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Title:
COMPOSITIONS COMPRISING MAGNOLOL OR HONOKIOL AND OTHER ACTIVE AGENTS FOR THE TREATMENT OF INFLAMMATORY DISEASES
Kind Code:
A1
Abstract:
The present invention relates to novel compositions comprising magnolol and/ or honokiol and at least one additional component e.g. selected from ligustilide, oleuropein (I), oleuropein aglycone (II), hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, cashew fruit extract and Glycyrrhiza foetida as well as to the use of these compositions as a medicament, in particular as a medicament for the treatment, co-treatment or prevention of inflammatory disorders.


Inventors:
RAEDERSTORFF, Daniel (5 Rue Etienne Bilger, Flaxlanden, Flaxlanden, F-68720, FR)
SCHWAGER, Joseph (Friedensgasse 23, Basel, CH-4056, CH)
WERTZ, Karin (Bahnhofstrasse 68 A, Rheinfelden, 79618, DE)
Application Number:
EP2007/006189
Publication Date:
01/17/2008
Filing Date:
07/12/2007
Assignee:
DSM IP ASSETS B.V. (Het Overloon 1, TE Heerlen, NL-6411, NL)
RAEDERSTORFF, Daniel (5 Rue Etienne Bilger, Flaxlanden, Flaxlanden, F-68720, FR)
SCHWAGER, Joseph (Friedensgasse 23, Basel, CH-4056, CH)
WERTZ, Karin (Bahnhofstrasse 68 A, Rheinfelden, 79618, DE)
International Classes:
A61K36/575; A61K31/05; A61K31/365; A61P19/02; A61P29/00
View Patent Images:
Attorney, Agent or Firm:
SCHWANDER, Kuno, Josef et al. (Wurmisweg 576, Kaiseraugst, CH-4303, CH)
Claims:

CLAIMS

1. A composition comprising magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2- hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-

3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5- (2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5- (2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives,

Glycyrrhiza foetida and white willow bark extract.

2. The composition as in claim 1 , wherein at least one additional component is selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, boswellic acid, cashew fruit extract and

Glycyrrhiza foetida.

3. The composition as in claim 1 and 2, wherein the magnolol and/ or honokiol is in the form of an extract from the bark of Magnolia officinalis comprising magnolol and/ or honokiol.

4. A use of a composition as in any one of claims 1 to 3 as an agent for the treatment, co- treatment or prevention of inflammatory disorders.

5. A use of a composition as in any one of claims 1 to 3 as an agent for treatment, co- treatment and prevention of joint disorders.

6. A use of a composition in any one of claims 1 to 3 for maintenance of joint health.

7. A nutraceutical comprising a composition as defined in any of claims 1 to 3 and a nutraceutically acceptable carrier.

8. The nutraceutical as in claim 7 which is a food product, foodstuff, dietary supplement, nutritional supplement or a supplement composition for a food product or a foodstuff.

9. The nutraceutical composition as in claim 7 and 8 wherein the amount of magnolol and/ or honokiol is 0.01 to Ig, more preferably 0.2 mg to 500 mg per serving.

10. The composition as in any one of claims 1 to 3 for use as a medicament.

1 1. A use of a composition as defined in any one of claims 1 to 3, for the manufacture of a medicament for the treatment, co-treatment or prevention of inflammatory disorders.

12. The use as in claim 11, wherein the inflammatory disorder is arthritis.

13. The use as in claim 11 wherein the inflammatory disorder is an inflammation of the skin.

14. A pharmaceutical comprising a composition as defined in any of claims 1 to 3 and a pharmaceutically acceptable carrier.

15. The pharmaceutical as in claim 14, which is in the form of a powder, tablet, capsule, gel, liquid or solid.

16. The pharmaceutical as in claim 14, which is for dermatological purposes.

17. A cosmetic composition comprising a composition as defined in any one of claims 1 to 3 and a cosmetically acceptable carrier.

18. The cosmetic composition as in claim 17 which is a skin care preparation.

19. A method for treatment, co-treatment or prevention of inflammatory disorders in animals said method comprising the step of administering an effective amount of the composition as defined in any one of claims 1 to 3 to an animal, which are in need of such a treatment.

20. The method as in claim 19, wherein the inflammatory disorder is arthritis.

21. The method as in claim 19, wherein the inflammatory disorder is an inflammation of the skin.

22. Use of magnolol and/ or honokiol for enhancing the anti-inflammatory activity of one or several compounds selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2- hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2- butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2- hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3- methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2- phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract.

23. Method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of one or several components selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2- hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid

(III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2- butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2- hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3- methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-

phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract.



Description:

COMPOSITIONS COMPRISING MAGNOLOL OR HONOKIOL AND OTHER ACTIVE AGENTS FOR THE TREATMENT OF INFLAMMATORY DISEASES

The present invention relates to novel compositions comprising magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, glucosamine, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2- hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3- butenyl)-6-pentyl -benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)- phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3- butenyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract as well as to the use of these compositions as a medicament, in particular as a medicament for the treatment, co-treatment or prevention of inflammatory disorders.

Inflammatory disorders are one of the most important health problems in the world. Inflammation is in general a localized protective response of the body tissues to invasion of the host by foreign material or injurious stimuli. The causes of inflammation can be infectious agents such as bacteria, viruses, and parasites; or physical agents such as burns or radiation; or chemicals like toxins, drugs or industrial agents; or immunological reactions such as allergies and autoimmune responses or conditions associated with oxidative stress.

Inflammation is characterized by pain, redness, swelling, heat, and eventual loss of function of the affected area. These symptoms are the results of a complex series of interactions mainly taking place between the cells of the immune system. The response of the cells results in an interacting network of several groups of inflammatory mediators: Proteins (e.g. cytokines, enzymes [e.g..proteases, peroxydase], major basic protein, adhesion molecules [ICAM, VCAM]),

lipid mediators (e.g.,eicosanoids, prostaglandins, leukotrienes, platelet activating factor [PAF]), reactive oxygen species (e.g..hydroperoxides, superoxyde anion O 2 " , nitric oxide [NO] etc). However, many of those mediators of inflammation are also regulators of normal cellular activity. Thus, deficiencies of inflammatory reactions lead to a compromised host (i.e. infection) while uncontrolled and thus chronic inflammation leads to inflammatory diseases mediated in part by the excessive production of several of the above mentioned mediators.

Acute and chronic inflammation resulting from an excessive biosynthesis of inflammatory mediators is involved in numerous inflammatory disorders such as arthritis (e.g. osteoarthritis, rheumatoid arthritis), asthma, inflammatory bowel diseases, inflammatory diseases of the skin (e.g. contact dermatitis [particularly diaper area dermatitis], atopic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, neurodermitis, acne, thermal and radiation burns such as sunburn,) and chronic inflammatory disorders, such as atherosclerosis, heart diseases, metabolic syndrome X, cancer, Alzheimer's disease and pre-stages thereof such as mild cognitive impairment or photoageing which is associated with chronic skin inflammation.

Rheumatoid arthritis is a chronic inflammatory disease of the joints and is one of many different forms of arthritis. For example, arthritis includes rheumatoid arthritis, spondyloarthopathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. Like asthma, rheumatoid arthritis is characterized at the molecular level by chronically unbalanced expression of cytokines, chemokines, kinins and their receptors, adhesion molecules and their respective receptors, as well as inflammatory enzymes.

Psoriasis is one of the most common skin problems, affecting 1-3% of the human population. Inflammatory bowel disease is a general term used to describe gastrointestinal tract diseases and includes disorders such as ulcerative colitis and Crohn's disease.

Beside the process of intravascular lipid deposition, inflammatory reactions of the endothelial (i.e. blood vessel) wall are considered to critically contribute to atherosclerosis i.e. atheroma formation. Atherosclerosis results from vascular injury which triggers inflammation. Activated macrophages, T-lymphocytes, and eventually smooth muscle cells are present in atherosclerotic plaques. Monocyte/macrophage and lymphocyte activation leads to the release of eicosanoids, cytokines and matrix metalloproteinases (MMPs) which are implicated in endothelial damage, as well as in the formation and eventually the rupture of atherosclerotic plaques. Finally, circulating inflammatory markers such as C-reactive protein (CRP), fibrinogen, and interleukins are

increased or altered in groups at high-risk of coronary artery diseases (CAD). Several clinical trials indicate that elevated CRP concentration correlates with increased risk of coronary, and vascular, events. Thus inflammation appears to play an important role in the initiation and progression of atheroma formation.

Inflammatory processes are also associated with the pathophysiology of Alzheimer's disease. There is evidence of inflammation in the brain of patients with Alzheimer's disease, as it is characterized by increased levels of cytokines and activated microglial cells. Thus, inflammation is not only involved in the classical inflammatory disorders (e.g., arthritis, asthma, bowel diseases) but is also associated with many chronic inflammatory disorders (e.g., atherosclerosis, heart diseases, metabolic syndrome X, cancer, Alzheimer disease).

Inflammatory events are also associated with the pathophysiology of different types of cancers (e.g. gastric and intestinal cancers, melanomas). Increased levels of inflammatory mediators such as prostaglandins have been found in cancers of breast, colon, lung and pancreas in humans.

Currently, two main classes of drugs, the corticosteroid and the nonsteroidal anti-inflammatory drugs (NSAIDs) are used to treat inflammatory disorders. NSAIDs and corticosteroids provide essentially symptomatic relief. Use of corticosteroids has declined due to a growing concern about the serious side effects of prolonged use.

NSAIDs are among the most widely used drugs, primarily for the treatment of pain and inflammatory disorders, in particular for the treatment of arthritis (i.e. pain relief). Epidemiological studies have suggested that patients taking NSAIDs have a lower risk of developing Alzheimer's disease than those not taking NSAIDs. A protective effect of NSAIDs suggests that the cyclooxygenases might be involved in the neurodegenerative process. Epidemiological studies showed a significant reduction in the risk of colorectal, gastric, esophageal, and breast cancers among people who take NSAIDs compared with those not taking NSAIDs. In animal models, NSAIDs significantly reduced tumor development.

However, long-term use of NSAIDs when treating chronic diseases such as arthritis, is limited by severe side-effects like serious gastrointestinal complications, renal toxicity or asthmatic reactions.

Therefore, there is a need for new anti-inflammatory agents with weak or no side effects. Patients with inflammatory diseases have a special interest in a type of treatment considered as "natural" with mild anti-inflammatory effects and without major side effects, which can be used for disease prevention and as adjuvant treatment. Furthermore, the treatment used needs to maintain the equilibrium between excessive and insufficient inflammatory reaction.

There are many known examples of such "natural" agents with shown anti-inflammatory action. However, a disadvantage of these "natural" compounds is that their biological and thus inhibitory activity is often inadequate. When two or more natural substances are applied concomitantly, their action can be additively or even synergistically enhanced. This lowers the required amount of each substance in order to effect disease development or treatment. Since lower doses of each of the natural substances individually can be used, there is less chance that deleterious levels are reached and also less chance of serious side-effects due to chronic use.

The invention relates to a composition comprising magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β- cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3- butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy- 4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)- benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract. Preferably, the invention relates to a composition comprising magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (II), hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, cashew fruit extract and Glycyrrhiza foetida. Even more preferably, the invention relates to a composition comprising magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, cashew fruit extract and Glycyrrhiza foetida. In a most preferred embodiment, the invention relates to a composition comprising

magnolol and/ or honokiol and at least one additional component selected from the group of ligustilide, rosehip, hydroxytyrosol, genistein, resveratrol and EGCG.

Thus in one preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol and ligustilide.

Thus in one preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol rosehip.

In another preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol and an olive derivable (poly)phenol such as oleuropein (I), oleuropein aglycone (II), tyrosol or hydroxytyrosol, in particular hydroxytyrosol.

In a further preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol and genistein.

In another preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol and resveratrol.

In a further preferred embodiment the invention relates to a composition comprising magnolol and/ or honokiol and EGCG.

It has surprisingly been found that the individual components in the composition of the present invention function synergistically in their anti-inflammatory activity. Moreover, the composition of the present invention may be especially useful in the treatment, co-treatment and prevention of inflammatory disorders, such as heart disease, multiple sclerosis, osteo- and rheumatoid arthritis, atherosclerosis, and osteoporosis.

The composition of the present invention is especially suitable for the treatment, co-treatment and prevention of different forms of arthritis, in particular osteoarthritis and rheumatoid arthritis. Also, the compositions of the present invention are suitable as an agent for treatment, co- treatment and prevention of joint disorders in particular for reduction of joint inflammation, maintenance and/or increase of joint health, prevention of joint stiffness, increase of joint mobility, providing supple and/or flexible joints, lubrication of the joints, relief of pain associated with joint inflammation, decrease of joint swelling, lessening joint problems, and providing joint

care. Thus, the invention also relates to the use of a composition according to the invention as an agent for the treatment, co-treatment or prevention of inflammatory disorders as well as joint disorders.

In another aspect the invention relates to the use of a composition of the invention as an agent for the treatment, co-treatment or prevention of inflammatory disorders more preferably of arthritis or skin inflammation, most preferably of osteoarthritis or sunburn.

In a different aspect, the invention also relates to the composition of the invention for use as a medicament.

In yet another embodiment, the invention relates to the use of a composition according to the invention for the manufacture of a nutraceutical, pharmaceutical, cosmetic or dermatological preparation suitable for the treatment, co-treatment or prevention of inflammatory disorders, more preferably of arthritis or skin inflammation, most preferably of osteoarthritis or sunburn.

Also, the invention relates to a method for treatment, co-treatment and prevention of inflammatory disorders, in particular of arthritis, more in particular of osteoarthritis or rheumatoid arthritis, in animals including humans said method comprising the step of administering 'an effective amount of the composition according to the invention' to animals including humans, which are in need thereof. Preferably, the inflammatory disorder is arthritis, most preferably osteoarthritis.

The term 'an effective amount of the composition according to the invention' refers to an amount necessary to obtain a physiological effect. The physiological effect may be achieved by one single dose or by repeated doses. The dosage administered may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired and can be adjusted by a person skilled in the art.

In the framework of the invention, with animals is meant all animals, including mammals, examples of which include humans. Preferred examples of mammals beside humans are non- ruminant or ruminant animals including cats, dogs, dromedaries, camels, elephants, and horses.

In another embodiment the invention relates to a nutraceutical composition comprising the composition according to the invention and a nutraceutically acceptable carrier.

The term nutraceutical composition as used herein include food product, foodstuff, dietary supplement, nutritional supplement or a supplement composition for a food product or a foodstuff.

Thus, in another embodiment the present invention relates to a nutraceutical wherein the nutraceutical is a food product, foodstuff, dietary supplement, nutritional supplement or a supplement composition for a food product or a foodstuff.

As used herein, the term food product refers to any food or feed suitable for consumption by humans or animals. The food product may be a prepared and packaged food (e.g., mayonnaise, salad dressing, bread, or cheese food) or an animal feed (e.g., extruded and pelleted animal feed, coarse mixed feed or pet food composition). As used herein, the term foodstuff refers to any substance fit for human or animal consumption. The term dietary supplement refers to a small amount of a compound for supplementation of a human or animal diet packaged in single or multiple dose units. Dietary supplements do not generally provide significant amounts of calories but may contain other micronutrients (e.g., vitamins or minerals). The term nutritional supplement refers to a composition comprising a dietary supplement in combination with a source of calories. In some embodiments, nutritional supplements are meal replacements or supplements (e.g., nutrient or energy bars or nutrient beverages or concentrates).

Food products or foodstuffs are for example beverages such as non-alcoholic and alcoholic drinks as well as liquid preparation to be added to drinking water and liquid food, non-alcoholic drinks are for instance soft drinks, sport drinks, fruit juices, such as for example orange juice, apple juice and grapefruit juice; lemonades, teas, near-water drinks and milk and other dairy drinks such as for example yoghurt drinks, and diet drinks. In another embodiment food products or foodstuffs refer to solid or semi-solid foods comprising the composition according to the invention. These forms can include, but are not limited to baked goods such as cakes and cookies, puddings, dairy products, confections, snack foods, or frozen confections or novelties (e.g., ice cream, milk shakes), prepared frozen meals, candy, snack products (e.g., chips), liquid food such as soups, spreads, sauces, salad dressings, prepared meat products, cheese, yogurt and any other fat or oil containing foods, and food ingredients (e.g., wheat flour).

The term food products or foodstuffs also includes functional foods and prepared food products, the latter referring to any pre-packaged food approved for human consumption.

Animal feed including pet food compositions advantageously include food intended to supply necessary dietary requirements, as well as treats (e.g., dog biscuits) or other food supplements. The animal feed comprising the composition according to the invention may be in the form of a dry composition (for example, kibble), semi-moist composition, wet composition, or any mixture thereof. Alternatively or additionally, the animal feed is a supplement, such as a gravy, drinking water, yogurt, powder, suspension, chew, treat (e.g., biscuits) or any other delivery form.

Dietary supplements of the present invention may be delivered in any suitable format. In preferred embodiments, dietary supplements are formulated for oral delivery. The ingredients of the dietary supplement of this invention are contained in acceptable excipients and/or carriers for oral consumption. The actual form of the carrier, and thus, the dietary supplement itself, is not critical. The carrier may be a liquid, gel, gelcap, capsule, powder, solid tablet (coated or non- coated), tea, or the like. The dietary supplement is preferably in the form of a tablet or capsule and most preferably in the form of a hard (shell) gelatin capsule. Suitable excipient and/or carriers include maltodextrin, calcium carbonate, dicalcium phosphate, tricalcium phosphate, microcrystalline cellulose, dextrose, rice flour, magnesium stearate, stearic acid, croscarmellose sodium, sodium starch glycolate, crospovidone, sucrose, vegetable gums, lactose, methylcellulose, povidone, carboxymethylcellulose, corn starch, and the like (including mixtures thereof). Preferred carriers include calcium carbonate, magnesium stearate, maltodextrin, and mixtures thereof. The various ingredients and the excipient and/or carrier are mixed and formed into the desired form using conventional techniques. The tablet or capsule of the present invention may be coated with an enteric coating that dissolves at a pH of about 6.0 to 7.0. A suitable enteric coating that dissolves in the small intestine but not in the stomach is cellulose acetate phthalate. Further details on techniques for formulation for and administration may be found in the latest edition of Remington's Pharmaceutical Sciences (Maack Publishing Co., Easton, PA).

In other embodiments, the dietary supplement is provided as a powder or liquid suitable for adding by the consumer to a food or beverage. For example, in some embodiments, the dietary supplement can be administered to an individual in the form of a powder, for instance to be used by mixing into a beverage, or by stirring into a semi-solid food such as a pudding, topping, sauce, puree, cooked cereal, or salad dressing, for instance, or by otherwise adding to a food e.g. enclosed in caps of food or beverage container for release immediately before consumption. The

dietary supplement may comprise one or more inert ingredients, especially if it is desirable to limit the number of calories added to the diet by the dietary supplement For example, the dietary supplement of the present invention may also contain optional ingredients including, for example, herbs, vitamins, minerals, enhancers, colorants, sweeteners, flavorants, inert ingredients, and the

In some embodiments, the dietary supplements further compπse vitamins and minerals including, but not limited to, calcium phosphate or acetate, tπbasic, potassium phosphate, dibasic, magnesium sulfate or oxide, salt (sodium chloπde), potassium chloπde or acetate, ascorbic acid, ferric orthophosphate, niacinamide, zinc sulfate or oxide, calcium pantothenate, copper gluconate, riboflavin, beta-carotene, pyπdoxine hydrochloπde, thiamin mononitrate, folic acid, biotin, chromium chloπde or picolonate, potassium iodide, sodium selenate, sodium molybdate, phylloquinone, vitamin D3, cyanocobalamin, sodium selemte, copper sulfate, vitamin A, vitamin C, inositol, potassium iodide Suitable dosages for vitamins and minerals may be obtained, for example, by consulting the U S RDA guidelines

In other embodiments, the present invention provides nutritional supplements (e g , energy bars or meal replacement bars or beverages) compπsing the composition according to the invention The nutπtional supplement may serve as meal or snack replacement and generally provide nutrient calories Preferably, the nutπtional supplements provide carbohydrates, proteins, and fats in balanced amounts The nutπtional supplement can further comprise carbohydrate, simple, medium chain length, or polysaccharides, or a combination thereof A simple sugar can be chosen for desirable organoleptic properties Uncooked cornstarch is one example of a complex carbohydrate If it is desired that it should maintain its high molecular weight structure, it should be included only in food formulations or portions thereof which are not cooked or heat processed since the heat will break down the complex carbohydrate into simple carbohydrates, wherein simple carbohydrates are mono- or disacchaπdes The nutritional supplement contains, in one embodiment, combinations of sources of carbohydrate of three levels of chain length (simple, medium and complex, e g , sucrose, maltodextπns, and uncooked cornstarch) Sources of protein to be incorporated into the nutntional supplement of the invention can be any suitable protein utilized in nutritional formulations and can include whey protein, whey protein concentrate, whey powder, egg, soy flour, soy milk soy protein, soy protein isolate, casemate (e g , sodium casemate, sodium calcium casemate, calcium casemate, potassium casemate), animal and vegetable protein and hydrolysates or mixtures thereof When choosing a protein source, the biological value of the protein should be considered first, with the highest biological values being found in casemate, whey, lactalbumin, egg albumin and whole egg proteins In a

preferred embodiment, the protein is a combination of whey protein concentrate and calcium caseinate. These proteins have high biological value; that is, they have a high proportion of the essential amino acids. See Modern Nutrition in Health and Disease, eighth edition, Lea & Febiger, publishers, 1986, especially Volume 1, pages 30-32. The nutritional supplement can also contain other ingredients, such as one or a combination of other vitamins, minerals, antioxidants, fiber and other dietary supplements (e.g., protein, amino acids, choline, lecithin). Selection of one or several of these ingredients is a matter of formulation, design, consumer preference and end- user. The amounts of these ingredients added to the dietary supplements of this invention are readily known to the skilled artisan. Guidance to such amounts can be provided by the U.S. RDA doses for children and adults. Further vitamins and minerals that can be added include, but are not limited to, calcium phosphate or acetate, tribasic; potassium phosphate, dibasic; magnesium sulfate or oxide; salt (sodium chloride); potassium chloride or acetate; ascorbic acid; ferric orthophosphate; niacinamide; zinc sulfate or oxide; calcium pantothenate; copper gluconate; riboflavin; beta-carotene; pyridoxine hydrochloride; thiamin mononitrate; folic acid; biotin; chromium chloride or picolonate; potassium iodide; sodium selenate; sodium molybdate; phylloquinone; vitamin D3 ; cyanocobalamin; sodium selenite; copper sulfate; vitamin A; vitamin C; inositol; potassium iodide.

The nutritional supplement can be provided in a variety of forms, and by a variety of production methods. In a preferred embodiment, to manufacture a food bar, the liquid ingredients are cooked; the dry ingredients are added with the liquid ingredients in a mixer and mixed until the dough phase is reached; the dough is put into an extruder, and extruded; the extruded dough is cut into appropriate lengths; and the product is cooled. The bars may contain other nutrients and fillers to enhance taste, in addition to the ingredients specifically listed herein. It is understood by those of skill in the art that other ingredients can be added to those described herein, for example, fillers, emulsifiers, preservatives, etc. for the processing or manufacture of a nutritional supplement.

Additionally, flavors, coloring agents, spices, nuts and the like may be incorporated into the nutraceutical composition. Flavorings can be in the form of flavored extracts, volatile oils, chocolate flavorings, peanut butter flavoring, cookie crumbs, crisp rice, vanilla or any commercially available flavoring. Examples of useful flavoring include, but are not limited to, pure anise extract, imitation banana extract, imitation cherry extract, chocolate extract, pure lemon extract, pure orange extract, pure peppermint extract, imitation pineapple extract, imitation rum extract, imitation strawberry extract, or pure vanilla extract; or volatile oils, such as balm oil,

bay oil, bergamot oil, cedarwood oil, walnut oil, cherry oil, cinnamon oil, clove oil, or peppermint oil; peanut butter, chocolate flavoring, vanilla cookie crumb, butterscotch or toffee. In one embodiment, the dietary supplement contains cocoa or chocolate.

Emulsifiers may be added for stability of the nutraceutical compositions. Examples of suitable emulsifiers include, but are not limited to, lecithin (e.g., from egg or soy), and/or mono- and di- glycerides. Other emulsifiers are readily apparent to the skilled artisan and selection of suitable emulsifier(s) will depend, in part, upon the formulation and final product. Preservatives may also be added to the nutritional supplement to extend product shelf life. Preferably, preservatives such as potassium sorbate, sodium sorbate, potassium benzoate, sodium benzoate or calcium disodium EDTA are used.

In addition to the carbohydrates described above, the nutraceutical composition can contain natural or artificial (preferably low calorie) sweeteners, e.g., saccharides, cyclamates, aspartamine, aspartame, acesulfame K, and/or sorbitol. Such artificial sweeteners can be desirable if the nutritional supplement is intended to be consumed by an overweight or obese individual, or an individual with type II diabetes who is prone to hyperglycemia.

Moreover, a multi-vitamin and mineral supplement may be added to the nutraceutical compositions of the present invention to obtain an adequate amount of an essential nutrient, which is missing in some diets. The multi-vitamin and mineral supplement may also be useful for disease prevention and protection against nutritional losses and deficiencies due to lifestyle patterns.

The dosage and ratios of magnolol and/ or honokiol and the at least one additional component administered via a nutraceutical will, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired which can be determined by the expert in the field with normal trials, or with the usual considerations regarding the formulation of a nutraceutical composition.

In a preferred embodiment, the nutraceutical comprises per serving an amount of 0.01 to Ig, more preferably 0.2 mg to 500 mg of magnolol and/ or honokiol preferably in the form of a magnolia bark extract and at least one component selected from • Ligustilide: 0.5 to 500 mg and/ or • Hydroxytyrosol: 0.2 mg to 500 mg of each, and/ or

• Rosehip: 0.1 to 1Og based on the weight of dried rosehip concentrate and/ or

• Genistein: 0.5 to 500 mg and/ or

• Resveratrol: 0.2-500 mg, and/ or

• EGCG: 2.0 to 500 mg and/ or • Cardol diene (XII) and/ or cardol triene (XIII): 0.2 to 1000 mg of each, preferably in the form of a cashew fruit extract (Anacardium occidentale) and/ or

• Glycyrrhiza foetida or one or several compounds selected from formula (III) to (XI): 0.5 - 1000 mg of each, preferably in the form of a Glycyrrhiza foetida extract in the indicated amounts.

In another aspect, the invention relates to a pharmaceutical comprising the composition according to the invention and a pharmaceutically acceptable carrier.

A person skilled in the art knows which carriers can be used as pharmaceutically acceptable carriers. Suitable pharmaceutical carriers are e.g. described in Remington's Pharmaceutical Sciences, supra, a standard reference text in this field. Examples of such pharmaceutically acceptable carriers are both inorganic and organic carrier materials, suitable for oral/parenteral/injectable administration and include water, gelatin, gum arabic, lactose, starch, magnesium stearate, talc, vegetable oils, and the like.

The pharmaceutical composition may further comprise conventional pharmaceutical additives and adjuvants, excipients or diluents, including, but not limited to, water, gelatin of any origin, vegetable gums, ligninsulfonate, talc, sugars, starch, gum arabic, vegetable oils, polyalkylene glycols, flavoring agents, preservatives, stabilizers, emulsifying agents, buffers, lubricants, colorants, wetting agents, fillers, and the like.

In a preferred embodiment the pharmaceutical is in the form of a powder, tablet, capsule, gel, liquid or solid embodiment.

The dosages and ratios of the individual components in a pharmaceutical composition can be determined by the expert in the field with normal preclinical and clinical trials, or with the usual considerations regarding the formulation of pharmaceutical composition.

In a preferred embodiment magnolol and/ or honokiol is administered via a pharmaceutical composition either in the form of a single dose or by multiple doses in an amount of at least 0.01

mg/ kg bodyweight/ day, preferably in an amount of 0.1-50 mg/ kg body weight/ day, most preferably in an amount of 0.3-15 mg/ kg body weight / day.

The nutraceutical and pharmaceutical according to the present invention may be in any galenic form that is suitable for administering to the animal body including the human body, more in particular in any form that is conventional for oral administration, e.g. in solid form, for example as (additives/supplements for) food or feed, food or feed premixes, fortified food or feed, tablets, pills, granules, dragees, capsules, and effervescent formulations such as powders and tablets, or in liquid form, for instance in the form of solutions, emulsions or suspensions, for example as beverages, pastes and oily suspensions. The pastes may be filled into hard or soft shell capsules. Examples for other application forms are forms for transdermal, parenteral, topical or injectable administration. The nutraceutical and pharmaceutical may be in the form of controlled (delayed) release formulation. Examples of pharmaceuticals also include compositions suitable for topical application such as cremes, gels, sprays, dry sticks, powders etc.

The term "magnolol" as used herein comprises the pure compound also known as 5,5'-Diallyl- 2,2'-biphenyldiol or 5,5'-di-2-propenyl-[l,l'-Biphenyl]-2,2'-diol (CAS [528-43-8]) and plant extracts containing the same. The term magnolol also comprises etherified or esterified hydroxy derivatives from 5,5'-Diallyl-2,2'-biphenyldiol or 5,5'-di-2-propenyl-[l,l'-Biphenyl]-2,2'-diol. The ester or ether groups may for example be derived from straight or branched alkyl groups having 1 to 26 carbon atoms or from substituted or unsubstituted straight or branched aliphatic, araliphatic or aromatic carboxylic acids having 1 to 26 carbon atoms. Examples of etherified hydroxy groups further include glycoside groups. Examples of esterified hydroxy group further include glucuronide or sulfate groups. Preferably magnolol as used herein is 5,5'-Diallyl-2,2'-biphenyldiol or 5,5'-di-2-propenyl-[l,l'-Biphenyl]-2,2'-diol.

The term "honokiol" as used herein comprises the pure compound also known as 3',5-Diallyl- 2,4'-biphenyldiol or 3',5-di-2-propenyl-[l ,l'-Biphenyl]-2,4'-diol (CAS [35354-74-6]) and plant extracts containing the same. The term honokiol also comprises etherified or esterified hydroxy derivatives from 3',5-Diallyl- 2,4'-biphenyldiol or 3',5-di-2-propenyl-[l,l'-Biphenyl]-2,4'-diol. The ester or ether groups may for example be derived from straight or branched alkyl groups having 1 to 26 carbon atoms or from substituted or unsubstituted straight or branched aliphatic, araliphatic or aromatic carboxylic acids having 1 to 26 carbon atoms. Examples of etherified hydroxy groups further include glycoside groups. Examples of esterified hydroxy group further include glucuronide or sulfate

groups. Preferably, "honokiol" as used herein is 3',5-Diallyl-2,4'-biphenyldiol or 3',5-di-2- propenyl-[ 1 , 1 '-Biphenyl]-2,4'-diol.

Magnolol and/ or honokiol may be obtained either by chemical synthesis or by isolation from plant material or by mixtures thereof. Alternatively, magnolol and/ or honokiol may be used in the form of a composition comprising the magnolol and/ or honokiol such as a plant extract. Thus, the term magnolol and/ or honokiol encompasses both "natural" (isolated) and "synthetic" (manufactured). The term magnolol and/ or honokiol also includes any plant material or extract comprising at least one of magnolol or honokiol. The amount of magnolol and/ or honokiol in a plant material or extract is not critical. Preferably an amount of at least 1 wt.% of at least one of magnolol or honokiol based on the total weight of the plant material or extract is present. More preferably an amount of at least 50 wt.%, even more preferably an amount of at least 90 wt. % based on the total weight of the plant material or extract is present.

Preferably, magnolol and/ or honokiol are used in the form of a plant extract derived from the bark of Magnolia officinalis obtainable e.g. by stripping the bark from stems, branches, and roots. If desirable, the plant extract comprising the biphenyl derivatives may be prepared, for example, by processing a natural source of Magnolia bark such that at least one of magnolol or honokiol has been selectively removed, retained, or enriched. Alternatively, purified magnolol and/ or honokiol can be used to make such compositions. Such a composition can also be prepared, for example, by adding an amount of at least one of magnolol and/ or honokiol to a natural source or processed form of a natural source comprising the magnolol and/ or honokiol. Most preferably in all embodiments of the invention a Magnolia Bark Extract, in particular an extract derived from the bark of Magnolia officinalis comprising magnolol as well as honokiol is used in all embodiments of the invention.

Plant extracts containing the magnolol and/ or honokiol include extracts from Magnolia officinalis, Magnolia obovata, Magnolia rostrata, Magnolia bilboa, Magnolia biondii, Magnolia quinquepeta, Magnolia sprengeri, Manglietia insignis, Manglietia szechuanica, Manglietia yuyuanensis, Cercidiphyllum japonicum, Machilus thunbergii and others.

Magnolol and/ or honokiol are preferably derived from Magnolia bark that may be obtained from conventional and commercially available sources. The Magnolia bark derived magnolol and/ or honokiol are obtainable via a number of methods known in the art.

The magnolia bark may be processed by any suitable means to obtain magnolol and/ or honokiol'. Plant extracts containing at least one of magnolol and/ or honokiol may be obtained by conventional extraction of Magnolia bark (optionally in dried or grinded form) with solvents like ethanol, dichloromethane at reflux temperature or at lower temperature. Alternatively, it may be extracted with supercritical fluids like liquid carbon dioxide or by steam distillation of the bark with water followed by sampling of the distilled organic part. Sampling may for example be done by extraction with an organic solvent like dichloromethane. Subsequent removal of the solvent gives the desired magnolia bark extract. Optionally, the thus obtained magnolia bark extract may be subjected to further processing steps to enrich the content of magnolol and/ or honokiol. Extraction and/ or purification processes are e.g. described in Journal of Separation Science (2006), 29(3), 351-357 or Journal of Chromatography, A (2004), 1036(2), 171-175 without being limited thereto. If desirable, the extract or the pure isolated compounds may be further derivatized by methods known by a person skilled in the art e.g. using alkylating or acetylating agents in order to obtain the desired derivatives.

More preferably, the plant extract comprising magnolol and/ or honokiol is obtained by supercritical carbon dioxide extraction of Magnolia bark.

The magnolol and/ or honokiol may alternatively be obtained by chemical synthesis. Honokiol may e.g. be synthesized starting from 5-bromosalicylic acid and p-hydroxybenzoic acid by utilizing a Pd-catalyzed Suzuki-Miyaura coupling reaction as a key step as described in Bioorganic & Medicinal Chemistry Letters (2004), 14(10), 2621-2625. A synthesis of magnolol is e.g. described in JP 2004292392.

Preferably magnolol and/ or honokiol are used in the form of an extract from the bark of Magnolia officinalis in compositions according to the invention.

Magnolol and/ or honokiol used in compositions according to the invention are preferably employed in a concentration so that at least 0.005 mg/ kg bodyweight/ day are administered to an animal including humans. Preferably, the daily consumption by an animal including human is in the range of 0.01 to 50 mg/ kg bodyweight/ day, most preferably in an amount of 0.1 to 15 mg/ kg bodyweight / day based on the weight of the pure magnolol and/ or honokiol.

A nutraceutical preferably comprises 2mg to 500 mg of magnolol and/ or honokiol per serving. A pharmaceutical may for example comprise magnolol and/ or honokiol in an amount from 1 mg to

500 mg per dosage unit, e.g. per capsule or tablet, of from 5 mg daily dose to 2000 mg per daily dose of a liquid formulation.

Ligustilide may be isolated by methods known in the art [see, e.g., Beck J.J. and Stermitz F.R., J. Natural Products, Vol. 58, No. 7, pp. 1047-1055, 1995] from various plants such as Angelica glauca, Angelica acutiloba, Angelica sinensis, Angelicae dahuricae, Ligusticum acutilobum, Ligusticum officinale, Ligusticum sinense, Ligusticum wallichii, Cnidium officinale, Rhizoma Chuanxiong, Pleurospermum hookeri, Trachyspermum roxburghianum, Meum athamanticum, Lomatium torreyi, Scutellaria baicalensis, Opopanax chironium, Cenolophium denudatum, Coriandrum sativuum, Silaum silaus, but may also be synthesized by methods known in the art. Preferably ligustilide is used in form of a purified plant extract, e.g., from Ligusticum species, especially L. wallichii, comprising at least 50 wt.-% of ligustilide, and no more than 10 wt.-% of fatty acids and triglycerides as obtainable by the process disclosed in European patent application No. 05 002333.2, the contents of which are incorporated herein by reference. Preferably ligustilide is used in an effective dose of 0.01 to 50 mg/kg body weight/day, more preferably 0.1 to 5 mg/kg body weight/day.

A nutraceutical preferably comprises 0.5 mg to 500 mg of ligustilide per serving. If the composition is a pharmaceutical, such composition may preferably comprise ligustilide in an amount from 1 mg to 500 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg per daily dose to 2000 mg per daily dose of a liquid formulation.

Magnolol and/ or Honokiol is preferably combined with an olive derivable (polyphenol such as oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol (in the following referred to as 'phenolic compounds'), or mixtures thereof, more preferably with hydroxytyrosol.

The phenolic compounds may either be of synthetic origin or may be obtained from natural sources such as from products and by-products derived from the olive tree by extraction and/or purification. Products and by products of olive trees encompass olives, olive tree leafs, olive pulps, olive oil, olive-derived vegetation water and olive oil dregs without being limited thereto. Based on the extraction procedure the amount, respectively the ratio of the phenolic compounds can be easily adjusted by a person skilled in the art.

Preferably, the phenolic compounds are derived from olives that may be obtained from conventional and commercially available sources such as growers.

In case of synthetic or purified hydroxytyrosol (3, 4 dihydroxyphenylethanol), hydroxytyrosol has a purity of at least 90%, more preferably a purity of at least 91%, even more preferably a purity of at least 92%, even more preferably a purity of at least 93%, even more preferably a purity of at least 94%, even more in particular a purity of at least 95%, in particular a purity of at least 96%, more in particular a purity of at least 97%, even more in particular a purity of at least 98%, most in particular a purity of at least 99%. The purity of hydroxytyrosol can be determined by methods known to a person skilled in the art such as e.g. by HPLC, or LC-MS.

The olive-derived phenolic compounds employed herein can be prepared by a number of methods known in the art. The olives may be processed by any suitable means to obtain the compositions described. For example, the olives and/or olive leaves may be pressed to obtain a mixture including olive oil, vegetation water and solid byproducts. The phenolic compounds may be obtained directly from the mixture or the mixture may be fractionated and/or purified to obtain the phenolic compounds. The compositions may be fractionated and/or purified by a number of methods known to the person skilled in the art. Examples of fractionating methods include partitioning with an organic solvent, chromatography, for example high pressure liquid chromatography (HPLC) or the use of supercritical fluids.

Examples of references that deal with the extraction of oleuropein and/or hydroxytyrosol from olive leaves are WO02/18310 Al, US 2002/0198415 Al, WO2004/005228 Al , US 6,416,808 and US 2002/0058078 Al which disclose a method for acidic hydrolysis of olive vegetation water for 2 to 12 months until at least 90% of the present oleuropein has been converted. A method of extraction of phenolic compounds from olives, olive pulps, olive oil and oil mill waste water is described by Usana Inc. patents US 6,361,803 and WOO 1/45514 Al and in US 2002/0004077 Al . EP 1 582 512 Al describes an extraction of hydroxytyrosol from olive leaves. A method for obtaining hydroxytyrosol and/or oleuropein from the vegetation water of de-pitted olives is disclosed in US 2004/0039066 Al in paragraphs [0080]-[0O91].

Commercially available hydroxytyrosol containing olive extracts which may be used in combination with rosehip according to the invention include e.g. extracts from olive fruits such as

Polyphen-Oil™ from Life Extension, OleaSelect™ from Indena, Hytolive ® from Genosa,

Prolivols from Seppic, OLIVE LEAF or OLIVE Water Extract of Olea europea from Lalilab,

Hitofulvic and Olife™ from Ebiser, Hydrolysed olive leaf extract, such as described in

EP 1582512, olive leaf extract, rich in oleuropein, such as available from Furfural and/or HIDROX ® from CreAgri.

Preferably magnolol and/ or Honokiol is combined with HIDROX ® from CreAgπ such as HIDROX ® 2% spray dried powder, HIDROX ® Gold freeze dπed powder (9%) and/ or HIDROX ® 6% freeze dried powder organic olive juice extract

An example of a synthetic process in which hydroxytyrosol may be prepared with a purity > 90% is a process compπsing the steps of hydrogenating 3,4-dihydroxymandelic acid or a 3,4- dihydroxymandehc acid Ci )0 -alkyl ester in a C 1 , 0 -alkanol in the presence of a precious metal hydrogenation catalyst and optional reduction of the formed (3,4-dihydroxyphenyl)-acetic acid Ci l o-alkyl ester is to form 2-(3,4-dihydroxyphenyl)-ethanol (= hydroxytyrosol) a specific example of which is described below

The hydrogenation may be carried out in the presence of a precious metal catalyst such as Pd and Rh, separately or in mixtures, in a manner known per se In order to increase the activity and stability of the catalysts they are preferably used on carriers such as activated carbon, alumina or kieselguhr The preferred hydrogenation catalyst in the present case is Pd/C

The hydrogenation is earned out in the presence of a lower alkanol, i e a Ci i 0 -alkanol, such as methanol, ethanol, propanol, isopropanol, butanol, preferably in methanol or ethanol, preferably in the presence of a strong acid, preferably hydrochloric acid, preferably at a temperature from ambient temperature to 100 0 C or higher, preferably from 40-65 0 C, preferably at a hydrogen pressure at least higher than the vapor pressure of the solvent at the hydrogenation temperature The pressure can be from normal, i e atmospheric pressure, to 100 bar or higher

If desired, the reaction which is preferably carried out as a through process can be accomplished in two separate steps, i e , a first step wherein an ester of 3,4-dihydroxymandehc acid is built by esteπfication of the acid and a second step wherein the 3,4-dihydroxymandehc acid lower alkyl ester is hydrogenated The reduction of the (3,4-dihydroxyphenyl)-acetic acid Ci io-alkyl ester to give hydroxytyrosol can be achieved in a known manner The preferred reduction agents are complex hydπds of aluminum and boron, such as LiAlH 4 and NaBH 4 The starting material, 3,4- dihydroxymandehc acid, is well-known and can be prepared in accordance with methods described in the literature, e g , by condensation of catechol with glyoxyhc acid

The phenolic compound is preferably used in a concentration so that the daily consumption by an animal including humans (e g weighing about 70 kg) is in the range of from 1 mg/day to 2000 mg/day, more preferably from 5 mg/day to 500 mg/day A nutraceutical composition preferably

comprises 0.5 mg to 1000 mg of phenolic compound per serving. If the composition is a pharmaceutical composition such composition may for example comprise a phenolic compound in an amount from 1 mg to 2000 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg per daily dose to 3000 mg per daily dose of a liquid formulation.

Examples of rosehip include dried rosehip concentrate, a lipophilic extract of rosehip (including rosehip oil, rosehip seed oil or a fractionated lipophilic extract) or a hydrophilic extract of rosehips (a rosehip extract comprising water-soluble parts of rosehips, such as for instance polysaccharides).

Rosehip extract may be obtained from rosehip, the fruit, petals and/or seeds from wild rose bushes, such as Rosa canina ("dog rose-hip"), Rosa gallica, Rosa condita, Rosa rugosa, Rosa hugonis, Rosa nitida, Rosa pendulina, Rosa pimpinellifolia, and Rosa sericea. Preferably, rosehip extract is prepared from the fruit {i.e. the rosehip).

Rosehip is a natural product and hence its composition may vary somewhat. The hydrophilic extract e.g. has a high vitamin C content which might be in the range of 0.6 and 1.5 mg per g and contains as well other vitamins and minerals. An example of a rosehip extract is that produced in accordance with the description in US 6,024,960. Of course, the quantities of the specific vitamins and minerals may vary by species or through use of different extraction/concentration methods. An exemplary rosehip extract is shown in Table I (page 4 and 5) of WO 02/342274, however the invention is not limited thereto.

Dried rosehip concentrate can be obtained from dried and milled rosehips that are reduced to powder. A rosehip concentrate may for example be obtained in the following method: Rosehips are harvested in a generally known manner when the hips are fully ripe. Rosehip can be obtained from any of the multiple species of plants that belong to the Rosa family, for example from rosehips from wild rose bushes, such as Rosa canina ("dog rose-hip"), Rosa gallica, Rosa condita, Rosa rugosa, Rosa hugonis, Rosa nitida, Rosa pendulina, Rosa pimpinellifolia, and Rosa sericea, more preferably hips of the Rosa canina are used.. After the hips are harvested, the hips are chopped into pieces. If further processing is delayed, the hips may be frozen for storage. In any event, the next step is to dry the chopped rosehips to a water content of about at most 5% by weight. Preferably, the drying is conducted in such a way that the vitamin content of the rosehips is preserved, for example by drying the rosehips at a temperature below 50°C with air and by avoiding sunlight.

The dried and chopped rosehips may then be passed through a separation step in which extraneous matter, for instance nuts, hairs etc., that may have accompanied the rosehips during harvesting is removed. The remaining fruit flesh is then crushed in a grinding mill. Preferably, the obtained material has a particle size of below 1 mm, more preferably between 0.1 and 0.5 mm.

Therefore, a process for obtaining a dried and milled rosehip concentrate may comprise the following steps: a) harvesting rosehips when the hips are fully ripe b) chopping the harvested rosehips into pieces c) drying the chopped rosehips to a water content of at most 5% by weight d) optionally passing the dried and chopped rosehips through a separation step in which extraneous matter is removed e) optionally the fruit flesh and the seeds may be separated and extracted separately f) crushing the remaining material in a grinding mill to a particle size of below 1 mm.

Preferably, the extract (fraction) comprises at least cyanidin-3-o-glucoside, cyanidin-3-o- rutinoside or glycosides of diacylglycerol such as 3-beta-D-galactopyranosyloxy-2-(octadeca- 9Z, 12Z, 15Z-trienoyloxy)propanyl octadeca-9Z, 12Z, 15Z-trienoate (GOPO), in particular at least GOPO.

In a preferred embodiment of the invention the rosehip is in the form of a dried rosehip concentrate.

Rosehip is preferably used in an amount sufficient to administer to animals including humans (e.g. weighing about 70 kg) a dosage of at least 0.02 g/day based on the weight of dried rosehip concentrate. Preferably an amount of 0.1 g/day to 30 g/day based on the weight of dried rosehip concentrate, more preferably from 2 g/day to 10 g/day based on the weight of dried rosehip concentrate is used.

Thus, the daily dosage based on the weight of dried rosehip concentrate is at least 0.3 mg/kg body weight, preferably an average dosage of 1-450 mg/kg body weight, most preferable of 3-140 mg/kg of bodyweight is used.

If the composition is a nutraceutical, the amount of a dried rosehip concentrate comprised therein is preferably in the range from about 0.1 g to about 10 g, and even more preferably between 0.5 and 2.0 g per serving. If the composition is a pharmaceutical composition such composition may for example comprise from 20 mg to 1 g per solid dosage unit, e.g., per capsule or tablet, or for example from 500 mg per daily dose to 6000 mg per daily dose of a liquid formulation.

If instead of dried rosehip concentrate, rosehip (seed) oil or an individual rosehip compound is used, the amount used may be derived from the amount of dried rosehip concentrate and finding the optimal dosage is a matter of routine experimentation for the person skilled in the art.

The term "genistein" as used herein comprises the aglycone (4', 5, 7-trihydroxyisoflavone) and derivatives thereof, e.g., genistein glycosides, genistein sulfates, genistein glucuronides.

Genistein is preferably used in a concentration so that the daily consumption by an animal including humans {e.g. weighing about 70 kg) is in the range of from 0.5 mg/day to 2000 mg/day. A nutraceutical preferably comprises for example 0.2 mg to 500 mg of genistein per serving. A pharmaceutical composition may for example comprise a genistein in an amount from 0.5 mg to 500 mg per dosage unit, e.g., per capsule or tablet, or from 0.5 mg per daily dose to 2000 mg per daily dose of a liquid formulation.

The term "resveratrol" as used herein comprises a derivative, metabolite or analogue thereof. The carbon-carbon double bond may be trans or cis and includes cis/trans mixtures. Etherifϊed or esterified hydroxy groups may be derived from unsubstituted or substituted, straight or branched chain alkyl groups having 1 to 26 carbon atoms or from unsubstituted or substituted, straight or branched chain aliphatic, araliphatic or aromatic carboxylic acids having 1 to 26 carbon atoms. Etherified hydroxy groups may further be glycoside groups and esterified hydroxy groups may further be glucuronide or sulfate groups. Of primary interest for the purposes of the invention is (trans)-res veratrol .

Resveratrol is preferably used in amount sufficient to administer to an animal including humans (e.g. weighing about 70 kg) a dosage from 0.5 mg/day to 2000 mg/day, more preferably from 5 mg/day to 500 mg/day. Thus, if the composition is a nutraceutical composition the amount of a resveratrol comprised therein is preferably in the range from 0.2 mg to 500 mg per serving. If the composition is a pharmaceutical composition such composition may preferably comprise from

0.5 mg to 500 mg per solid dosage unit, e.g., per capsule or tablet, or from 0.5 mg per daily dose to 2000 mg per daily dose of a liquid formulation.

The term "EGCG" as used herein comprises (-)-epigallocatechin gallate (EGCG in the narrower sense) and/or one or more derivatives (esterified forms, glycosides, sulphates) thereof, or other catechins found in green tea such as (-) epigallocatechin (EGC), (-) epicatechin-3-gallate (ECG), (-) epicatechin (EC), (+) gallocatechin, and (+) catechin and derivatives thereof. Of primary interest for use in the present invention is (-)-epigallocatechin gallate.

EGCG is preferably used in a concentration so that the daily consumption by an animal including humans (e.g. weighing about 70 kg) is in the range of from 5 mg/day to 2000 mg/day, preferably from 20 mg/day to 300 mg/day. A nutraceutical composition preferably comprises for 2 mg to 500 mg of EGCG per serving. If the composition is a pharmaceutical composition such composition may comprise EGCG for example in an amount from 5 mg to 500 mg per dosage unit, for example per capsule or tablet, or from 10 mg per daily dose to 2000 mg per daily dose of a liquid formulation.

The term boswellic acid encompasses pure boswellic acid and derivatives thereof as well as extracts comprising boswellic acid. Boswellic extract comprising e.g. 3-O-acetyl-l l-keto-beta- boswellic acid, are known to the person skilled in the art. For instance, it is available on the market in a dietary supplement called 5-LOXIN ® (company PL Thomas). The extract itself it available as WokVel ® from Geni Herbs. It may be extracted from Boswellia serrata.

The daily intake by a human adult (weighing approximately 70kg) of boswellic acid (extracts) is preferably between 5 and 1000 mg per day, preferably between 100 and 500 mg per day.

A nutraceutical composition preferably comprises between 5 mg and 500 mg of boswellic acid or boswellic acid extract per serving. If the composition is a pharmaceutical composition such composition may preferably comprise boswellic acid or boswellic acid extract in an amount from 50 mg to 500 mg per dosage unit, e.g., per capsule or tablet, or from 50 mg per daily dose to 1000 mg per daily dose of a liquid formulation.

Methylsulfonylmethane (MSM) may be synthesized by methods known to the person skilled in the art. Daily intake of methylsulfonylmethane by a human adult (weighing approximately 70kg)

is preferably between 100 and 7000 mg per day, more preferably between 500 and 2000 mg/day, most preferably between 250 and 750 mg per day.

A nutraceutical preferably comprises 5 mg to 3000 mg of MSM per serving. A pharmaceutical may preferably comprise MSM in an amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or tablet, or from 250 mg per daily dose to 750mg per daily dose of a liquid formulation.

Within the framework of the invention SAMe is defined as S-adenosylmethionine. SAMe is commercially available and is preferably dosed between 50 and 3000 mg/day. Examples of amounts used in commercially available products are: 200 mg SAMe (from 400 mg of SAMe- tosylate disulfate); 400 mg S-adenosyl L-methionine (from SAMe); 200mg S-adenosyl methionine; 400 mg SAMe (as S-adenosylmethionine 1, 4-butanedisulfonate). A nutraceutical preferably comprises 5 mg to 1000 mg of SAMe per serving. A pharmaceutical may preferably comprise SAMe in an amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or tablet, or from 10 mg per daily dose to 3000 mg per daily dose of a liquid formulation.

Collagen hydrolysate is a protein mixture which may be extracted from animal cartilage. It is commercially available from many supplement companies. Collagen hydrolysate and collagen are commercially available and the daily intake thereof by a human adult (weighing approximately 70kg) is preferably between 500 and 10000 mg per day, preferably between 2000 and 8000 mg per day.

Unhydrolyzed or undenatured collagen, herein referred to as 'collagen' may be isolated from chicken sternum by methods known to the person skilled in the art.

A nutraceutical preferably comprises between 5 mg and 5000 mg of collagen or collagen hydrolysate per serving. A pharmaceutical composition may preferably comprise collagen in an amount from 10 mg to 1000 mg per dosage unit, e.g., per capsule or tablet, or from 10 mg per daily dose to 5000 mg per daily dose of a liquid formulation.

The term "ascorbyl phosphate" as used herein denotes metal salts of mono- and poly- phosphoric acid esters of ascorbic acid wherein the phosphorylated hydroxy group of the ascorbic acid molecule features one or more phosphoric acid (phosphate) units, and metal cations, e.g. sodium and/or magnesium or calcium ions, are also present. The term "poly" generally denotes 2 - 10, preferably 2 - 4, phosphate units. The ascorbyl phosphates may also be referred to in general as

"ascorbyl (polyphosphates" to embrace both mono- and polyphosphates. Typical ascorbyl phosphates for use in the present invention are L-ascorbic acid phosphate ester salts such as

sodium ascorbyl phosphate, potassium ascorbyl phosphate, magnesium ascorbyl phosphate, calcium ascorbyl phosphate and sodium magnesium L-ascorbyl-2-monophosphate. Commercially available ascorbyl phosphates comprise trisodium L-ascorbyl-2-monophosphate which is available as STAY-C ® 50 from DSM Nutritional Products AG, (4303 Kaiseraugst, Switzerland) and magnesium L-ascorbyl phosphate available from Showa Denko) and sodium magnesium L- ascorbyl-2-monophosphate and L-ascorbic acid-monophosphate which is available as ROVIMIX ® STAY-C ® 35 from DSM Nutritional Products AG, (4303 Kaiseraugst, Switzerland). The preferred ascorbyl phosphate for the purposes of the present invention is trisodium L- ascorbyl-2-monophosphate. The ascorbyl phosphate may be incorporated into the nutraceutical, pharmaceutical, cosmetic or dermatological preparations in many dosage amounts as known to the person skilled in the art.

Lycopene (ψ,ψ carotene; C 40 H 56 ; CAS-number: 502-65-8) belongs to the carotenoid family and contains 1 1 conjugated double-bonds and an additional two non-conjugated carbon-carbon double-bonds. Lycopene is one of the major dietary carotenoids and is found in various fruits and vegetables, especially in tomatoes and tomato products. It also occurs e.g. in water melon, pink grapefruit, guava.

Lycopene is preferably used in a concentration so that the daily consumption by an animal including humans (e.g. weighing about 70 kg) is in the range of from 0.05 mg/day to 50 mg/day, more preferably from 0.5 mg/day to 30 mg/day. A nutraceutical composition preferably comprises 0.05 mg to 50 mg of lycopene per serving. If the composition is a pharmaceutical composition such composition may preferably comprise Lycopene in an amount from 0.5 mg to 50 mg per dosage unit, e.g., per capsule or tablet, or a liquid formulation.

The chemical structure of cardol diene is given in Fig. 1, structure (XII). The chemical structure of cardol triene is given in Fig. 1 , structure (XIII)

Preferably cardol diene (XII) is used in the composition of the present invention.

Cardol diene (XII) and/ or cardol triene (XIII) is preferably used in a concentration so that the daily consumption by an animal including humans (e.g. weighing about 70 kg) is in the range of from 1 mg/day to 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A nutraceutical composition preferably comprises between 0.2 mg and 1000 mg of cardol diene (XII) and/ or cardol triene (XIII) per serving. In case of a pharmaceutical composition the amount of cardol diene (XII) and/ or cardol triene (XIII) may be selected from 0.5 mg and 2000 mg per dosage

unit, e.g., per capsule or tablet, or between 1 mg per daily dose and 3000 mg per daily dose of a liquid formulation.

Cardol diene (XII) and/ or cardol triene (XIII) may also be used in the form of an extract for instance an - preferably organic phase or supercritical fluid - extract of the cashew plant (Anacardium occidentale)) or a part of the cashew plant, for example in the form of an extract of cashew fruit.

Cardol diene (XII) and/ or cardol triene (XIII) may be synthesized or extracted and/or purified by methods known to the person skilled in the art.

Cardol diene (XII) and/ or cardol triene (XιII)are preferably derived from the cashew plant that may be obtained from conventional and commercially available sources such as growers. A number of phenolic compounds are found in Anacardium occidentale, the cashew nut, the cashew nut shell, the cashew apple, and from various Toxicodendron species like T. radicans, T. diversilobum, also from Rhus verniciflua, and Melanorrhoea usitata.

Cardol diene (XII) and/ or cardol triene (XIII) as employed herein may be prepared by a number of methods known in the art. The mentioned plants may be processed by any suitable means to obtain the compositions described. For example, cashew apple may be extracted to obtain a mixture. Cardol diene (XII) and/ or cardol triene (XIII) may be obtained directly from the mixture or the mixture may be fractionated and/or purified to obtain cardol diene (XII) and/ or cardol triene (XIII). The compositions may be fractionated and/or purified by a number of methods known to the person skilled in the art. Examples of fractionating methods include partitioning with an organic solvent, chromatography, for example high pressure liquid chromatography (HPLC) or the use of supercritical fluids.

Cardol diene (XII) and/ or cardol triene (XIH) can for example be obtained by extraction of dried plant material of Anacardium occidentale with methanol: methyl tert butyl ether (9: 1) and by subsequent fractionation of the thus obtained crude extract by preparative HPLC in a buffered solvent system.

Cashew fruit extract is preferably used in such an amount that the amount of cardol diene (XII) and/ or cardol triene (XIII) is as described above.

Magnolol and/ or honokiol may also be combined with Glycyrrhiza foetida. The term 1 Glycyrrhiza foetida' encompasses all parts of the plants derived from Glycyrrhiza foetida as well as extracts derived thereof.

Magnolol and/ or honokiol may also be combined with compounds isolated from Glycyrrhiza foetida such as 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)- benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2- butenyl)-6-pentyl -benzoic acid (VI), Cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4- methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3- methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4- methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (XI), more preferably enriched in at least one compound from the group of cannabigerolic acid monomethyl ether, 2- hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid and 3-methoxy-2- (3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol.

Glycyrrhiza foetida as a whole or parts thereof such as the seedlings, the young plants, the leaves, the flowers (optionally in dried or ground form) or seeds may be used in dried and grinded form or may be extracted conventionally with solvents like ethanol, dichloromethane at reflux temperature or at lower temperature. Alternatively, it may be extracted with supercritical fluids like SF carbondioxyde or by steam distillation of the plant with water followed by sampling of the distilled organic part. Sampling may for example be done by extraction with an organic solvent like dichloromethane, ethylacetate etc. Subsequent removal of the solvent gives the desired Glycyrrhiza foetida extract. Optionally, the thus obtained Glycyrrhiza foetida extract may be subjected to further processing steps to enrich the content of specific compounds to give an extract of Glycyrrhiza foetida e.g. enriched in 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6- pentyl-benzoic acid (VI), Cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3- (2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2- butenyl)-5-(2-phenylethyl)-phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy- 5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (XI), more preferably enriched in at least one compound from the group of cannabigerolic acid monomethyl ether, 2-hydroxy-4- methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid and 3-methoxy-2-(3-methyl-2- butenyl)-5-(2-phenylethyl)-phenol. Compounds III to XI are depicted in Fig. 1.

Glycyrrhiza foetida extracts enriched in at least one compound selected from the group of cannabigerolic acid monomethyl ether, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)- 6-pentyl -benzoic acid and 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol are preferred.

All compounds (III) -(XI) can e.g. be obtained by extraction of dried plant material of Glycyrrhiza foetida with methanol: methyl tert butyl ether (MTB) (9: 1) and by subsequent fractionation of the thus obtained crude extract by preparative HPLC, for example in a buffered solvent system or can be synthesized.. Examples of fractionating methods include partitioning with an organic solvent, chromatography, for example high pressure liquid chromatography (HPLC) or the use of supercritical fluids. Of course the compounds of (III) -(XI) may also be accessible via chemical synthesis)

Preferably compounds (III) to (XI) are used in the form of an extract derived from Glycyrrhiza foetida.

The Glycyrrhiza foetida extract and/or the compounds contained therein are preferably derived from Glycyrrhiza foetida that may be obtained from conventional and commercially available sources such as growers.

The Glycyrrhiza foetida as well as the extracts derived thereof are preferably used so that the daily consumption by an animal including humans {e.g. weighing about 70 kg) is in the range of from 0.5 mg/day to 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A nutraceutical composition preferably comprises 0.5 mg to 1000 mg of a Glycyrrhiza foetida extract. If the composition is a pharmaceutical composition such composition may comprise the Glycyrrhiza foetida extract in an amount from preferably 1 mg to 2000 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg per daily dose to 3000 mg per daily dose of a liquid formulation.

The individual compounds isolated from the Glycyrrhiza foetida are preferably used in a concentration so that the daily consumption by an animal including humans (e.g. weighing about 70 kg) is in the range of from 0.5 mg/day to 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A nutraceutical composition preferably comprises 0.5 mg to 1000 mg of such a compound. If the composition is a pharmaceutical composition such composition may comprise one or more of the compounds contained in Glycyrrhiza foetida in an amount from preferably 1

mg to 2000 mg per dosage unit, e.g., per capsule or tablet, or from 1 mg per daily dose to 3000 mg per daily dose of a liquid formulation.

If the individual compounds are used in form of a Glycyrrhiza foetida extract, the extract is preferably used in such an amount that the amount of individual compound(s) is as described above.

Extracts of of Harpagophytum procumbens (Devil's claw) are on the market. The active ingredient in Devil's Claw is a glycoside called harpagoside. Other constituents of Devil's Claw include beta-sitosterol, harpagide, procumbine, sugars, gum resin and bitter ingredients. Devil's Claw's dosage can easily be determined by the person skilled in the art and is preferably within the same range as on the market.

Milk protein concentrate includes milk protein hydrolysates and is commercially available for example as MicroLactin™ from Brandenburg nutrition or as Peptopro from DSM Food Specialities. It's dosage can easily be determined by the person skilled in the art and is preferably within the same range as on the market.

Horse chestnut extract refers to an extract obtained from Aesculus hippocastanum comprising a mixture of saponins.

Other examples of compounds with which magnolol and/ or honokiol may be combined to get a synergistic effect are solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, lutein, zeaxanthin and β-cryptoxanthin.

In another aspect, the invention relates to a cosmetic or dermatological preparation (the latter preparation are a specific type of a pharmaceutical) comprising an effective amount of the composition of the invention and a cosmetically or dermatologically acceptable carrier. The cosmetic or dermatological composition may further comprise conventional cosmetic respectively dermatological adjuvants and/or additives and/or additional active ingredients.

Preferably the cosmetic or dermatological preparations are skin care formulations for the treatment, co-treatment or prevention of inflammation of the skin, in particular of sunburn caused by UV-radiation, of contact dermatitis (particularly diaper area dermatitis), atopic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, neurodermitis, thermal burns, photoageing or for

the treatment, co-treatment or prevention of impure skin. Examples of impure skin include pimples, acne and other skin impurities with an inflammatory aspect.

The term "effective amount" means preferably at least 0.001% of each active agents as listed above based on the total weight of the cosmetic or dermatological composition. Preferably, the cosmetic or dermatological preparations comprise the active agents selected from the list above in an amount between 0.01 wt.-% and 20 wt.-%, more preferably between 0.05 and 10 wt.-%, still more preferably between 0.1 and 5 wt.-%.

The amount of the cosmetic or dermatological preparation which is to be applied to the skin depends on the concentration of the active ingredients in the preparation and the desired cosmetic or pharmaceutical effect. For example, the application can be such that a creme is applied to the skin. A creme is usually applied in an amount of about 1 to 2 mg creme/cm 2 skin. The amount of the composition which is applied to the skin is, however, not critical, and if with a certain amount of applied composition the desired effect cannot be achieved, a higher concentration of the active preparations which contain more active ingredient might be employed.

The invention also relates to the use of the cosmetic preparation for the cosmetic treatment, co- treatment or prevention of inflammation of the skin, in particular for the cosmetic treatment, co- treatment or prevention of sunburn, contact dermatitis (particularly diaper area dermatitis), atopic dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, neurodermitis, thermal burns or photoageing.

Also, the invention relates to a method for the treatment, co-treatment or prevention of inflammation of the skin, in particular of sunburn in humans, of impure skin such as for example acne or of photoageing which is associated with chronic skin inflammation, said method comprising the step of administering an effective amount of the dermatological composition according to the invention to humans, which are in need thereof. Also, the invention relates to a method for cosmetic treatment, co-treatment or prevention of inflammation of the skin, in particular of sunburn or of impure skin by a cosmetic preparation according to the invention. Sunburn prevention is preferably achieved with topical application comprising the composition of the invention preferably in combination with suitable light screening agents.

The cosmetic or dermatological preparations according to the invention may be in the form of a suspension or dispersion in solvents or fatty substances, or alternatively in the form of an emulsion or micro emulsion (in particular of O/W or W/O type, 0/W/O or W/O/W-type, wherein

O stands for oil phase and wherein W stands for water phase), such as a cream, a paste, a lotion, a thickened lotion or a milk, a vesicular dispersion in the form of an ointment, a gel, a solid tube stick or an aerosol mousse, and may be provided in the form of a mousse, foam or a spray foams, sprays, sticks or aerosols or wipes. Examples of cosmetic or dermatological preparations are skin care preparations, in particular, body oils, body lotions, body gels, treatment creams, skin protection ointments, moisturizing gels, moisturizing sprays, revitalizing body sprays, after sun preparations or sunscreen formulations.

The cosmetic or dermatological composition for the treatment, co-treatment or prevention of inflammation of the skin, such as for example sunburn, photoageing or impure skin may be in a form that is conventional for oral administration, examples of which are described above and also include beauty foods and supplements.

The cosmetic or dermatological preparations of the invention for instance as sunscreen formulations or after sun preparations may further comprise the usual cosmetic respectively dermatological adjuvants and/or additives such as preservatives/ antioxidants, fatty substances/ oils, water, organic solvents, silicones, thickeners, softeners, emulsifiers, additional light screening agents, antifoaming agents, moisturizers, fragrances, surfactants, fillers, sequestering agents, anionic, cationic, nonionic or amphoteric polymers or mixtures thereof, propellants, acidifying or basifying agents, dyes, colorants, pigments or nanopigments, light stabilizers, insect repellants, skin tanning agents, skin whitening agents, antibacterial agents, preservatives active ingredients or any other ingredients usually formulated into cosmetics.

Light screening agents which may be incorporated into cosmetic or dermatological preparations of the invention for instance sunscreen formulations are advantageously selected from IR, UV-A,

UV-B, UV-C and/ or broadband filters. Examples of UV-B or broad spectrum screening agents, i.e. substances having absorption maximums between about 290 and 340 nm may be organic or inorganic compounds. Organic UV-B or broadband screening agents are e.g. acrylates such as 2- ethylhexyl 2-cyano-3,3-diphenylacrylate (octocrylene, PARSOL ® 340), ethyl 2-cyano-3,3- diphenylacrylate and the like; camphor derivatives such as 4-methyl benzylidene camphor

(PARSOL ® 5000), 3-benzylidene camphor, camphor benzalkonium methosulfate, polyacrylamidomethyl benzylidene camphor, sulfo benzylidene camphor, sulphomethyl benzylidene camphor, therephthalidene dicamphor sulfonic acid and the like; Cinnamate derivatives such as ethylhexyl methoxycinnamate (PARSOL ® MCX), ethoxyethyl methoxycinnamate, diethanolamine methoxycinnamate (PARSOL ® Hydro), isoamyl

methoxycinnamate and the like as well as cinnamic acid deπvatives bond to siloxanes, p- aminobenzoic acid deπvatives, such as p-aminobenzoic acid, 2-ethylhexyl p- dimethylaminobenzoate, N-oxypropylenated ethyl p-aminobenzoate, glyceryl p-aminobenzoate, benzophenones such as benzophenone-3, benzophenone-4, 2,2', 4, 4'-tetrahydroxy-benzophenone, 2,2'-dihydroxy-4,4'-dimethoxybenzophenone and the like, esters of benzalmalonic acid such as di-(2-ethylhexyl) 4-methoxybenzalmalonate, esters of 2-(4-ethoxy-anihnomethylene)propandioic acid such as 2-(4-ethoxy amlinomethylene) propandioic acid diethyl ester as described in the European Patent Publication EP 0895 776, organosiloxane compounds containing benzmalonate groups as described in the European Patent Publications EP 0358584 Bl, EP 0538431 Bl and EP 0709080 Al such as polysilicone-15 (PARSOL ® SLX), drometπzole tπsiloxane (Mexoryl XL), imidazole deπvatives such as e g 2-phenyl benzimidazole sulfonic acid and its salts (PARSOL ® HS) Salts of 2-phenyl benzimidazole sulfonic acid are e g alkali salts such as sodium- or potassium salts, ammonium salts, morphohne salts, salts of pπmary, sec and tert amines like monoethanol amine salts, diethanol amine salts and the like, salicylate deπvatives such as isopropylbenzyl salicylate, benzyl salicylate, butyl salicylate, ethylhexyl salicylate (PARSOL ® EHS, NEO Hehopan OS), isooctyl salicylate or homomenthyl salicylate (homosalate, PARSOL ® HMS, NEO Hehopan OS) and the like, tπazine deπvatives such as ethylhexyl tπazone (Uvinul T-150), diethylhexyl butamido tπazone (Uvasorb HEB) Encapsulated UV-filters such as encapsulated ethylhexyl methoxycinnamate (Eusolex UV-pearls) or microcapsules loaded with UV-filters as e g disclosed in EP 1471995 and the like Inorganic compounds are pigments such as microparticulated TiO 2 , ZnO and the like The term "microparticulated" refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm The T1O 2 particles may also be coated by metal oxides such as e g aluminum or zirconium oxides or by organic coatings such as e g polyols, methicone, aluminum stearate, alkyl silane Such coatings are well known in the art

Examples of broad spectrum or UV A screening agents 1 e substances having absorption maxima between about 320 and 400 nm may be organic or inorganic compounds e g dibenzoylmethane derivatives such as 4-tert butyl-4'-methoxydibenzoyl-methane (PARSOL® 1789), dimethoxydibenzoylmethane, isopropyl dibenzoylmethane and the like, benzotπazole derivatives such as 2,2'-methylene-bis-(6-(2H-benzotπazole-2-yl)-4-(l,l,3,3,-tetramethylbutyl)-phenol (TINOSORB M) and the like, bis-ethylhexyloxyphenol methoxyphenyl tπazine (Tinosorb S) and the like, phenylene-l,4-bis-benzimidazolsulfonic acids or salts such as 2,2-(l,4-phenylene)bis- (lH-benzimidazol-4,6-disulfonic acid) (Neohehopan AP), amino substituted hydroxybenzophenones such as 2-(4-Diethylamino-2-hydroxy-benzoyl)-benzoic acid hexylester

(Uvinul A plus) as described in the European Patent Publication EP 1046391 ; Ionic UV-A filters as described in the International Patent Publication WO2005080341 Al. Pigments such as microparticulated ZnO or TiO2 and the like. The term "microparticulated" refers to a particle size from about 5 nm to about 200 nm, particularly from about 15 nm to about 100 nm. The particles may also be coated by other metal oxides such as e.g. aluminum or zirconium oxides or by organic coatings such as e.g. polyols, methicone, aluminum stearate, alkyl silane. Such coatings are well known in the art.

As dibenzoylmethane derivatives have limited photostability, it may be desirable to photostabilize these UV-A screening agents. Thus, the term "conventional UV-A screening agent" also refers to dibenzoylmethane derivatives such as e.g. PARSOL ® 1789 stabilized by, e.g. 3,3-

Diphenylacrylate derivatives as described in the European Patent Publications EP 0 514 491 Bl and EP 0 780 1 19 Al ; Benzylidene camphor derivatives as described in the US Patent No.

5,605,680; Organosiloxanes containing benzmalonate groups as described in the European Patent Publications EP 0358584 Bl, EP 0538431 Bl and EP 0709080 Al.

Active ingredients which may be included in the cosmetic or dermatological preparations of the invention are for example vitamins and derivatives thereof, for example tocopherol, tocopherol acetate, ascorbic acid, ascorbyl phosphate, vitamin Q, D, and K, retinol, retinal, retinoic acid, retinol acetate, retinol palmitate, biotin, carotenoid derivatives such as beta-carotene, lycopene, asthaxanthin, vegetable extracts, antibacterial ingredients, instable amino acids comprising dipeptides, oligopeptides and polypeptides such as methionine, cysteine, cystine, tryptophan, phenylalanine, tyrosine, phenols, polyphenols or flavanoids, bisabolol, allantoin, phytantriol, panthenol, AHA acids, ubiquinones such as coenzyme Q 10, ceramides, pseudoceramides, essential oils, plant extracts deoxyribonucleic acid, phytanic acid.

The necessary amounts of the cosmetic and dermatological adjuvants, additives and/or additional active ingredients can, based on the desired product, easily be chosen by a person skilled in the art and will be illustrated in the examples, without being limited hereto.

In yet another embodiment, the invention relates to the use of magnolol and/ or honokiol for enhancing the anti -inflammatory activity of one or several compounds selected from the group of ligustilide, oleuropein (I), oleuropein aglycone (H), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate,

solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy- 4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl- 3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)- phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3- butenyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract. Preferably, the invention relates to the use of magnolol and/ or honokiol for enhancing the anti -inflammatory activity of one or several compounds selected from the group of from the group of ligustilide, rosehip, hydroxytyrosol, genistein, resveratrol and/ or EGCG.

Thus, the invention relates to the use of magnolol and/ or honokiol for enhancing the anti- inflammatory activity of ligustilide.

In an additional embodiment the invention relates to the use of magnolol and/ or honokiol for enhancing the anti -inflammatory activity of rosehip.

In another embodiment invention relates to the use of magnolol and/ or honokiol for enhancing the anti -inflammatory activity of an olive derivable (polyphenol such as oleuropein (I), oleuropein aglycone (II), tyrosol or hydroxytyrosol, in particular hydroxytyrosol.

In a further embodiment the invention relates to the use magnolol and/ or honokiol for enhancing the anti-inflammatory activity of genistein.

In an additional embodiment the invention relates to use of magnolol and/ or honokiol for enhancing the anti-inflammatory activity of resveratrol.

In a further embodiment the invention relates to use of magnolol and/ or honokiol for enhancing the anti-inflammatory activity of EGCG.

Furthermore, the invention also relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of one or several components selected from the group of ligustilide, oleuropein

(I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2- hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3- butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)- phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3- butenyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, carnosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract, in particular selected from ligustilide, rosehip, hydroxytyrosol, genistein, resveratrol and/ or EGCG. The term 'an effective amount' refers to an amount necessary to obtain a synergistic effect. The dosage may, of course, vary depending upon known factors, such as the physiological characteristics of the particular composition and its mode and route of administration; the age, health and weight of the recipient; the nature and extent of the symptoms; the kind of concurrent treatment; the frequency of treatment; and the effect desired and can be adjusted by a person skilled in the art.

Thus, in one preferred embodiment the invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of ligustilide.

In another preferred embodiment the invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of rosehip.

In another preferred embodiment invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of an olive derivable (poly)phenol such as oleuropein (I), oleuropein aglycone (II), tyrosol or hydroxytyrosol, in particular hydroxytyrosol.

In a further preferred embodiment the invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of genistein.

In an additional preferred embodiment the invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of resveratrol.

In a further preferred embodiment the invention relates to a method of enhancing the efficacy of magnolol and/ or honokiol which comprises adding to a composition containing magnolol and/ or honokiol an effective amount of EGCG.

It has been found that the compositions according to the invention are also suitable for the treatment, co-treatment or prevention of another joint disorder namely cartilage degradation or cartilage damage in joints and as such for treatment of the cartilage degradation component of joint disorders, for example degenerative joints disorders such as osteoarthritis; or sport injuries.

Cartilage degradation is defined within the framework of the invention as a metabolic disorder of joint cartilage characterized by increased production of cartilage-degrading enzymes such as matrix metalloproteases.

Osteoarthritis is a chronic degenerative disease of the joint of non-inflammatory origin, which develops by wear and tear of the joints during aging and results in pain and diminished joint function. Symptoms of osteoarthritis include pain, stiffness and loss of mobility in one or more joints. Excessive joint loading increases the risk of osteoarthritis, hence osteoarthritis mostly affects the weight-bearing joints such as spine, knees and hips, but thumb and finger joints may also be affected. Joint disorders can also results from injury, i.e. microdamage or blunt trauma, fractures, damage to tendons, menisci or ligaments or can be the result of excessive mechanical stress or other biomechanical instability resulting from for example an injury or obesity.

Joint disorders due to cartilage degradation are leading causes of disability and dysfunction in the elderly; almost 80% of people over age 60 show some evidence of these disorders. Age, genetic factors, muscle disuse and weakness, trauma, obesity and anatomical abnormalities contribute to the development of the disorder.

Joint disorders are difficult to treat. Up till now, treatment was largely limited to addressing the symptoms mainly with non-steroidal anti-inflammatory drugs. The drugs are given to control the pain and to restrain swelling, but do not prevent or treat damage to the cartilage. The patients experiencing severe cartilage damage frequently require surgery, including joint replacement surgery. Therefore, there was a great need for agents that treat or prevent cartilage loss and damage, which need has been solved by the present invention.

The compositions of the present invention may have one or more of the following properties: it maintains and/or improves joint health, it prevents joint stiffness, it promotes joint mobility, it provides supple and/or flexible joints, it lubricates the joints, it relieves arthritis pain, it lessens joint problems, it provides joint care, it treats or prevents joint degradation, it provides joint integrity, it retards or prevents the progression of joint damage, it supports joint function, it promotes joint health and function, it naturally supports joint health and mobility for active individuals, it maintains the active flexibility of joints, it promotes joint flexibility and promotes joint mobility. Thus, further objects of the present invention are:

• Use of a composition according to the invention as cartilage-regenerating and - maintaining agents.

A use of a composition according to the invention for maintenance of joint health.

• Use of a composition according to the invention (for the manufacture of a composition) for the maintenance and regeneration of articular cartilage.

• A method for the regeneration and/or maintenance of (articular) cartilage in a mammal which comprises administering to a mammal in need of such regeneration and/or maintenance an effective amount of a composition according to the invention.

The invention will now be elucidated by way of the following examples, without however being limited thereto.

Examples

In the following examples, "Group (A)" is defined as the following group of compounds: ligustilide, oleuropein (I), oleuropein aglycone (II), tyrosol, hydroxytyrosol, rosehip, genistein, resveratrol, EGCG, methylsulfonylmethane, SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, β-cryptoxanthin, Devil's Claw, milk protein concentrate, solubilized keratin, celery seed extract, cetylated fatty acids, carnitine, thymoquinone, 2-hydroxy- 4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid

(VI), cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl- 3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)- phenol (IX), the compound of formula (X) and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3- butenyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit extract, boswellic acid, camosic acid, ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, diosgenin, curcumin and derivatives, Glycyrrhiza foetida and white willow bark extract.

Example 1 : Synergistic effect The anti-inflammatory effects of combinations of magnolia bark extracts [MBE] (or its main constituents honokiol and magnolol) and representatives of other groups of natural substances such as resveratrol, EGCG, ligustilide and hydroxytyrosol were evaluated in activated macrophages by determining the inhibition of the synthesis of nitric oxide and/or proinflammatory prostaglandins (PG). PGE 2 plays a critical role in the inflammation process, while nitric oxide (NO) is a hallmark of inflammation in various chronic inflammatory diseases including various forms of arthritis, gastro-intestinal diseases and metabolic syndrome.

Resveratrol, ligustilide, EGCG and genistein was synthesized by DSM Nutritional Products. Hydroxytyrosol was from Cayman Chemicals or synthesized by DSM Nutritional Products. Magnolol and Honokiol were from Apin Chemicals Ltd, UK. Magnolia Bark extract was from Novanat Bioresources Co. Ltd. China and contained according to the specification > 80% Magnolol and Honokiol.

They compounds were dissolved in DMSO in concentrated form and did not contain byproducts that interfered with the assays. Final vehicle (DMSO) concentration did not exceed 0.2 % v/v in the assays.

The anti inflammatory effect of compounds was tested in cellular assays using a murine macrophage indicator cell line, RAW267.7, which were purchased from American Type Culture Collection (ATCC) and cultured in DMEM Cells (~50'000/well) were seeded into flat-bottomed microtiter plates and cultured for one day. Cells were then starved in complete medium containing 0.25% FCS (D-025). After overnight culture, medium was removed and replaced by 100 μL of D-025 containing the test compounds at twice the final concentration. Subsequently, 100 μL of D-025 containing 2 μg/ml lipopolysaccaride (LPS) was added {i.e. final LPS concentration of 1 μg/ml) and the cells were cultured for 24 hours. Substances were usually tested

in a concentration range from 0.2 to 50 μM (or μg/ml in the case of extracts) in two-fold dilution steps. Concentrations of nitrite which was generated from nitric oxide released by cells were determined by the Griess reaction (see e.g Imai et al. Biochem Biophys Res Comm, 197, 105 [1993]) using sodium nitrite as standard. Briefly, 50 μl of supernatant was mixed with Griess reagent 1 (25 μL) and Griess reagent 2 (25 μL), centrifuged and the optical density at 540 nm determined. PGE 2 secreted into the cell culture medium was determined by EIA obtained from Cayman Chemicals (Ann Harbor, WI, USA) and used according to the manufacturer's instructions. IC 50 values were calculated using a two-parametric least-square fitting equation [ y = A+((B-A) / (l+((C-x) λ D))] for best-fit curves (Excel fit software program).

In Table 1 it is shown that individually, all substances inhibited the production of inflammatory mediators (Table 1). This is indicated by IC 50 values, which vary between substances reflecting substance-specific biological potencies.

In Table 2 it is shown that magnolia bark extract when combined with resveratrol, ligustilide, EGCG or hydroxytyrosol (OH-Tyrosol), synergistically inhibits nitric oxide production. A positive value for δ (observed-additive) means that the two substances out-perform the inhibitory power of the two individual components of the mixture. With 'observed' is meant the actual observed inhibition. With 'additive' is meant the theoretical sum of the inhibition of the two compounds. In Table 3, it is shown that magnolia bark when combined with EGCG, resveratrol or genistein synergistically inhibit PGE 2 production.

Table 1: IC 50 values for single substances

Table 2: Synergistic effects on production of nitric oxide

* observed - additive; Additive = σ (compound A (e.g. MB) + compound B (e.g. RES/ LIG etc.))

Table 3: Synergistic effects on PGE-, production

* observed - additive; Additive = σ (compound A (e.g. MB) + compound B (e.g. RES etc.))

Example 2: Soft gelatin capsule

Soft gelatin capsules are prepared by conventional procedures providing a dose of magnolol and/ or honokiol of 100 mg and at least one compound selected from the group of Group (A) as defined above of 50 mg (e.g. EGCG). A suitable daily dose is 1 to 8 capsules. Other ingredients: glycerol. Water, gelatine, vegetable oil

Example 3: Hard gelatin capsule Hard gelatin capsules are prepared by conventional procedures providing a dose of magnolol and/ or honokiol of 75 mg and at least one component selected from the group of Group (A) as defined above of 100 mg (EGCG). A suitable daily dose is 1 to 5 capsules.

Other ingredients:

Fillers: lactose or cellulose or cellulose derivatives q.s. Lubricant: magnesium stearate if necessary (0.5%)

Example 4: Tablet

Tablets are prepared by conventional procedures providing as active ingredient 50 mg of magnolol and/ or honokiol per tablet and at least one component selected from the group of Group (A) as defined above of 50 mg Ligustilide, and as excipients microcrystalline cellulose, silicone dioxide (SiO 2 ), magnesium stearate, crospovidone NF (which is a disintegration agent) ad 500 mg.

Example 5: soft drink An orange juice drink coloured with beta-Carotene 10% CWS and with magnolol and/ or honokiol and at least one component selected from the group of Group (A) as defined above e.g. Genistein may be prepared as follows:

Ingredients FgI

Sugar syrup 64°Brix 156.2

Sodium benzoate 0.2

Ascorbic acid, fine powder 0.2 Citric acid 50% w/w 5.0

Pectin solution 2% w/w 10.0

Magnolol and/ or honokiol 0.2

Genistein 0.05

Juice compound* 30.0 Water to 250.0 Preparation

- Dissolve sodium benzoate in water whilst stirring

- Continue stirring and add sugar syrup, ascorbic acid, citric acid, pectin solution, juice compound, one after the other. Do not use a high speed mixer - Dilute the bottling syrup with (carbonated) water to one liter of beverage

* Ingredients Juice compound [g]

Orange juice concentrate 65°Brix 483.3

Lemon Juice Concentrate 45°Brix 173.3 Oily orange flavour 5.0 beta-Carotene 10% C WS as 10% stock solution 10.0

Deionized water 328.4

Preparation of juice compound

Add the deionized water to the juice concentrates, stir gently and allow the juice concentrates to hydrate.

Add the oily flavour and beta-Carotene 10% CWS stock solution and pre-emulsify in a rotor-stator-homogenizer.

Homogenize in a high-pressure homogenizer at 200 bar.

Example 6: Preparation of a dermatological composition comprising magnolol and/ or honokiol (treatment cream) which may be used for (cosmetic) treatment of inflammation of the skin caused by sunburn.

A treatment cream may be prepared with the following ingredients, in the following amounts:

Procedure : Heat part A) and B) to 85°C while stirring. When homogeneous, add part B) to A) under agitation. Cool to about 45°C while stirring. Add part C). Homogenize at 11000 rpm to achieve a small particle size. Cool to ambient temperature while stirring. Then add part D).

Example 7: OAV sun milk

Procedure:

Heat part A) and B) to 85°C while stirring. When homogeneous, add part B) to A) under agitation. Cool to ambient temperature while stirring and add part C). Homogenize to achieve a small particle size.

Example 8: Sun milk waterproofed

Procedure:

Heat part A) and B) to 85°C while stirring. When homogeneous, add part B) to A) under agitation. Cool to ambient temperature while stirring and add part C). Homogenize to achieve a small particle size.

Example 9: Sun milk for babies and children

Procedure:

Heat part A) and B) to 85 0 C while stirring. When homogeneous, add part B) to A) under agitation. Cool to ambient temperature while stirring and add part C). Homogenize to achieve a small particle size.

Example 10: Anti pimple skin-tonic

Procedure: Add all ingredients of part 1 and mix intensively until a homogeneous solution is obtained. Adjust the pH to 6.5 with acetic acid.

Example 11 : Anti-acne treatment with Stav-C 50

Procedure: Heat part 1 up to 85 0 C; and heat also part 2 up to 85°C. When both have the same temperature add part 2 to part 1 while homogenizing intensively. Cool down the product to 35°C while stirring. Now add part 3 and homogenize intensively again. It is generally recommended to use vacuum while producing the emulsion.

Example 12: Protective day cream

Procedure:

Heat part A), B) and C) to 85°C while stirring. When homogeneous, add part B) and C) to A) under agitation. Cool to ambient temperature while stirring and add part D) and E). Homogenize t too aacchhiieevvee aa ssmmaallll o paarrttiiccllee ssiizzee.

Example 13: Dry dog feed comprising magnolol and/ or honokiol and genistein Commercial dry dog food (Hill's Science diet "Canine Maintenance dry" for dogs as supplied by Hill's Pet Nutrition GmbH, Liebigstrasse 2-20, D- 221 13) is sprayed with a suspension of magnolol and/ or honokiol and genistein in an amount sufficient to administer to a subject a daily dose of 0.5 mg to 1 mg of magnolol and/ or honokiol and 0.1 mg to 3 mg genistein per kg body weight. Further Vitamin C and E and beta-carotene are incorporated in an amount sufficient to provide 30 mg vitamin C/kg, and 300 IU vitamin E/kg and 280 mg beta-carotene/kg in the final food composition before extruding the entire blend. The food composition is dried to contain dry matter of about 90 % by weight.

Example 14: Wet cat food comprising magnolol and/ or honokiol and sodium ascorbyl phosphate Commercial wet cat food (Hill's Science diet "Feline Maintenance wet" for cats as supplied by Hill's Pet Nutrition GmbH, Liebigstrasse 2-20, D- 22113) is mixed with magnolol and/ or honokiol in an amount sufficient to administer to a subject a daily dose of 1 mg to 5 mg magnolol and/ or honokiol. Further ROVIMIX ® STAY-C ® 35 available from DSM Nutritional Products AG, Vitamin E and beta-carotene are incorporated in an amount sufficient to provide 30 mg ROVIMIX ® STAY-C ® 35/kg, and 300 IU vitamin E/kg and 280 mg beta-carotene/kg in the final food composition before cooking the entire blend. The food composition is dried to contain a dry matter of about 90 % by weight.

Example 15 Cereal bar / non baked comprising magnolia bark extract

*used to support the apple flavour 2. Preparation: