanoformulations of Health Ingredients Toxicology 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.

14. 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 Ingredients Current Market Observations

15. Fine Chemicals Division Nanotagung Zürich 2006 Final 210806 – 15 Nanoformulations of Health Ingredients Conclusion 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.