US 2010.0056463A1 (19) United States (2) Patent Application Publication (10) Pub. No.: US 2010/0056463 A1 Raederstorff et al. (43) Pub. Date: Mar. 4, 2010

(54) NOVEL COMPOSITIONS (30) Foreign Application Priority Data (76) Inventors: Daniel Raederstorff, Flaxlanden Jul. 14, 2006 (EP) ...... 060.14645.3 (FR),(FR); NathalieJoseph Schwager, Richard, BaselMulhouse Publication- - - Classificatione e (CH); Karin Wertz, Rheinfelden (51) Int. Cl. (DE) A61 K. 3 1/7004 (2006.01) C d Add A61 K 3.1/05 (2006.01) NIXONorrespondence & VANDERHYE, I eSS. PC (52) U.S. Cl...... 514/23:- 514/734 901 NORTH GLEBE ROAD, 11TH FLOOR (57) ABSTRACT ARLINGTON, VA 22203 (US) The present invention relates to novel compositions compris (21) Appl. No.: 12/373,584 ing hydroxytyrosol and/or oleuropein (I) and at least one additional component e.g. selected from the group of ligustil (22) PCT Filed: Jul. 12, 2007 ide, oleuropeinaglycone, magnolol, , , res veratrol, EGCG, bark extract, cashew fruit extract (86) PCT No.: PCT/EP2007/006.188 and Glycyrrhiza foetida as well as to the use of these compo sitions as a medicament, in particular as a medicament for the § 371 (c)(1), treatment, co-treatment or prevention of inflammatory disor (2), (4) Date: Nov. 4, 2009 ders. Patent Application Publication Mar. 4, 2010 US 2010/0056463 A1

(I) (II) (III)

Figure I US 2010/0056463 A1 Mar. 4, 2010

NOVEL COMPOSITIONS neurodermitis, thermal and radiation burns such as sunburn, other types of skin inflammation, and the tissue-degenerating effects of aging) and chronic inflammatory disorders, such as [0001] The present invention relates to novel compositions atherosclerosis, heart diseases, metabolic syndrome X, can comprising hydroxytyrosol and/or oleuropein (I) and at least cer, Alzheimer’s disease and pre-stages thereof such as mild one additional component selected from the group of ligustil cognitive impairment or photoageing which is associated ide, oleuropeinaglycone (II), tyrosol, extract from the bark of with chronic skin inflammation. Magnolia officinalis, magnolol, honokiol, genistein, resvera [0005] Rheumatoid arthritis is a chronic inflammatory dis trol, EGCG, methylsulfonylmethane, SAMe, collagen ease of the joints and is one of many different forms of hydrolysate, collagen, ascorbyl phosphate, lycopene, lutein, arthritis. For example, arthritis includes rheumatoid arthritis, zeaxanthin, fl-cryptoxanthin, Devil’s Claw, milk protein con spondyloarthopathies, gouty arthritis, osteoarthritis, sys centrate, solubilized keratin, celery seed extract, cetylated temic lupus erythematosus and juvenile arthritis. Like fatty acids, carnitine, thymoquinone, 2-hydroxy-4-methoxy asthma, rheumatoid arthritis is characterized at the molecular 3-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-ben level by chronically unbalanced expression of cytokines, zoic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hy chemokines, kinins and their receptors, adhesion molecules droxy-4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic and their respective receptors, as well as inflammatory acid (VI), cannabigerolic acid monomethyl ether (VII), 2-hy . droxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pen [0006] Psoriasis is one of the most common skin problems, tyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl) affecting 1-3% of the human population. Inflammatory bowel 5-(2-phenylethyl)- (IX), the compound offormula (X) disease is a general term used to describe gastrointestinal tract and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-bute diseases and includes disorders such as ulcerative colitis and nyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), Crohn’s disease. cardol triene (XIII), cashew fruit extract, boswellic acid, car [0007] Beside the process of intravascular lipid deposition, nosic acid, , horse chestnut extract, diosmetin, inflammatory reactions of the endothelial (i.e. blood vessel) tryptanthrin, diosgenin, curcumin and derivatives, Glycyr wall are considered to critically contribute to atherosclerosis rhiza foetida and white willow bark extract as well as to the i.e. atheroma formation. Atherosclerosis results from vascu use of these compositions as a medicament, in particular as a lar injury which triggers inflammation. Activated macroph medicament for the treatment, co-treatment or prevention of ages, T-lymphocytes, and eventually smooth muscle cells are inflammatory disorders. present in atherosclerotic plaques. Monocyte/macrophage [0002] Inflammatory disorders are one of the most impor and lymphocyte activation leads to the release of eicosanoids, tant health problems in the world. Inflammation is in general cytokines and matrix metalloproteinases (MMPs) which are a localized protective response of the body tissues to invasion implicated in endothelial damage, as well as in the formation of the host by foreign material orinjurious stimuli. The causes and eventually the rupture of atherosclerotic plaques. Finally, of inflammation can be infectious agents such as bacteria, circulating inflammatory markers such as C-reactive protein viruses, and parasites; or physical agents such as burns or (CRP), fibrinogen, and interleukins are increased or altered in radiation; or chemicals like toxins, drugs orindustrial agents; groups at high-risk of coronary artery diseases (CAD). Sev or immunological reactions such as allergies and autoim eral clinical trials indicate that elevated CRP concentration mune responses or conditions associated with oxidative correlates with increased risk of coronary, and vascular StreSS. events. Thus inflammation appears to play an important role [0003] Inflammation is characterized by pain, redness, in the initiation and progression of atheroma formation. swelling, heat, and eventual loss of function of the affected [0008] Inflammatory processes are also associated with the area. These symptoms are the results of a complex series of pathophysiology of Alzheimer’s disease. There is evidence of interactions mainly taking place between the cells of the inflammation in the brain of patients with Alzheimer’s dis immune system. The response of the cells results in an inter ease, as it is characterized by increased levels of cytokines acting network of several groups of inflammatory mediators: and activated microglial cells. Thus, inflammation is not only Proteins (e.g., cytokines, enzymes [e.g., proteases, peroxy involved in the classical inflammatory disorders (e.g., arthri dase], major basic protein, adhesion molecules [ICAM, tis, asthma, bowel diseases) but is also associated with many VCAMI), lipid mediators (e.g., eicosanoids, prostaglandins, chronic inflammatory disorders (e.g., atherosclerosis, heart leukotrienes, platelet activating factor [PAF]), reactive oxy diseases, metabolic syndrome X, cancer, Alzheimer disease). gen species (e.g., hydroperoxides, superoxyde anion O2–, [0009] Inflammatory events are also associated with the [NO] etc). However, many of those mediators of pathophysiology of different types of cancers (e.g. gastric and inflammation are also regulators of normal cellular activity. intestinal cancers, melanomas). Increased levels of inflam Thus, deficiencies of inflammatory reactions lead to a com matory mediators such as prostaglandins have been found in promised host (i.e. infection) while uncontrolled and thus cancers of breast, colon, lung and pancreas in humans. chronic inflammation leads to inflammatory diseases medi [0010] Currently, two main classes of drugs, the corticos ated in part by the excessive production of several of the teroid and the nonsteroidal anti-inflammatory drugs above mentioned mediators. (NSAIDs) are used to treat inflammatory disorders. NSAIDs [0004] Acute and chronic inflammation resulting from an and corticosteroids provide essentially symptomatic relief. excessive biosynthesis of inflammatory mediators is involved Use of corticosteroids has declined due to a growing concern in numerous inflammatory disorders such as arthritis (e.g. about the serious side effects of prolonged use. osteoarthritis, rheumatoid arthritis), asthma, inflammatory [0011) NSAIDs are among the most widely used drugs, bowel diseases, inflammatory diseases of the skin (e.g. con primarily for the treatment of pain and inflammatory disor tact dermatitis [particularly diaper area dermatitis], atopic ders, in particular for the treatment of arthritis (i.e. pain dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, relief). Epidemiological studies have suggested that patients US 2010/0056463 A1 Mar. 4, 2010 taking NSAIDs have a lower risk of developing Alzheimer’s ment selected from the group of ligustilide, magnolol, disease than those not taking NSAIDs. A protective effect of genistein, resveratrol, EGCG, magnolia bark extract, cashew NSAIDs suggests that the cyclooxygenases might be fruit extract and Glycyrrhiza foetida. In a most preferred involved in the neurodegenerative process. Epidemiological embodiment, the invention relates to a composition compris studies showed a significant reduction in the risk of colorec ing hydroxytyrosol and/or oleuropein (I), in particular tal, gastric, esophageal, and breast cancers among people who hydroxytyrosol, and at least one additional component take NSAIDs compared with those not taking NSAIDs. In selected from the group of ligustilide, honokiol, genistein, animal models, NSAIDs significantly reduced tumor devel resveratrol and EGCG. opment. [0016] Thus in one preferred embodiment the invention [0012] However, long-term use of NSAIDs when treating relates to a composition comprising hydroxytyrosol and/or chronic diseases such as arthritis, is limited by severe side oleuropein (I) and ligustilide, most preferably to a composi effects like serious gastrointestinal complications, renal tox tion comprising hydroxytyrosol and ligustilide or a compo icity or asthmatic reactions. sition comprising oleuropein and ligustilide. [0013] Therefore, there is a need for new anti-inflammatory [0017] In another preferred embodiment the invention agents with weak or no side effects. Patients with inflamma relates to a composition comprising hydroxytyrosol and/or tory diseases have a special interest in a type of treatment oleuropein (I) and honokiol, most preferably to a composition considered as “natural” with mild anti-inflammatory effects comprising hydroxytyrosol and honokiol. Most preferably, and without major side effects, which can be used for disease honokiol is used in the form of an extract from the bark of prevention and as adjuvant treatment. Furthermore, the treat Magnolia officinalis comprising honokiol and magnolol. ment used needs to maintain the equilibrium between exces [0018] In a further preferred embodiment the invention sive and insufficient inflammatory reaction. relates to a composition comprising hydroxytyrosol and/or [0014] There are many known examples of such “natural” oleuropein (I) and genistein, most preferably to a composition agents with shown anti-inflammatory action. However, a dis comprising hydroxytyrosol and genistein. advantage of these “natural” compounds is that their biologi [0019. In an additional preferred embodiment the invention cal and thus inhibitory activity is often inadequate. When two relates to a composition comprising hydroxytyrosol and/or or more natural substances are applied concomitantly, their oleuropein (I) and resveratrol, most preferably to a composi action can be additively or even synergistically enhanced. tion comprising hydroxytyrosol and resveratrol or a compo This lowers the required amount of each substance in order to sition comprising oleuropein and resveratrol. effect disease developmentor treatment. Since lower doses of [0020] In a further preferred embodiment the invention each of the natural substances individually can be used, there relates to a composition comprising hydroxytyrosol and/or is less chance that deleterious levels are reached and also less oleuropein (I) and EGCG, most preferably to a composition chance of serious side-effects due to chronic use. comprising hydroxytyrosol and EGCG. [0015] The invention relates to a composition comprising [0021] In all of the above mentioned embodiments prefer hydroxytyrosol and/or oleuropein (I), in particular hydroxy ably the molar ratio of hydroxy-tyrosol, respectively oleu tyrosol, and at least one additional component selected from ropein to the additional ingredient is about 1 to 1. the group of ligustilide, oleuropein aglycone (II), tyrosol, [0022] In another preferred embodiment the invention extract from the bark of Magnolia officinalis, magnolol, relates to a composition comprising hydroxytyrosol and/or honokiol, genistein, resveratrol, EGCG, methylsulfonyl oleuropein (I), in particular hydroxytyrosol, and lycopene methane, SAMe, collagen hydrolysate, collagen, ascorbyl and resveratrol. Particular preferred are compositions phosphate, lycopene, lutein, zeaxanthin, fl-cryptoxanthin, wherein the molar ratio of lycopene is smaller than the molar Devil’s Claw, milk protein concentrate, solubilized keratin, amount of resveratrol and of hydroxytyrosol and the molar celery seed extract, cetylated fatty acids, carnitine, thymo amount of resveratrol and hydroxytyrosol is equal. Most pref quinone, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3 erably, the molar ratio of lycopene to resveratrol to hydroxy butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B tyrosol is in the range of about 1:2:2 to 1:10:10, in particular (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl 1:4:4 to 1:8:8, most in particular in the range of 1:6:6. 2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid [0023] It has surprisingly been found that the individual monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hy components in the composition of the present invention func droxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), tion synergistically in their anti-inflammatory activity. More 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phe over, the composition of the present invention may be espe nol (IX), the compound of formula (X) and 2-hydroxy-4 cially useful in the treatment, co-treatment and prevention of methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenyl inflammatory disorders, such as heart disease, multiple scle ethyl)-benzoic acid (XI), cardol diene (XII), cardol triene rosis, osteo- and rheumatoid arthritis, atherosclerosis, and (XIII), cashew fruit extract, boswellic acid, carnosic acid, osteoporosis. ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, [0024] The composition of the present invention is espe diosgenin, curcumin and derivatives, Glycyrrhiza foetida and cially suitable for the treatment, co-treatment and prevention white willow bark extract. Preferably, the invention relates to of different forms of arthritis, in particular osteoarthritis and a composition comprising hydroxytyrosol and/or oleuropein rheumatoid arthritis. Also, the composition of the present (I), in particular hydroxytyrosol, and at least one additional invention is suitable as an agent for treatment, co-treatment component selected from the group of ligustilide, oleuropein and prevention of joint disorders in particular for reduction of aglycone, magnolol, honokiol, genistein, resveratrol, EGCG, joint inflammation, maintenance and/or increase of joint magnolia bark extract, cashew fruit extract and Glycyrrhiza health, prevention of joint stiffness, increase of joint mobility, foetida. Even more preferably, the invention relates to a com providing supple and/or flexible joints, lubrication of the position comprising hydroxytyrosol and/or oleuropein (I), in joints, relief of pain associated with joint inflammation, particular hydroxytyrosol, and at least one additional compo decrease of joint swelling, lessening joint problems, and pro US 2010/0056463 A1 Mar. 4, 2010

viding joint care. Thus, the invention also relates to the use of composition comprising a dietary supplement in combination a composition of the invention as an agent for the treatment, with a source of calories. In some embodiments, nutritional co-treatment or prevention of inflammatory disorders as well supplements are meal replacements or supplements (e.g., as joint disorders. nutrient or energy bars or nutrient beverages or concentrates). [0025] In a different aspect, the invention also relates to the [0034] Food products or foodstuffs are for example bever composition of the invention for use as a medicament. ages such as non-alcoholic and alcoholic drinks as well as [0026] In yet another embodiment, the invention relates to liquid preparation to be added to drinking water and liquid the use of a composition according to the invention for the manufacture of a nutraceutical, pharmaceutical, cosmetic or food, non-alcoholic drinks are for instance soft drinks, sport dermatological preparation suitable for the treatment, co drinks, fruit juices, such as for example orange juice, apple treatment or prevention of inflammatory disorders, more juice and grapefruit juice; lemonades, teas, near-water drinks preferably of arthritis or skin inflammation, most preferably and milk and other dairy drinks such as for example yoghurt of osteoarthritis or sunburn. drinks, and diet drinks. In another embodiment food products [0027| Also, the invention relates to a method for treatment, or foodstuffs refer to solid or semi-solid foods comprising the co-treatment and prevention of inflammatory disorders, in composition according to the invention. These forms can particular of arthritis, more in particular of osteoarthritis or include, but are not limited to baked goods such as cakes and rheumatoid arthritis, in animals including humans said cookies, puddings, dairy products, confections, snack foods, method comprising the step of administering ‘an effective or frozen confections or novelties (e.g., ice cream, milk amount of the composition according to the invention’ to shakes), prepared frozen meals, candy, snack products (e.g., animals including humans, which are in need thereof. Pref chips), liquid food such as soups, spreads, sauces, salad dress erably, the inflammatory disorder is arthritis, most preferably ings, prepared meat products, cheese, yogurt and any other fat osteoarthritis. or oil containing foods, and food ingredients (e.g., wheat [0028] The term ‘an effective amount of the composition flour). according to the invention’ refers to an amount necessary to [0035] The term food products or foodstuffs also includes obtain a physiological effect. The physiological effect may be functional foods and prepared food products, the latter refer achieved by one single dose or by repeated doses. The dosage ring to any pre-packaged food approved for human consump administered may, of course, vary depending upon known tion. factors, such as the physiological characteristics of the par [0036] Animal feed including pet food compositions ticular composition and its mode and route of administration; advantageously include food intended to supply necessary the age, health and weight of the recipient; the nature and dietary requirements, as well as treats (e.g., dog biscuits) or extent of the symptoms; the kind of concurrent treatment; the other food supplements. The animal feed comprising the frequency of treatment; and the effect desired and can be composition according to the invention may be in the form of adjusted by a person skilled in the art. a dry composition (for example, kibble), semi-moist compo [0029. In the framework of the invention, with animals is sition, wet composition, or any mixture thereof. Alternatively meant all animals, including mammals, examples of which or additionally, the animal feed is a supplement, such as a include humans. Preferred examples of mammals beside gravy, drinking water, yogurt, powder, suspension, chew, humans are non-ruminant or ruminant animals including cats, treat (e.g., biscuits) or any other delivery form. dogs, dromedaries, camels, elephants, and horses. [0037] Dietary supplements of the present invention may [0030] In another embodiment the invention relates to a be delivered in any suitable format. In preferred embodi nutraceutical composition comprising the composition ments, dietary supplements are formulated for oral delivery. according to the invention and a nutraceutically acceptable The ingredients of the dietary supplement of this invention carrier. are contained in acceptable excipients and/or carriers for oral [0031] The term nutraceutical composition as used herein consumption. The actual form of the carrier, and thus, the include food product, foodstuff, dietary supplement, nutri dietary supplement itself, is not critical. The carrier may be a tional supplement or a supplement composition for a food liquid, gel, gelcap, capsule, powder, solid tablet (coated or product or a foodstuff. non-coated), tea, or the like. The dietary supplement is pref [0032] Thus, in another embodiment the present invention erably in the form of a tablet or capsule and most preferably relates to a nutraceutical wherein the nutraceutical is a food in the form of a hard (shell) gelatin capsule. Suitable excipient product, foodstuff, dietary supplement, nutritional supple and/or carriers include maltodextrin, calcium carbonate, ment or a supplement composition for a food product or a dicalcium phosphate, tricalcium phosphate, microcrystalline foodstuff. cellulose, dextrose, rice flour, magnesium stearate, stearic [0033] As used herein, the term food product refers to any acid, croscarmellose sodium, sodium starch glycolate, food or feed suitable for consumption by humans or animals. crospovidone, sucrose, vegetable gums, lactose, methylcel The food product may be a prepared and packaged food (e.g., lulose, povidone, carboxymethylcellulose, corn starch, and mayonnaise, salad dressing, bread, or cheese food) or an the like (including mixtures thereof). Preferred carriers animal feed (e.g., extruded and pelleted animal feed, coarse include calcium carbonate, magnesium stearate, maltodex mixed feed or pet food composition). As used herein, the term trin, and mixtures thereof. The various ingredients and the foodstuff refers to any substance fit for human or animal excipient and/or carrier are mixed and formed into the desired consumption. The term dietary supplement refers to a small form using conventional techniques. The tablet or capsule of amount of a compound for supplementation of a human or the present invention may be coated with an enteric coating animal diet packaged in single or multiple dose units. Dietary that dissolves at a pH of about 6.0 to 7.0. A suitable enteric supplements do not generally provide significant amounts of coating that dissolves in the small intestine but not in the calories but may contain other micronutrients (e.g., vitamins stomach is cellulose acetate phthalate. Further details on tech or minerals). The term nutritional supplement refers to a niques for formulation for and administration may be found US 2010/0056463 A1 Mar. 4, 2010

in the latest edition of Remington’s Pharmaceutical Sciences caseinate, whey, lactalbumin, egg albumin and whole egg (Maack Publishing Co., Easton, Pa.). proteins. In a preferred embodiment, the protein is a combi [0038] In other embodiments, the dietary supplement is nation of whey protein concentrate and calcium caseinate. provided as a powder or liquid suitable for adding by the These proteins have high biological value; that is, they have a consumer to a food or beverage. For example, in some high proportion of the essential amino acids. See Modern embodiments, the dietary supplement can be administered to Nutrition in Health and Disease, eighth edition, Lea & an individual in the form of a powder, for instance to be used Febiger, publishers, 1986, especially Volume 1, pages 30-32. by mixing into a beverage, or by stirring into a semi-solid The nutritional supplement can also contain other ingredi food such as a pudding, topping, sauce, puree, cooked cereal, ents, such as one or a combination of other vitamins, miner or salad dressing, for instance, or by otherwise adding to a als, antioxidants, fiber and other dietary supplements (e.g., food e.g. enclosed in caps of food or beverage container for protein, amino acids, choline, lecithin). Selection of one or release immediately before consumption. The dietary supple several of these ingredients is a matter of formulation, design, ment may comprise one or more inert ingredients, especially consumer preference and end-user. The amounts of these if it is desirable to limit the number of calories added to the ingredients added to the dietary supplements of this invention diet by the dietary supplement. For example, the dietary are readily known to the skilled artisan. Guidance to such supplement of the present invention may also contain amounts can be provided by the U.S. RDA doses for children optional ingredients including, for example, herbs, vitamins, and adults. Further vitamins and minerals that can be added minerals, enhancers, colorants, sweeteners, flavorants, inert include, but are not limited to, calcium phosphate or acetate, ingredients, and the like. tribasic; potassium phosphate, dibasic; magnesium sulfate or [0039] In some embodiments, the dietary supplements fur oxide; salt (sodium chloride); potassium chloride or acetate; ther comprise vitamins and minerals including, but not lim ascorbic acid; ferric orthophosphate, niacinamide; zinc sul ited to, calcium phosphate or acetate, tribasic; potassium fate or oxide; calcium pantothenate; copper gluconate; ribo phosphate, dibasic; magnesium sulfate or oxide; salt (sodium flavin; beta-carotene; pyridoxine hydrochloride; thiamin chloride); potassium chloride or acetate; ascorbic acid; ferric mononitrate; folic acid; biotin; chromium chloride or orthophosphate; niacinamide; zinc sulfate or oxide; calcium picolonate; potassium iodide; sodium selenate; sodium pantothenate; copper gluconate; riboflavin; beta-carotene; molybdate; phylloquinone; vitamin D3; cyanocobalamin; pyridoxine hydrochloride; thiamin mononitrate; folic acid; sodium selenite; copper sulfate; vitamin A; vitamin C; inosi biotin; chromium chloride or picolonate; potassium iodide; tol; potassium iodide. sodium selenate; sodium molybdate; phylloquinone; vitamin [0042] The nutritional supplement can be provided in a D3; cyanocobalamin; sodium selenite; copper sulfate; vita variety of forms, and by a variety of production methods. In a min A; vitamin C; inositol; potassium iodide. Suitable dos preferred embodiment, to manufacture a food bar, the liquid ages for vitamins and minerals may be obtained, for example, ingredients are cooked; the dry ingredients are added with the by consulting the U.S. RDA guidelines. liquidingredients in a mixer and mixed until the dough phase [0040] In other embodiments, the present invention pro is reached; the dough is put into an extruder, and extruded; the vides nutritional supplements (e.g., energy bars or meal extruded dough is cut into appropriate lengths; and the prod replacement bars or beverages) comprising the composition uct is cooled. The bars may contain other nutrients and fillers according to the invention. The nutritional supplement may to enhance taste, in addition to the ingredients specifically serve as meal or snack replacement and generally provide listed herein. nutrient calories. Preferably, the nutritional supplements pro [0043] It is understood by those of skill in the art that other vide carbohydrates, proteins, and fats in balanced amounts. ingredients can be added to those described herein, for The nutritional supplement can further comprise carbohy example, fillers, emulsifiers, preservatives, etc. for the pro drate, simple, medium chain length, or polysaccharides, or a cessing or manufacture of a nutritional supplement. combination thereof. A simple sugar can be chosen for desir [0044] Additionally, flavors, coloring agents, spices, nuts able organoleptic properties. Uncooked cornstarch is one and the like may be incorporated into the nutraceutical com example of a complex carbohydrate. If it is desired that it position. Flavorings can be in the form of flavored extracts, should maintain its high molecular weight structure, it should volatile oils, chocolate flavorings, peanut butter flavoring, be included only in food formulations or portions thereof cookie crumbs, crisp rice, vanilla or any commercially avail which are not cooked or heat processed since the heat will able flavoring. Examples of useful flavoring include, but are break down the complex carbohydrate into simple carbohy not limited to, pure anise extract, imitation banana extract, drates, wherein simple carbohydrates are mono- or disaccha imitation cherry extract, chocolate extract, pure lemon rides. The nutritional supplement contains, in one embodi extract, pure orange extract, pure peppermint extract, imita ment, combinations of sources of carbohydrate of three levels tion pineapple extract, imitation rum extract, imitation straw of chain length (simple, medium and complex; e.g., sucrose, berry extract, or pure vanilla extract; or volatile oils, such as maltodextrins, and uncooked cornstarch). balm oil, bay oil, bergamot oil, cedarwood oil, walnut oil, [0041) Sources of protein to be incorporated into the nutri cherry oil, cinnamon oil, clove oil, or peppermint oil; peanut tional supplement of the invention can be any suitable protein butter, chocolate flavoring, vanilla cookie crumb, butter utilized in nutritional formulations and can include whey scotch or toffee. In one embodiment, the dietary supplement protein, whey protein concentrate, whey powder, egg, soy contains cocoa or chocolate. flour, soy milk soy protein, soy protein isolate, caseinate (e.g., [0045] Emulsifiers may be added for stability of the nutra sodium caseinate, sodium calcium caseinate, calcium casein ceutical compositions. Examples of suitable emulsifiers ate, potassium caseinate), animal and vegetable protein and include, but are not limited to, lecithin (e.g., from egg or soy), hydrolysates or mixtures thereof. When choosing a protein and/or mono- and di-glycerides. Other emulsifiers are readily source, the biological value of the protein should be consid apparent to the skilled artisan and selection of suitable emul ered first, with the highest biological values being found in sifier(s) will depend, in part, upon the formulation and final US 2010/0056463 A1 Mar. 4, 2010

product. Preservatives may also be added to the nutritional gelatin of any origin, vegetable gums, ligninsulfonate, talc, supplement to extend product shelf life. Preferably, preserva sugars, starch, gum arabic, vegetable oils, polyalkylene gly tives such as potassium sorbate, sodium sorbate, potassium cols, flavoring agents, preservatives, stabilizers, emulsifying benzoate, sodium benzoate or calcium disodium EDTA are agents, buffers, lubricants, colorants, wetting agents, fillers, used. and the like. [0046) In addition to the carbohydrates described above, the nutraceutical composition can contain natural or artificial [0060] In a preferred embodiment the pharmaceutical is in (preferably low calorie) sweeteners, e.g., saccharides, cycla the form of a powder, tablet, capsule, gel, liquid or solid mates, aspartamine, aspartame, acesulfame K, and/or sorbi embodiment. tol. Such artificial sweeteners can be desirable if the nutri [0061] The dosages and ratios of the individual compo tional supplement is intended to be consumed by an ments in a pharmaceutical composition can be determined by overweight or obese individual, or an individual with type II the expert in the field with normal preclinical and clinical diabetes who is prone to hyperglycemia. trials, or with the usual considerations regarding the formu [0047] Moreover, a multi-vitamin and mineral supplement lation of pharmaceutical composition. may be added to the nutraceutical compositions of the present [0062] In a preferred embodiment hydroxytyrosol and/or invention to obtain an adequate amount of an essential nutri oleuropein (I) is administered via a pharmaceutical compo ent, which is missing in some diets. The multi-vitamin and sition either in the form of a single dose or by multiple doses mineral supplement may also be useful for disease prevention in an amount of at least 0.3 mg/kg bodyweight/day, preferably and protection against nutritional losses and deficiencies due to lifestyle patterns. in an amount of 1-450 mg/kg body weight/day, most prefer [0048] The dosage and ratios of hydroxytyrosol and/or ably in an amount of 4-140 mg/kg body weight/day. oleuropein (I) and the at least one additional component [0063] The nutraceutical and pharmaceutical according to administered via a nutraceutical will, of course, vary depend the present invention may be in any galenic form that is ing upon known factors, such as the physiological character suitable for administering to the animal body including the istics of the particular composition and its mode and route of human body, more in particular in any form that is conven administration; the age, health and weight of the recipient; the tional for oral administration, e.g. in solid form, for example nature and extent of the symptoms; the kind of concurrent as (additives/supplements for) food or feed, food or feed treatment; the frequency of treatment; and the effect desired premixes, fortified food or feed, tablets, pills, granules, dra which can be determined by the expert in the field with gées, capsules, and effervescent formulations such as pow normal trials, or with the usual considerations regarding the ders and tablets, or in liquid form, for instance in the form of formulation of a nutraceutical composition. solutions, emulsions or suspensions, for example as bever [0049] In a preferred embodiment, the nutraceutical com ages, pastes and oily suspensions. The pastes may be filled prises per serving an amount of 0.01 to 1 g, more preferably into hard or soft shell capsules. Examples for other applica 0.2 mg to 500 mg of hydroxytyrosol and/or oleuropein (I) and tion forms are forms for transdermal, parenteral, topical or at least one component selected from injectable administration. The nutraceutical and pharmaceu [0050] Ligustilide: 0.5 to 500 mg and/or tical may be in the form of controlled (delayed) release for [0051] Honokiol and/or Magnolol: 0.2 mg to 500 mg of mulation. Examples of pharmaceuticals also include compo each, preferably in the form of a magnolia bark extract sitions suitable for topical application such as crèmes, gels, and/or sprays, dry sticks, powders etc. [0052] Genistein: 0.5 to 500 mg and/or [0064] The term hydroxytyrosol relates to ‘pure hydroxy [0053] Resveratrol: 0.2-500 mg, and/or tyrosol’ of either synthetic origin or obtainable from natural [0054] EGCG: 2.0 to 500 mg and/or sources such as from products and by-products derived from [0055] Cardoldiene (XII) and/or cardol triene (XIII): 0.2 the olive tree by extraction and/or purification. Additionally to 1000 mg of each, preferably in the form of a cashew the term hydroxytyrosol encompasses hydroxytyrosol com fruit extract (Anacardium occidentale) and/or prising extracts obtainable e.g. from products and by-prod [0056] Glycyrrhiza foetida or one or several compounds ucts derived from the olive tree. selected from formula (III) to (XI): 0.5-1000mg of each, [0065] Products and by products of olive trees encompass preferably in the form of a Glycyrrhiza foetida extract olives, olive tree leafs, olive pulps, olive oil, olive-derived in the indicated amounts. vegetation water and olive oil dregs without being limited [0057] In another aspect, the invention relates to a pharma thereto. Based on the extraction procedure the amount, ceutical comprising the composition according to the inven respectively the ratio of the hydroxytyrosol can be easily tion and a pharmaceutically acceptable carrier. adjusted by a person skilled in the art. Preferably, hydroxy [0058] A person skilled in the art knows which carriers can tyrosol is derived from olives that may be obtained from be used as pharmaceutically acceptable carriers. Suitable conventional and commercially available sources such as pharmaceutical carriers are e.g. described in Remington’s growers. Pharmaceutical Sciences, supra, a standard reference text in [0066] In case of synthetic or purified hydroxytyrosol, the this field. Examples of such pharmaceutically acceptable car term ‘pure hydroxytyrosol relates to hydroxytyrosol having a riers are both inorganic and organic carrier materials, suitable purity of at least 90%, more preferably a purity of at least for oral/parenteral/injectable administration and include 91%, even more preferably a purity of at least 92%, even more water, gelatin, gum arabic, lactose, starch, magnesium stear preferably a purity of at least 93%, even more preferably a ate, talc, vegetable oils, and the like. purity of at least 94%, even more in particular a purity of at [0059] The pharmaceutical composition may further com least 95%, in particular a purity of at least 96%, more in prise conventional pharmaceutical additives and adjuvants, particular a purity of at least 97%, even more in particular a excipients or diluents, including, but not limited to, water, purity of at least 98%, most in particular a purity of at least US 2010/0056463 A1 Mar. 4, 2010

99%. The purity of hydroxytyrosol can be determined by or ethanol, preferably in the presence of a strong acid, pref methods known to a person skilled in the art such as e.g. by erably hydrochloric acid, preferably at a temperature from HPLC, or LC-MS. ambient temperature to 100° C. or higher, preferably from [0067] The hydroxytyrosol employed herein can be pre 40-65°C., preferably at a hydrogen pressure at least higher pared by a number of methods known in the art. The olives than the vapor pressure of the solvent at the hydrogenation may be processed by any suitable means to obtain the com temperature. The pressure can be from normal, i.e. atmo positions described. For example, the olives and/or olive spheric pressure, to 100 bar or higher. leaves may be pressed to obtain a mixture including olive oil, [0074] If desired, the reaction which is preferably carried vegetation water and solid byproducts. The hydroxytyrosol out as a through process can be accomplished in two separate may be obtained directly from the mixture or the mixture may steps, i.e., a first step wherein an ester of 3,4-dihydroxyman be fractionated and/or purified to obtain the hydroxytyrosol. delic acid is built by esterification of the acid and a second The compositions may be fractionated and/or purified by a step wherein the 3,4-dihydroxymandelic acid lower alkyl number of methods known to the person skilled in the art. ester is hydrogenated. The reduction of the (3,4-dihydrox Examples of fractionating methods include partitioning with yphenyl)-acetic acid C1-io-alkyl ester to give hydroxytyrosol an organic solvent, chromatography, for example high pres can be achieved in a known manner. The preferred reduction sure liquid chromatography (HPLC) or the use of supercriti agents are complex hydrids of aluminum and boron, such as cal fluids. LiAlH4 and NaBH4. The starting material, 3,4-dihydroxy [0068] Examples of references that deal with the extraction mandelic acid, is well-known and can be prepared in accor of hydroxytyrosol from olive leaves are WOO2/18310A1, US dance with methods described in the literature, e.g., by con 2002/0198415A1, WO2004/005228A1, U.S. Pat. No. 6,416, densation of catechol with glyoxylic acid. 808 and US 2002/0058078 A1 which disclose a method for [0075] Preferably hydroxytyrosol is used in the form of a acidic hydrolysis of olive vegetation water for 2 to 12 months hydroxytyrosol containing olive extract. until at least 90% of the present oleuropein has been con [0076] Hydroxytyrosol is used in an amount of sufficient to verted. A method of extraction of hydroxytyrosol from olives, administer to animals including humans (e.g. weighing about olive pulps, olive oil and oil mill waste water is described by 70 kg) a dosage of at least 0.02 mg/day. Preferably hydroxy Usana Inc. U.S. Pat. No. 6,361,803 and WOO1/45514A1 and tyrosol is used in a concentration so that the daily consump in US 2002/0004077 A1. EP 1 582 512 A1 describes an tion by an animal including humans (e.g. weighing about 70 extraction of hydroxytyrosol from olive leaves. A method for kg) is in the range of from 1 mg/day to 2000 mg/day, more obtaining hydroxytyrosol from the vegetation water of de preferably from 5 mg/day to 500 mg/day. Thus, the daily pitted olives is disclosed in US 2004/0039066 A1 in para dosage is at least about 0.3 plg/kg body weight, preferably an graphs [0080|-|0091]. average dosage of 0.01-30 mg/kg body weight, most prefer [0069] Commercially available hydroxytyrosol containing able of 0.1-10 mg/kg of bodyweight is used. olive extracts which may be used according to the invention [0077] A nutraceutical composition preferably comprises include e.g. extracts from olive fruits such as Polyphen-Oil"M 0.2 mg to 500 mg of hydroxytyrosol per serving, preferably 1 from Life Extension, OleaSelect? M from Indena, Hytolive R. mg to 250 mg. If the composition is a pharmaceutical com from Genosa, Prolivols from Seppic, OLIVE LEAF or position such composition may for example comprise OLIVE Water Extract of Olea europea from Lalilab, Hitof hydroxytyrosol in an amount from 1 mg to 500 mg perdosage ulvic and OliferM from Ebiser, hydrolysed olive leaf extract, unit, e.g., per capsule or tablet, or from 1 mg per daily dose to such as described in EP1582512, olive leaf extract, rich in 500 mg per daily dose of a liquid formulation. oleuropein, such as available from Furfural and HIDROXR [0078] If instead of ‘pure hydroxytyrosol' a hydroxytyrosol from CreAgri. comprising extract is used, the amount of the extract to be [0070] Preferably HIDROXR from CreAgri such as used may be derived from the concentration of ‘pure HIDROXOR 2% spray dried powder, HIDROX(R) Gold hydroxytyrosol within the extract and the finding of the opti freeze dried powder (9%) and HIDROXR 6% freeze dried mal dosage is a matter of routine experimentation for the powder organic olive juice extract are used. person skilled in the art. [0071] An example of a synthetic process in which [0079] The phenolic compounds oleuropein (I), oleuropein hydroxytyrosol may be prepared with a purity >90% is a aglycone (II) and/or tyrosol may either be of synthetic origin process comprising the steps of hydrogenating 3,4-dihy or may be obtained from natural sources such as from prod droxymandelic acid or a 3,4-dihydroxymandelic acid C1-10 ucts and by-products derived from the olive tree by extraction alkyl ester in a C-to-alkanol in the presence of a precious and/or purification. Products and by products of olive trees metal hydrogenation catalyst and optional reduction of the encompass olives, olive tree leafs, olive pulps, olive oil, olive formed (3,4-dihydroxyphenyl)-acetic acid C1-io-alkyl esteris derived vegetation water and olive oil dregs without being to form 2-(3,4-dihydroxyphenyl)-ethanol (=hydroxytyrosol) limited a specific example of which is described below. [0080] The phenolic compounds oleuropein (I), oleuropein [0072] The hydrogenation may be carried out in the pres aglycone (II) or tyrosol employed herein can be prepared by ence of a precious metal catalyst such as Pd and Rh, sepa a number of methods known in the art. E.g. the compounds rately or in mixtures, in a manner known per se. In order to may be derived from olives which may be processed by any increase the activity and stability of the catalysts they are suitable means to obtain the compounds described. For preferably used on carriers such as activated carbon, alumina example, the olives and/or olive leaves may be pressed to or kieselguhr. The preferred hydrogenation catalyst in the obtain a mixture including olive oil, vegetation water and present case is Pd/C. solid byproducts. The phenolic compounds may be obtained [0073] The hydrogenation is carried out in the presence of directly from the mixture or the mixture may be fractionated a lower alkanol, i.e. a C-to-alkanol, such as , etha and/or purified to obtain the phenolic compounds. The com nol, propanol, isopropanol, butanol, preferably in methanol positions may be fractionated and/or purified by a number of US 2010/0056463 A1 Mar. 4, 2010

methods known to the person skilled in the art. Examples of japonicum and others. Magnolol is a known anti-inflamma fractionating methods include partitioning with an organic tory agent and is preferably used in the form of an extract from solvent, chromatography, for example high pressure liquid the bark of Magnolia officinalis, but may of course also be chromatography (HPLC) or the use of supercritical fluids. used in pure form. [0081] The phenolic compounds oleuropein (I), oleuropein [0087] Magnolol is preferably used in a concentration so aglycone (II) or tyrosol or mixtures thereof are preferably that the daily consumption by an animal including humans used in a concentration so that the daily consumption by an (e.g. weighing about 70 kg) is in the range of from 1 mg/day animal including humans (e.g. weighing about 70 kg) is in the range of from 1 mg/day to 2000 mg/day, more preferably to 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A from 5 mg/day to 500 mg/day. A nutraceutical composition nutraceutical preferably comprises 0.2 mg to 500 mg of mag preferably comprises 0.2 mg to 500 mg of phenolic com nolol per serving. A pharmaceutical may for example com pound per serving. If the composition is a pharmaceutical prise magnolol in an amount from 1 mg to 500 mg perdosage composition such composition may for example comprise a unit, e.g. per capsule or tablet, offrom 5 mg daily dose to 2000 phenolic compound in an amount from 1 mg to 2000 mg per mg per daily dose of a liquid formulation. dosage unit, e.g., per capsule or tablet, or from 1 mg per daily [0088] The term “honokiol” as used herein comprises the dose to 3000 mg per daily dose of a liquid formulation. pure compound also known as 3',5-Diallyl-2,4'-biphenyldiol [0082] Ligustilide may be isolated by methods known in or 3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol (CAS the art [see, e.g., Beck J. J. and Stermitz F. R., J. Natural [35354-74-6) and plant extracts containing the same. Products, Vol. 58, No. 7, pp. 1047-1055, 1995] from various [0089] The term honokiol also comprises etherified or plants such as Angelica glauca, Angelica acutiloba, Angelica esterified hydroxy derivatives from 3',5-Diallyl-2,4'-biphe sinensis, Angelicae dahuricae, Ligusticum acutilobum, nyldiol or 3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol. The Ligusticum officinale, Ligusticum sinense, Ligusticum walli chii, Cnidium officinale, Rhizoma Chuanxiong, Pleurosper ester or ether groups may for example be derived from mum hookeri, Trachyspermum roxburghianum, Meum atha straight or branched alkyl groups having 1 to 26 carbonatoms manticum, Lomatium torreyi, baicalensis, or from substituted or unsubstituted straight or branched ali Opopanax chironium, Cenolophium denudatum, Corian phatic, araliphatic or aromatic carboxylic acids having 1 to 26 drum sativuum, Silaum silaus, but may also be synthesized by carbon atoms. Examples of etherified hydroxy groups further methods known in the art. Preferably ligustilide is used in include groups. Examples of esterified hydroxy form of a purified plant extract, e.g., from Ligusticum species, group further include glucuronide or sulfate groups. Prefer especially L. wallichii, comprising at least 50 wt.-% of ably, “honokiol” as used herein is 3',5-Diallyl-2,4'-biphenyl ligustilide, and no more than 10 wt.-% of fatty acids and diol or 3',5-di-2-propenyl-[1,1'-Biphenyl]-2,4'-diol. triglycerides as obtainable by the process disclosed in Euro [0090] Plant extracts containing the compound include pean patent application No. 05 002333.2, the contents of extracts from Magnolia officinalis, Magnolia obovata, Mag which are incorporated herein by reference. nolia rostrata, Magnolia bilboa, Magnolia biondii, Magnolia [0083) Preferably ligustilide is used in an effective dose of quinquepeta, Magnolia sprengeri, Manglietia insignis, Man 0.01 to 50 mg/kg body weight/day, more preferably 0.1 to 5 glietia szechuanica, Manglietiayuyuanensis, Cercidiphyllum mg/kg body weight/day. japonicum, Machilus thunbergii and others. Honokiol is a [0084] A nutraceutical preferably comprises 0.5 mg to 500 known anti-inflammatory agent and is preferably used in the mg of ligustilide per serving. If the composition is a pharma form of an extract from the bark of Magnolia officinalis, buy ceutical, such composition may preferably comprise ligustil may of course also be used in pure form. ide 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 [0091] Honokiol is preferably use in a concentration so that per daily dose of a liquid formulation. the daily consumption by an animal including humans (e.g. [0085] The term “magnolol” as used herein comprises the weighing about 70 kg) is in the range of from 1 mg/day to pure compound also known as 5,5'-Diallyl-2,2'-biphenyldiol 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A or 5,5'-di-2-propenyl-[1,1'-Biphenyl]-2,2'-diol (CAS [528 nutraceutical preferably comprises 0.2 mg to 500 mg of 43-8]) and plant extracts containing the same. The term mag honokiol per serving. A pharmaceutical may for example nolol also comprises etherified or esterified hydroxy deriva comprise honokiol in an amount from 1 mg to 500 mg per tives from 5,5'-Diallyl-2,2'-biphenyldiol or 5,5'-di-2 dosage unit, for example per capsule or table, or from 5 mg propenyl-[1,1'-Biphenyl]-2,2'-diol. The ester or ether groups per daily dose to about 2000 mg per daily dose of a liquid may for example be derived from straight or branched alkyl formulation. groups having 1 to 26 carbon atoms or from substituted or [0092] Magnolia bark (optionally in dried or ground form) unsubstituted straight or branched aliphatic, araliphatic or may be extracted conventionally with solvents like ethanol, aromatic carboxylic acids having 1 to 26 carbon atoms. at reflux temperature or at lower tempera Examples of etherified hydroxy groups further include gly ture. Alternatively, it may be extracted with supercritical flu coside groups. Examples of esterified hydroxy group further ids like SF carbondioxyde or by steam distillation of the bark include glucuronide or sulfate groups. Preferably magnolol with water followed by sampling of the distilled organic part. as used herein is 5,5'-Diallyl-2,2'-biphenyldiol or 5,5'-di-2 Sampling may for example be done by extraction with an propenyl-[1,1'-Biphenyl]-2,2'-diol. organic solvent like dichloromethane. Subsequent removal of [0086] Plant extracts containing the compound include the solvent gives the desired magnolia bark extract. Option extracts from Magnolia officinalis, Magnolia obovata, Mag ally the thus obtained magnolia bark extract may be subjected nolia rostrata, Magnolia bilboa, Magnolia biondii, Magnolia to further processing steps to enrich the content of magnolol quinquepeta, Magnolia sprengeri, Manglietia insignis, Man and/or honokiol to give an extract of magnolia bark enriched glietia szechuanica, Manglietiayuyuanensis, Cercidiphyllum in magnolol and/or honokiol. US 2010/0056463 A1 Mar. 4, 2010

[0093] Most preferably in all embodiments of the invention supplement called 5-LOXINR (company PL Thomas). The an extract derived from the bark of Magnolia officinalis com extractitselfit available as WokVelº from Geni Herbs. It may prising magnolol as well as honokiol is used in all embodi be extracted from Boswellia serrata. ments of the invention. [0101] The daily intake by a human adult (weighing [0094] The term “genistein” as used herein comprises the approximately 70 kg) of boswellic acid (extracts) is prefer aglycone (4,5,7-trihydroxyisoflavone) and derivatives ably between 5 and 1000 mg per day, preferably between 100 thereof, e.g., genistein , genistein sulfates, and 500 mg per day. genistein glucuronides. [0102) A nutraceutical composition preferably comprises [0095] Genistein is preferably used in a concentration so between 5 mg and 500 mg of boswellic acid or boswellic acid that the daily consumption by an animal including humans extract per serving. If the composition is a pharmaceutical (e.g. weighing about 70 kg) is in the range offrom 0.5 mg/day composition such composition may preferably comprise to 2000 mg/day. A nutraceutical preferably comprises for boswellic acid or boswellic acid extractin an amount from 50 example 0.2 mg to 500 mg of genistein per serving. A phar mg to 500 mg per dosage unit, e.g., per capsule or tablet, or maceutical composition may for example comprise a from 50 mg per daily dose to 1000 mg per daily dose of a genistein in an amount from 0.5 mg to 500 mg per dosage liquid formulation. unit, e.g., per capsule or tablet, or from 0.5 mg per daily dose [0103] Methylsulfonylmethane (MSM) may be synthe to 2000 mg per daily dose of a liquid formulation. sized by methods known to the person skilled in the art. Daily [0096] The term “resveratrol” as used herein comprises a intake of methylsulfonylmethane by a human adult (weighing derivative, metabolite or analogue thereof. The carbon-car approximately 70 kg) is preferably between 100 and 7000 mg bon double bond may be trans or cis and includes cis/trans per day, more preferably between 500 and 2000 mg/day, most mixtures. Etherified or esterified hydroxy groups may be preferably between 250 and 750 mg per day. derived from unsubstituted or substituted, straight or [0104] A nutraceutical preferably comprises 5 mg to 3000 branched chain alkyl groups having 1 to 26 carbon atoms or mg of MSM per serving. A pharmaceutical may preferably from unsubstituted or substituted, straight or branched chain comprise MSM in an amount from 10 mg to 1000 mg per aliphatic, araliphatic or aromatic carboxylic acids having 1 to dosage unit, e.g., per capsule or tablet, or from 250 mg per 26 carbon atoms. Etherified hydroxy groups may further be daily dose to 750 mg per daily dose of a liquid formulation. glycoside groups and esterified hydroxy groups may further [0105] Within the framework of the invention SAMe is be glucuronide or sulfate groups. Of primary interest for the defined as S-adenosylmethionine. SAMe is commercially purposes of the invention is (trans)-resveratrol. available and is preferably dosed between 50 and 3000 [0097] Resveratrol is preferably used in amount sufficient mg/day. Examples of amounts used in commercially avail to administer to an animal including humans (e.g. weighing able products are: 200 mg SAMe (from 400 mg of SAMe about 70 kg) a dosage from 0.5 mg/day to 2000 mg/day, more tosylate disulfate); 400 mg S-adenosyl L-methionine (from preferably from 5 mg/day to 500 mg/day. Thus, if the com SAMe); 200 mg S-adenosyl methionine; 400 mg SAMe (as position is a nutraceutical composition the amount of a res S-adenosylmethionine 1,4-butanedisulfonate). veratrol comprised therein is preferably in the range from 0.2 [0106] A nutraceutical preferably comprises 5 mg to 1000 mg to 500 mg per serving. If the composition is a pharma mg of SAMe per serving. A pharmaceutical may preferably ceutical composition such composition may preferably com comprise SAMe in an amount from 10 mg to 1000 mg per prise from 0.5 mg to 500 mg per solid dosage unit, e.g., per dosage unit, e.g., percapsule ortablet, or from 10 mg per daily capsule ortablet, or from 0.5 mg per daily dose to 2000 mg per dose to 3000 mg per daily dose of a liquid formulation. daily dose of a liquid formulation. [0107] Collagen hydrolysate is a protein mixture which [0098] The term “EGCG” as used herein comprises (–) may be extracted from animal cartilage. It is commercially epigallocatechingallate (EGCG in the narrower sense) and/or available from many supplement companies. Collagen one or more derivatives (esterified forms, glycosides, sul hydrolysate and collagen are commercially available and the phates) thereof, or other found in green tea such as daily intake thereof by a human adult (weighing approxi (—) epigallocatechin (EGC), (-) epicatechin-3-gallate (ECG), mately 70 kg) is preferably between 500 and 10000 mg per (—) epicatechin (EC), (+) gallocatechin, and (+) and day, preferably between 2000 and 8000 mg per day. derivatives thereof. Of primary interest for use in the present [0108] Unhydrolyzed or undenatured collagen, herein invention is (–)-. referred to as ‘collagen’ may be isolated from chicken ster [0099] EGCG is preferably used in a concentration so that num by methods known to the person skilled in the art. the daily consumption by an animal including humans (e.g. [0109] A nutraceutical preferably comprises between 5 mg weighing about 70 kg) is in the range of from 5 mg/day to and 5000 mg of collagen or collagen hydrolysate per serving. 2000 mg/day, preferably from 20 mg/day to 300 mg/day. A A pharmaceutical composition may preferably comprise col nutraceutical composition preferably comprises from 2 mg to lagen in an amount from 10 mg to 1000 mg per dosage unit, 500 mg of EGCG per serving. If the composition is a phar e.g., per capsule or tablet, or from 10 mg per daily dose to maceutical composition such composition may comprise 5000 mg per daily dose of a liquid formulation. EGCG for example in an amount from 5 mg to 500 mg per [0110] The term “ascorbyl phosphate” as used herein dosage unit, for example per capsule or tablet, or from 10 mg denotes metal salts of mono- and poly-phosphoric acid esters per daily dose to 2000 mg per daily dose of a liquid formu of ascorbic acid wherein the phosphorylated hydroxy group lation. of the ascorbic acid molecule features one or more phospho [0100] The term boswellic acid encompasses pure boswel ric acid (phosphate) units, and metal cations, e.g. sodium lic acid and derivatives thereofas well as extracts comprising and/or magnesium or calcium ions, are also present. The term boswellic acid. Boswellic extract comprising e.g. 3-O-acetyl “poly” generally denotes 2-10, preferably 2-4, phosphate 11-keto-beta-boswellic acid, are known to the person skilled units. The ascorbyl phosphates may also be referred to in in the art. For instance, it is available on the marketina dietary general as “ascorbyl (poly)phosphates” to embrace both US 2010/0056463 A1 Mar. 4, 2010

mono- and polyphosphates. Typical ascorbyl phosphates for obtained from conventional and commercially available use in the present invention are L-ascorbic acid phosphate sources such as growers. A number of phenolic compounds ester salts such as sodium ascorbyl phosphate, potassium are found in Anacardium occidentale, the cashew nut, the ascorbyl phosphate, magnesium ascorbyl phosphate, calcium cashew nut shell, the cashew apple, and from various Toxico ascorbyl phosphate and sodium magnesium L-ascorbyl-2 dendron species like T. radicans, T diversilobum, also from monophosphate. Commercially available ascorbyl phos Rhus verniciflua, and Melanorrhoea usitata. phates comprise trisodium L-ascorbyl-2-monophosphate [0119) Cardol diene (XII) and/or cardol triene (XIII) as which is available as STAY-CO(R50 from DSM Nutritional employed herein may be prepared by a number of methods Products AG, (4303 Kaiseraugst, Switzerland) and magne known in the art. The mentioned plants may be processed by sium L-ascorbyl phosphate available from Showa Denko) any suitable means to obtain the compositions described. For and sodium magnesium L-ascorbyl-2-monophosphate and example, cashew apple may be extracted to obtain a mixture. L-ascorbic acid-monophosphate which is available as ROVI Cardol diene (XII) and/or cardol triene (XIII) may be MIX(R) STAY-CR 35 from DSM Nutritional Products AG, obtained directly from the mixture or the mixture may be (4303 Kaiseraugst, Switzerland). The preferred ascorbyl fractionated and/or purified to obtain cardol diene (XII) and/ phosphate for the purposes of the present invention is triso or cardol triene (XIII). The compositions may be fractionated dium L-ascorbyl-2-monophosphate. The ascorbyl phosphate and/or purified by a number of methods known to the person may be incorporated into the nutraceutical, pharmaceutical, skilled in the art. Examples of fractionating methods include cosmetic or dermatological preparations in many dosage partitioning with an organic solvent, chromatography, for amounts as known to the person skilled in the art. example high pressure liquid chromatography (HPLC) or the [0111] Lycopene (p,up carotene; CaoHsa; CAS-number: use of supercritical fluids. 502-65-8) belongs to the carotenoid family and contains 11 [0120) Cardol diene (XII) and/or cardol triene (XIII) can conjugated double-bonds and an additional two non-conju for example be obtained by extraction of dried plant material gated carbon-carbon double-bonds. Lycopene is one of the of Anacardium occidentale with methanol: methyl tert butyl major dietary carotenoids and is found in various fruits and ether (9:1) and by subsequent fractionation of the thus vegetables, especially in tomatoes and tomato products. It obtained crude extract by preparative HPLC in a buffered also occurs e.g. in water melon, pink grapefruit, guava. solvent system. [0112] Lycopene is preferably used in a concentration so [012.1] Cashew fruit extract is preferably used in such an that the daily consumption by an animal including humans amount that the amount of cardol diene (XII) and/or cardol (e.g. weighing about 70 kg) is in the range of from 0.05 triene (XIII) is as described above. mg/day to 50 mg/day, more preferably from 0.5 mg/day to 30 [0122] Hydroxytyrosol and/or oleuropein (I) may also be mg/day. A nutraceutical composition preferably comprises combined with Glycyrrhiza foetida. The term ‘Glycyrrhiza 0.05 mg to 50 mg of lycopene per serving. If the composition foetida’ encompasses all parts of the plants derived from is a pharmaceutical composition such composition may pref Glycyrrhiza foetida as well as extracts derived thereof. erably comprise Lycopene in an amount from 0.5 mg to 50mg [0123] Hydroxytyrosol and/or oleuropein (I) may also be per dosage unit, e.g., per capsule or tablet, or a liquid formu combined with compounds isolated from Glycyrrhiza foetida lation. such as 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3 [0113] The chemical structure of cardol diene is given in butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B FIG. 1, structure (XII). The chemical structure of cardol (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl triene is given in FIG. 1, structure (XIII) 2-butenyl)-6-pentyl-benzoic acid (VI), Cannabigerolic acid [0114] Preferably cardol diene (XII) is used in the compo monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hy sition of the present invention. droxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), [0115] Cardol diene (XII) and/or cardol triene (XIII) is 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phe preferably used in a concentration so that the daily consump nol (IX), the compound of formula (X) and 2-hydroxy-4 tion by an animal including humans (e.g. weighing about 70 methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenyl kg) is in the range of from 1 mg/day to 2000 mg/day, prefer ethyl)-benzoic acid (XI), more preferably enriched in at least ably from 5 mg/day to 500 mg/day. A nutraceutical compo one compound from the group of cannabigerolic acid sition preferably comprises between 0.2 mg and 1000 mg of monomethyl ether, 2-hydroxy-4-methoxy-3-(2-hydroxy-3 cardol diene (XII) and/or cardol triene (XIII) per serving. In methyl-3-butenyl)-6-pentyl-benzoic acid and 3-methoxy-2 case of a pharmaceutical composition the amount of cardol (3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol. diene (XII) and/or cardol triene (XIII) may be selected from [012.4] Glycyrrhiza foetida as a whole or parts thereof such 0.5 mg and 2000 mg per dosage unit, e.g., per capsule or as the seedlings, the young plants, the leaves, the flowers tablet, or between 1 mg per daily dose and 3000 mg per daily (optionally in dried or ground form) or seeds may be used in dose of a liquid formulation. dried and grinded form or may be extracted conventionally [0116] Cardol diene (XII) and/or cardol triene (XIII) may with solvents like ethanol, dichloromethane at reflux tem also be used in the form of an extract for instance an—pref perature or at lower temperature. Alternatively, it may be erably organic phase or supercritical fluid–extract of the extracted with supercritical fluids like SF carbon dioxide or cashew plant (Anacardium occidentale)) or a part of the by steam distillation of the plant with water followed by cashew plant, for example in the form of an extract of cashew sampling of the distilled organic part. Sampling may for fruit. example be done by extraction with an organic solvent like [0117] Cardol diene (XII) and/or cardol triene (XIII) may dichloromethane, ethylacetate etc. Subsequent removal of the be synthesized or extracted and/or purified by methods solvent gives the desired Glycyrrhiza foetida extract. known to the person skilled in the art. [0125] Optionally, the thus obtained Glycyrrhiza foetida [0118] Cardol diene (XII) and/or cardol triene (XIII) are extract may be subjected to further processing steps to enrich preferably derived from the cashew plant that may be the content of specific compounds to give an extract of Gly US 2010/0056463 A1 Mar. 4, 2010

cyrrhiza foetida e.g. enriched in 2-hydroxy-4-methoxy-3-(2 [0132) If the individual compounds are used in form of a hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic Glycyrrhiza foetida extract, the extract is preferably used in acid (III), Amorfrutin B (IV), Amorfiutin A (V), 2-hydroxy such an amount that the amount of individual compound(s) is 4-methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid as described above. (VI), Cannabigerolic acid monomethyl ether (VII), 2-hy [0133) Extracts of Harpagophytum procumbens (Devil’s droxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pen claw) are on the market. The active ingredient in Devil’s Claw tyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl) is a glycoside called harpagoside. Other constituents of Dev 5-(2-phenylethyl)-phenol (IX), the compound offormula (X) il’s Claw include beta-sitosterol, harpagide, procumbine, and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-bute sugars, gum resin and bitter ingredients. Devil’s Claw’s dos nyl)-6-(2-phenylethyl)-benzoic acid (XI), more preferably age can easily be determined by the person skilled in the art and is preferably within the same range as on the market. enriched in at least one compound from the group of can [0134] Milk protein concentrate includes milk protein nabigerolic acid monomethyl ether, 2-hydroxy-4-methoxy hydrolysates and is commercially available for example as 3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid MicroLactin"M from Brandenburg nutrition or as Peptopro and 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl) from DSM Food Specialities. It’s dosage can easily be deter phenol. Compounds III to XI are depicted in FIG. 1. mined by the person skilled in the art and is preferably within [0126] Glycyrrhiza foetida extracts enriched in at least one the same range as on the market. compound selected from the group of cannabigerolic acid [0135| Horse chestnut extract refers to an extract obtained monomethyl ether, 2-hydroxy-4-methoxy-3-(2-hydroxy-3 from Aesculus hippocastanum comprising a mixture of methyl-3-butenyl)-6-pentyl-benzoic acid and 3-methoxy-2 saponins. (3-methyl-2-butenyl)-5-(2-phenylethyl)-phenol are pre [0136] Other examples of compounds with which hydroxy ferred. tyrosol and/or oleuropein (I) may be combined to get a syn [0127] All compounds (III)-(XI) can e.g. be obtained by ergistic effect are solubilized keratin, celery seed extract, extraction of dried plant material of Glycyrrhiza foetida with cetylated fatty acids, carnitine thymoduinone, lutein, zeaxan methanol: methyl tert butyl ether (MTB) (9:1) and by subse thin and fl-cryptoxanthin. quent fractionation of the thus obtained crude extract by [0137] In another aspect, the invention relates to a cosmetic preparative HPLC, for example in a buffered solvent system or dermatological preparation (the latter preparation are a or can be synthesized. Examples of fractionating methods specific type of a pharmaceutical) comprising an effective amount of the composition of the invention and a cosmeti include partitioning with an organic solvent, chromatogra cally or dermatologically acceptable carrier. phy, for example high pressure liquid chromatography [0138] The cosmetic or dermatological composition may (HPLC) or the use of supercritical fluids. Of course the com further comprise conventional cosmetic respectively derma pounds of (III)-(XI) may also be accessible via chemical tological adjuvants and/or additives and/or additional active synthesis) ingredients. [0128] Preferably compounds (III) to (XI) are used in the [0139] Preferably the cosmetic or dermatological prepara form of an extract derived from Glycyrrhiza foetida. tions are skin care formulations for the treatment, co-treat [0129] The Glycyrrhiza foetida extract and/or the com ment or prevention of inflammation of the skin, in particular pounds contained therein are preferably derived from Glycyr of sunburn caused by UV-radiation, of contact dermatitis rhiza foetida that may be obtained from conventional and (particularly diaper area dermatitis), atopic dermatitis, xero commercially available sources such as growers. sis, eczema, rosacea, seborrhea, psoriasis, neurodermitis, [0130] The Glycyrrhiza foetida as well as the extracts thermal burns, photoageing or for the treatment, co-treatment derived thereofare preferably used so that the daily consump or prevention of impure skin. Examples of impure skin tion by an animal including humans (e.g. weighing about 70 include pimples, acne and other skin impurities with an kg) is in the range of from 0.5 mg/day to 2000 mg/day, inflammatory aspect. preferably from 5 mg/day to 500 mg/day. A nutraceutical [0140] The term “effective amount” means preferably at composition preferably comprises 0.5 mg to 1000 mg of a least 0.001% of each active agents as listed above based on the Glycyrrhiza foetida extract. If the composition is a pharma total weight of the cosmetic or dermatological composition. ceutical composition such composition may comprise the Preferably, the cosmetic ordermatological preparations com Glycyrrhiza foetida extract in an amount from preferably 1 prise the active agents selected from the list above in an mg to 2000 mg per dosage unit, e.g., per capsule or tablet, or amount between 0.01 wt.-% and 20 wt.-%, more preferably from 1 mg per daily dose to 3000 mg per daily dose of a liquid between 0.05 and 10 wt.-%, still more preferably between 0.1 formulation. and 5 wt.-%. [0131] The individual compounds isolated from the Gly [0141] The amount of the cosmetic or dermatological cyrrhiza foetida are preferably used in a concentration so that preparation which is to be applied to the skin depends on the the daily consumption by an animal including humans (e.g. concentration of the active ingredients in the preparation and weighing about 70 kg) is in the range of from 0.5 mg/day to the desired cosmetic or pharmaceutical effect. For example, 2000 mg/day, preferably from 5 mg/day to 500 mg/day. A the application can be such that a crème is applied to the skin. nutraceutical composition preferably comprises 0.5 mg to A crème is usually applied in an amount of about 1 to 2 mg 1000 mg of such a compound. If the composition is a phar crème/cm skin. The amount of the composition which is maceutical composition such composition may comprise one applied to the skin is, however, not critical, and if with a or more of the compounds contained in Glycyrrhiza foetida in certain amount of applied composition the desired effect can an amount from preferably 1 mg to 2000 mg per dosage unit, not be achieved, a higher concentration of the active prepa e.g., per capsule or tablet, or from 1 mg per daily dose to 3000 rations which contain more active ingredient might be mg per daily dose of a liquid formulation. employed. US 2010/0056463 A1 Mar. 4, 2010

[0142] The invention also relates to the use of the cosmetic Organic UV-B or broadband screening agents are e.g. acry preparation for the cosmetic treatment, co-treatment or pre lates such as 2-ethylhexyl 2-cyano-3,3-diphenylacrylate (oc vention of inflammation of the skin, in particular for the tocrylene, PARSOLR 340), ethyl 2-cyano-3,3-diphenylacry cosmetic treatment, co-treatment or prevention of sunburn, late and the like; camphor derivatives such as 4-methyl contact dermatitis (particularly diaper area dermatitis), atopic benzylidene camphor (PARSOLR 5000), 3-benzylidene dermatitis, xerosis, eczema, rosacea, seborrhea, psoriasis, camphor, camphor benzalkonium methosulfate, polyacryla neurodermitis, thermal burns or photoageing. midomethyl benzylidene camphor, sulfo benzylidene cam [0143| Also, the invention relates to a method for the treat phor, sulphomethyl benzylidene camphor, therephthalidene ment, co-treatment or prevention of inflammation of the skin, dicamphor sulfonic acid and the like; Cinnamate derivatives in particular of sunburn in humans, of impure skin such as for such as ethylhexyl methoxycinnamate (PARSOLR. MCX), example acne or of photoageing which is associated with ethoxyethyl methoxycinnamate, diethanolamine methoxy chronic skin inflammation, said method comprising the step cinnamate (PARSOLR Hydro), isoamyl methoxycinnamate of administering an effective amount of the dermatological and the like as well as cinnamic acid derivatives bond to composition according to the invention to humans, which are siloxanes; p-aminobenzoic acid derivatives, such as p-ami in need thereof. Also, the invention relates to a method for nobenzoic acid, 2-ethylhexyl p-dimethylaminobenzoate, cosmetic treatment, co-treatment or prevention of inflamma N-oxypropylenated ethyl p-aminobenzoate, glyceryl p-ami tion of the skin, in particular of sunburn or of impure skin by nobenzoate; benzophenones such as benzophenone-3, ben a cosmetic preparation according to the invention. Sunburn Zophenone-4,2,2,4,4'-tetrahydroxy-benzophenone, 2,2'-di prevention is preferably achieved with topical application hydroxy-4,4'-dimethoxybenzophenone and the like; esters of comprising the composition of the invention preferably in benzalmalonic acid such as di-(2-ethylhexyl) 4-methoxyben combination with suitable light screening agents. Zalmalonate; esters of 2-(4-ethoxy-anilinomethyl ene)pro [0144] The cosmetic or dermatological preparations pandioic acid such as 2-(4-ethoxyanilinomethylene) propan according to the invention may be in the form of a suspension dioic acid diethyl ester as described in the European Patent or dispersion in solvents or fatty substances, or alternatively Publication EP 0895 776; organosiloxane compounds con in the form of an emulsion or micro emulsion (in particular of taining benzmalonate groups as described in the European O/W or W/O type, O/W/0 or W/O/W-type, wherein O stands Patent Publications EP 0358584 B1, EP 0538431 B1 and EP for oil phase and wherein W stands for water phase), such as 0709080 A1 such as polysilicone-15 (PARSOLR SLX); a cream, a paste, a lotion, a thickened lotion or a milk, a drometrizole trisiloxane (Mexoryl XL); deriva vesicular dispersion in the form of an ointment, a gel, a solid tives such as e.g. 2-phenylbenzimidazole sulfonic acid and its tube stick or an aerosol mousse, and may be provided in the salts (PARSOLRHS). Salts of 2-phenyl benzimidazole sul form of a mousse, foam or a spray foams, sprays, sticks or fonic acid are e.g. alkali salts such as sodium- or potassium aerosols or wipes. Examples of cosmetic or dermatological salts, ammonium salts, morpholine salts, salts of primary, sec. preparations are skin care preparations, in particular, body and tert, amines like monoethanol amine salts, diethanol oils, body lotions, body gels, treatment creams, skin protec amine salts and the like; salicylate derivatives such as isopro tion ointments, moisturizing gels, moisturizing sprays, revi pylbenzyl salicylate, benzyl salicylate, butyl salicylate, eth talizing body sprays, after sun preparations or sunscreen for ylhexyl salicylate (PARSOLR, EHS, NEO Heliopan OS), mulations. isooctyl salicylate or homomethyl salicylate (homosalate, [0145] The cosmetic or dermatological composition for the PARSOLR HMS, NEO Heliopan OS) and the like; triazine treatment, co-treatment or prevention of inflammation of the derivatives such as ethylhexyl triazone (Uvinul T-150), dieth skin, such as for example sunburn, photoageing or impure ylhexyl butamido triazone (Uvasorb HEB). Encapsulated skin may be in a form that is conventional for oral adminis UV-filters such as encapsulated ethylhexyl methoxycin tration, examples of which are described above and also namate (Eusolex UV-pearls) or microcapsules loaded with include beauty foods and supplements. UV-filters as e.g. disclosed in EP 1471995 and the like. Inor [0146] The cosmetic or dermatological preparations of the ganic compounds are pigments such as microparticulated invention for instance as sunscreen formulations or after sun TiO2, ZnO and the like. The term “microparticulated” refers preparations may further comprise the usual cosmetic respec to a particle size from about 5 nm to about 200 nm, particu tively dermatological adjuvants and/or additives such as pre larly from about 15 nm to about 100 nm. The TiO2 particles servatives/antioxidants, fatty substances/oils, water, organic may also be coated by metal oxides such as e.g. aluminum or solvents, silicones, thickeners, softeners, emulsifiers, addi zirconium oxides or by organic coatings such as e.g. polyols, tional light screening agents, antifoaming agents, moisturiz methicone, aluminum stearate, alkylsilane. Such coatings are ers, fragrances, surfactants, fillers, sequestering agents, well known in the art. anionic, cationic, nonionic or amphoteric polymers or mix [0148] Examples of broad spectrum or UV A screening tures thereof, propellants, acidifying or basifying agents, agents i.e. substances having absorption maxima between dyes, colorants, pigments or nanopigments, light stabilizers, about 320 and 400 nm may be organic or inorganic com insect repellants, skin tanning agents, skin whitening agents, pounds e.g. dibenzoylmethane derivatives such as 4-tert. antibacterial agents, preservatives active ingredients or any butyl-4'-methoxydibenzoyl-methane (PARSOLR, 1789), other ingredients usually formulated into cosmetics. dimethoxydibenzoylmethane, isopropyldibenzoylmethane [0147| Light screening agents which may be incorporated and the like; benzotriazole derivatives such as 2,2'-methyl into cosmetic or dermatological preparations of the invention ene-bis-(6-(2H-benzotriazole-2-yl)-4-(1,1,3,3,-tetramethyl for instance sunscreen formulations are advantageously butyl)-phenol (TINOSORB M) and the like; bis-ethylhexy selected from IR, UV-A, UV-B, UV-C and/or broadband fil loxyphenol methoxyphenyl triazine (Tinosorb S) and the like; ters. Examples of UV-B or broad spectrum screening agents, phenylene-1,4-bis-benzimidazolsulfonic acids or salts such i.e. substances having absorption maximums between about as 2,2-(1,4-phenylene)bis-(1H-benzimidazol-4,6-disulfonic 290 and 340 nm may be organic or inorganic compounds. acid) (Neoheliopan AP); amino substituted hydroxyben US 2010/0056463 A1 Mar. 4, 2010

Zophenones such as 2-(4-Diethylamino-2-hydroxy-benzoyl) tryptanthrin, diosgenin, curcumin and derivatives, Glycyr benzoic acid hexylester (Uvinul A plus) as described in the rhiza foetida and white willow bark extract, in particular of European Patent Publication EP 1046391; Ionic UV-A filters ligustilide, honokiol, genistein, resveratrol and EGCG. as described in the International Patent Publication [0153] Preferably, the invention relates to the use of WO2005080341 A1. Pigments such as microparticulated hydroxytyrosol and/or oleuropein (I), in particular hydroxy ZnO or TiO2 and the like. The term “microparticulated” tyrosol, for enhancing the anti-inflammatory activity of one refers to a particle size from about 5 nm to about 200 nm, or several compounds selected from the group of ligustilide, particularly from about 15 nm to about 100 nm. The particles honokiol, genistein, resveratrol and EGCG. may also be coated by other metal oxides such as e.g. alumi [0154] Thus, the invention relates to the use of hydroxyty num or zirconium oxides or by organic coatings such as e.g. rosol and/or oleuropein (I), in particular hydroxytyrosol, for polyols, methicone, aluminum stearate, alkyl silane. Such enhancing the anti-inflammatory activity of ligustilide. coatings are well known in the art. [0155] In another embodiment invention relates to the use [0149] As dibenzoylmethane derivatives have limited pho of hydroxytyrosol and/or oleuropein (I), in particular tostability, it may be desirable to photostabilize these UV-A hydroxytyrosol, for enhancing the anti-inflammatory activity screening agents. Thus, the term “conventional UV-A screen of honokiol. Most preferably, honokiol is used in the form of ing agent” also refers to dibenzoylmethane derivatives such an extract from the bark of Magnolia officinalis comprising as e.g. PARSOLR 1789 stabilized by, e.g. 3,3-Diphenylacry honokiol and magnolol. late derivatives as described in the European Patent Publica [0156] In a further embodiment the invention relates to the tions EP 0 514,491 B1 and EP 0 780 119 A1; Benzylidene use hydroxytyrosol and/or oleuropein (I), in particular camphor derivatives as described in the U.S. Pat. No. 5,605, hydroxytyrosol, for enhancing the anti-inflammatory activity 680; Organosiloxanes containing benzmalonate groups as of genistein. described in the European Patent Publications EP 0358584 [0157] In an additional embodiment the invention relates to B1, EP 0538431 B1 and EP 0709080 A1. use of hydroxytyrosol and/or oleuropein (I), in particular [0150] Active ingredients which may be included in the hydroxytyrosol, for enhancing the anti-inflammatory activity cosmetic or dermatological preparations of the invention are of resveratrol. for example vitamins and derivatives thereof, for example [0158] In an additional embodiment the invention relates to tocopherol, tocopherol acetate, ascorbic acid, ascorbyl phos use of hydroxytyrosol and/or oleuropein (I), in particular phate, vitamin Q, D, and K, retinol, retinal, retinoic acid, hydroxytyrosol, for enhancing the anti-inflammatory activity retinol acetate, retinol palmitate, biotin, carotenoid deriva of EGCG. tives such as beta-carotene, lycopene, astaxanthin, vegetable [0159] In another embodiment the invention relates to a extracts, antibacterial ingredients, instable amino acids com method of enhancing the efficacy of hydroxytyrosol and/or prising dipeptides, oligopeptides and polypeptides such as oleuropein (I) which comprises adding to a composition con methionine, cysteine, cystine, tryptophan, phenylalanine, taining hydroxytyrosol and/or oleuropein (I) an effective tyrosine, , polyphenols or flavanoids, bisabolol, allan amount of one or several components selected from the group toin, phytantriol, panthenol, AHA acids, ubiquinones such as of ligustilide, oleuropein aglycone (II), tyrosol, extract from coenzyme Q10, ceramides, pseudoceramides, essential oils, the bark of Magnolia officinalis, magnolol, honokiol, plant extracts deoxyribonucleic acid, phytanic acid. genistein, resveratrol, EGCG methylsulfonylmethane, [0151] The necessary amounts of the cosmetic and derma SAMe, collagen hydrolysate, collagen, ascorbyl phosphate, tological adjuvants, additives and/or additional active ingre lycopene, lutein, zeaxanthin, fl-cryptoxanthin, Devil’s Claw, dients can, based on the desired product, easily be chosen by milk protein concentrate, solubilized keratin, celery seed a person skilled in the art and will be illustrated in the extract, cetylated fatty acids, carnitine, thymoduinone, 2-hy examples, without being limited hereto. droxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-(2 [0152] In yet another embodiment, the invention relates to phenylethyl)-benzoic acid (III), Amorfrutin B (IV), Amorfru the use of hydroxytyrosol and/oroleuropein (I) for enhancing tin A (V), 2-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-6 the anti-inflammatory activity of one or several compounds pentyl-benzoic acid (VI), cannabigerolic acid monomethyl selected from the group of ligustilide, oleuropein aglycone ether (VII), 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl (II), tyrosol, extract from the bark of Magnolia officinalis, 3-butenyl)-6-pentyl-benzoic acid (VIII), 3-methoxy-2-(3 magnolol, honokiol, genistein, resveratrol, EGCG, methyl methyl-2-butenyl)-5-(2-phenylethyl)-phenol (IX), the com sulfonylmethane, SAMe, collagen hydrolysate, collagen, pound of formula (X) and 2-hydroxy-4-methoxy-5-(2 ascorbyl phosphate, lycopene, lutein, zeaxanthin, fl-cryptox hydroxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic anthin, Devil’s Claw, milk protein concentrate, solubilized acid (XI), cardol diene (XII), cardol triene (XIII), cashew fruit keratin, celery seed extract, cetylated fatty acids, carnitine, extract, boswellic acid, carnosic acid, ursolic acid, horse thymoquinone, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-me chestnut extract, diosmetin, tryptanthrin, diosgenin, cur thyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amor cumin and derivatives, Glycyrrhiza foetida and white willow frutin B (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3 bark extract, in particular of ligustilide, honokiol, genistein, methyl-2-butenyl)-6-pentyl-benzoic acid (VI), resveratrol and EGCG. The term ‘an effective amount’ refers cannabigerolic acid monomethyl ether (VII), 2-hydroxy-4 to an amount necessary to obtain a synergistic effect. The methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pentyl-ben dosage may, of course, vary depending upon known factors, zoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl)-5-(2 such as the physiological characteristics of the particular phenylethyl)-phenol (IX), the compound of formula (X) and composition and its mode and route of administration; the 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-butenyl) age, health and weight of the recipient; the nature and extent 6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), car of the symptoms; the kind of concurrent treatment; the fre dol triene (XIII), cashew fruit extract, boswellic acid, car quency of treatment; and the effect desired and can be nosic acid, ursolic acid, horse chestnut extract, diosmetin, adjusted by a person skilled in the art. US 2010/0056463 A1 Mar. 4, 2010

[0160] Thus, in a preferred embodiment the invention do not prevent or treat damage to the cartilage. The patients relates to a method of enhancing the efficacy of hydroxyty experiencing severe cartilage damage frequently require sur rosol and/oroleuropein (I) which comprises adding to a com gery, including joint replacement surgery. Therefore, there position containing hydroxytyrosol and/or oleuropein (I) an was a great need for agents that treat or prevent cartilage loss effective amount of ligustilide. and damage, which need has been solved by the present [0161] In another preferred embodiment the invention also invention. relates to a method of enhancing the efficacy of hydroxyty [0169] The composition of the present invention may have rosol and/oroleuropein (I) which comprises adding to a com one or more of the following properties: it maintains and/or position containing hydroxytyrosol and/or oleuropein (I), in improves joint health, it prevents joint stiffness, it promotes particular hydroxytyrosol, an effective amount of honokiol. joint mobility, it provides supple and/or flexible joints, it Most preferably, honokiol is used in the form of an extract lubricates the joints, it relieves arthritis pain, it lessens joint from the bark of Magnolia officinalis comprising honokiol problems, it provides joint care, it treats or prevents joint and magnolol. degradation, it provides joint integrity, it retards or prevents [0162] In a further preferred embodiment the invention the progression of joint damage, it supports joint function, it relates to a method of enhancing the efficacy of hydroxyty promotes joint health and function, it naturally supports joint rosol and/or oleuropein (I), in particular hydroxytyrosol, health and mobility for active individuals, it maintains the which comprises adding to a composition containing active flexibility of joints, it promotes joint flexibility and hydroxytyrosol and/or oleuropein (I) an effective amount of promotes joint mobility. genistein. [0170] Thus, further objects of the present invention are: [0163] In an additional preferred embodiment the invention [0171] Use of a composition according to the invention relates to a method of enhancing the efficacy of hydroxyty as cartilage-regenerating and maintaining agent. rosol and/or oleuropein (I), in particular hydroxytyrosol, [0172] Use of a composition according to the invention which comprises adding to a composition containing for maintenance of joint health. hydroxytyrosol and/or oleuropein (I) an effective amount of [0173] Use of a composition according to the invention resveratrol. (for the manufacture of a composition) for the mainte [0164] In an additional preferred embodiment the invention nance and regeneration of articular cartilage. relates to a method of enhancing the efficacy of hydroxyty [0174] A method for the regeneration and/or mainte rosol and/or oleuropein (I), in particular hydroxytyrosol nance of (articular) cartilage in a mammal which com which comprises adding to a composition containing prises administering to a mammal in need of such regen hydroxytyrosol and/or oleuropein (I) an effective amount of eration and/or maintenance an effective amount of a EGCG. composition according to the invention. [0165] It has been found that the compositions according to (0175] The invention will now be elucidated by way of the the invention are also suitable for the treatment, co-treatment following examples, without however being limited thereto. or prevention of cartilage degradation or cartilage damage in joints and as such for treatment of the cartilage degradation EXAMPLES component of joint disorders, for example degenerative joints [0176). In the following examples, “Group (A)” is defined disorders such as osteoarthritis; or sport injuries. Cartilage as the following group of compounds: ligustilide, oleuropein degradation is defined within the framework of the invention aglycone (II), tyrosol, extract from the bark of Magnolia as a metabolic disorder of joint cartilage characterized by officinalis, magnolol, honokiol, genistein, resveratrol, EGCG increased production of cartilage-degrading enzymes such as methylsulfonylmethane, SAMe, collagen hydrolysate, col matrix metalloproteases. lagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, [0166] Osteoarthritis is a chronic degenerative disease of fl-cryptoxanthin, Devil’s Claw, milk protein concentrate, the joint of non-inflammatory origin, which develops by wear solubilized keratin, celery seed extract, cetylated fatty acids, and tear of the joints during aging and results in pain and carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2-hy diminished joint function. Symptoms of osteoarthritis droxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid include pain, stiffness and loss of mobility in one or more (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4 joints. Excessive joint loading increases the risk of osteoar methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid thritis, hence osteoarthritis mostly affects the weight-bearing (VI), cannabigerolic acid monomethyl ether (VII), 2-hy joints such as spine, knees and hips, but thumb and finger droxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pen joints may also be affected. Joint disorders can also results tyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl) from injury, i.e. microdamage or blunt trauma, fractures, 5-(2-phenylethyl)-phenol (IX), the compound of formula (X) damage to tendons, menisci or ligaments or can be the result and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-bute of excessive mechanical stress or other biomechanical insta nyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), bility resulting from for example an injury or obesity. cardol triene (XIII), cashew fruit extract, boswellic acid, car [0167] Joint disorders due to cartilage degradation are lead nosic acid, ursolic acid, horse chestnut extract, diosmetin, ing causes of disability and dysfunction in the elderly; almost tryptanthrin, diosgenin, curcumin and derivatives, Glycyr 80% of people over age 60 show some evidence of these rhiza foetida and white willow bark extract. disorders. Age, genetic factors, muscle disuse and weakness, [0177] Hydroxytyrosol is commercially available from trauma, obesity and anatomical abnormalities contribute to Cayman Chemicals or was synthesized by DSM Nutritional the development of the disorder. Products. Resveratrol, ligustilide, EGCG and genistein was [0168] Joint disorders are difficult to treat. Up till now, synthesized by DSM Nutritional Products. Magnolia Bark treatment was largely limited to addressing the symptoms extract was from Novanat Bioresources Co. Ltd. China and mainly with non-steroidal anti-inflammatory drugs. The contained according to the specification >80% Magnolol and drugs are given to control the pain and to restrain swelling, but Honokiol. Oleuropein, Magnolol and Honokiol may be pur

US 2010/0056463 A1 Mar. 4, 2010 15

Example 5 TABLE 3 Tablet Synergistic effects on production of nitric oxide

% inhibition [0190] Tablets are prepared by conventional procedures of NO ICso of pure providing as active ingredient 100 mg of hydroxytyrosol and/ Substance Concentration production A* compound or oleuropein (I) per tablet and at least one component Lycopene (Ly) 0.5 pmol/L 4 - >8 pmol/L selected from the group of Group (A) as defined above of 100 Resveratrol (Res) 3.13 pmol/L –2 – 19.3 pmol/L mg Ligustilide, and as excipients microcrystalline cellulose, OH-tyrosol (OT) 3.13 pmol/L –4 – 24.1 pmol/L silicone dioxide (SiO2), magnesium stearate, crospovidone Ly 4. Res + OT (0.5 + 3.13 + 17 15 Not applicable 3.13) pumol/L NF (which is a disintegration agent) ad 500 mg. *observed - additive; Additive = X (Ly + Res + OT) Example 6

TABLE 3 Soft Drink Synergistic effects on PGE2 production [0191) An orange juice drink coloured with beta-Carotene % inhibition 10% CWS and with hydroxytyrosol and at least one compo of PGE, ICso of pure ment selected from the group of Group (A) as defined above Substance Concentration production A* compound may be prepared as follows: Lycopene (Ly) 0.25 pmol/L –5 - >8 pmol/L Resveratrol (Res) + 1.56 pmol/L + 23 — 23.4 pmol/L OH-tyrosol (OT) 1.56 pmol/L — 22.7 pmol/L Ly 4. Res + OT (0.25 + 1.56 + 49 26 Not applicable 1.56) plmol/L Ingredients [g] *observed - additive; Additive = X (Ly + Res + OT) Sugar syrup 64° Brix 156.2 Sodium benzoate 0.2 [0183] The data surprisingly showed that a combination of Ascorbic acid, fine powder 0.2 lycopeneto resveratrol to OH-tyrosol at a molarratio of about Citric acid 50% w/w 5.0 1:6:6 exert a synergistic inhibitory effects on production of Pectin solution 2% w/w 10.0 hydroxytyrosol 0.5 inflammatory mediators as exemplified for nitric oxide and compound selected from the group of Group (A) as defined above 0.3 PGE2. Juice compound” 30.0 Water to 250.0 Example 3 Soft Gelatin Capsule [0192] Preparation [0193] Dissolve sodium benzoate in water whilst stirring [0184] Soft gelatin capsules are prepared by conventional [0194] Continue stirring and add sugar syrup, ascorbic procedures providing a dose of hydroxytyrosol and/or oleu acid, citric acid, pectin solution, juice compound, one ropein (I) of 200 mg and at least one compound selected from after the other. Do not use a high speed mixer the group of Group (A) as defined above of 50 mg (e.g. [0195] Dilute the bottling syrup with (carbonated) water EGCG). A suitable daily dose is 1 to 8 capsules. to one liter of beverage [0185] Other ingredients: glycerol. Water, gelatine, veg etable oil *Ingredients Juice compound Example 4 Orange juice concentrate 65° Brix 483.3 Lemon Juice Concentrate 45° Brix 173.3 Hard Gelatin Capsule Oily orange flavour 5.0 beta-Carotene 10% CWS as 10% stock solution 10.0 [0186] Hard gelatin capsules are prepared by conventional Deionized water 3.28.4 procedures providing a dose of hydroxytyrosol and/or oleu ropein (I) of 400 mg and at least one component selected from [0196) Preparation of Juice Compound the group of Group (A) as defined above of 100 mg (e.g. [0197] Add the deionized water to the juice concentrates, magnolia bark extract). A suitable daily dose is 1 to 5 cap stir gently and allow the juice concentrates to hydrate. sules. [0198] Add the oily flavour and beta-Carotene 10% [0187] Other ingredients: CWS stock solution and pre-emulsify in a rotor-stator [0188] Fillers: lactose or cellulose or cellulose derivatives homogenizer. q.S. [0199| Homogenize in a high pressure homogenizer at [0189] Lubricant: magnesium stearate if necessary (0.5%) 200 bar.

US 2010/0056463 A1 Mar. 4, 2010

Example 11 -continued Anti Pimple Skin-Tonic ngredients/INCI Nomenclature wt.% [0204] Phenoxyethanol & Methylparaben & Ethylparaben & 0.60 Propylparaben & Butylparaben Disodium EDTA 0.10 Ingredients/INCI Nomenclature wt % Potassium Cetyl Phosphate 2.00 B) Aqua (e.g. deionized water) ad 100 A) Alkohol 15.00 Propylene Glycol 2.00 Glycerin 3.00 Aqua (e.g. deionized water) Ad 100 Panthenol 2.00 Disodium EDTA 0.10 Ethanol 5.00 HIDROX R 6% freeze dried powder 1.00 Allantoin 0.20 Compound selected from the group of Group (A) as 0.05 Carbomer 0.30 defined above Potassium Hydroxide 1.50 C) Aqua?e.g. deionized water) 10.00 Procedure: Add all ingredients of part 1 and mix intensively until a homoge Sodium Ascorbyl Phosphate 0.50 neous solution is obtained. Adjust the pH to 6.5 with acetic acid. D) HIDROX (R, 2% spray dried powder 0.50 Compound selected from the group of Group (A) as 0.2 Example 12 defined above E) Perfume C.S. Anti-Acne Treatment with Stay-C 50 Procedure: Heat partA), B) and C) to 85°C. while stirring. When homoge [0205] neous, add part B) and C) to A) under agitation. Cool to ambient temperature while stirring and add part D) and E). Homogenize to achieve a small par ticle size.

ngredients/INCI Nomenclature wt % Example 14 A) Glyceryl Myristate 1.50 Cetyl 1.50 Dry Dog Feed Comprising Hydroxytyrosol and C12-15 Alkyl Benzoate 4.00 Phenoxyethanol & Methylparaben & Ethylparaben & 0.80 Genistein Butylparaben & Propylparaben & Isobutylparaben sononyl Isononanoate 2.00 Steareth-2 1.50 [0207] Commercial dry dog food (Hill’s Science diet Steareth-21 1.50 “Canine Maintenance dry” for dogs as supplied by Hill’s Pet 2 Butylene Glycol 2.00 Nutrition GmbH, Liebigstrasse 2-20, D-22113) is sprayed Glycerin 3.00 Disodium EDTA 0.10 with an aqueous solution of hydroxytyrosol and genistein in Xanthan Gum 0.30 an amount sufficient to administer to a subject a daily dose of Arcylates/C10-30 Alkyl Acrylate Crosspolymer 0.25 200 mg to 1 g hydroxytyrosol and 0.1 mg to 3 mg genistein Hydroxytyrosol 1.00 Aqua (e.g. deionized water) Ad 100 per kg body weight. Further Vitamin C and E and beta 3 Aqua (e.g. deionized water) 10.00 carotene are incorporated in an amount sufficient to provide Sodium Ascorbyl Phosphate 3.00 30 mg vitamin C/kg, and 300 IU vitamin E/kg and 280 mg Sodium Metabisulfite 0.05 beta-carotene/kg in the final food composition before extrud Procedure: Heat part 1 up to 85°C.; and heat also part 2 up to 85°C. When ing the entire blend. The food composition is dried to contain 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 dry matter of about 90% by weight. and homogenize intensively again. It is generally recommended to use vacuum while producing the emulsion. Example 15 Example 13 Wet Cat Food Comprising Hydroxytyrosol and Genistein Protective Day Cream [0206] [0208] 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 HIDROXR 2% spray dried powder in an amount sufficient to Ingredients/INCI Nomenclature wt % administer to a subject a daily dose of 200 mg to 1 g hydroxy A) Polysilicone-15Dimethico Diethylbenzalmalonate 4.00 tyrosol. Further ROVIMIXR STAY-CR 35 available from Butyl Methoxydibenzoylmethane 1.50 Glyceryl Myristate 2.00 DSM Nutritional Products AG, Vitamin E and beta-carotene Cetyl Alcohol 0.50 are incorporated in an amount sufficient to provide 30 mg Caprylic/Capric Triglyceride 5.00 ROVIMIXR STAY-CR 35/kg, and 300 IU vitamin E/kg and Diisopropyl Adipate 5.00 Tocopheryl Acetate 2.00 280 mg beta-carotene/kg in the final food composition before BHT 0.05 cooking the entire blend. The food composition is dried to contain a dry matter of about 90% by weight. US 2010/0056463 A1 Mar. 4, 2010 18

Example 16 celery seed extract, cetylated fatty acids, carnitine, thymo quinone, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3 Cereal Bar/Non Baked butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B [0209) (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-hy droxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), Ingredients Quantity [g] 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phe Sugar 138.0 nol (IX), the compound of formula (X) and 2-hydroxy-4 Water 54.0 methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenyl Salt 1.5 ethyl)-benzoic acid (XI), cardol diene (XII), cardol triene Glucose syrup DE38, 43° Be 130.0 nvert sugar syrup (74-76%) 95.0 (XIII), cashew fruit extract, boswellic acid, carnosic acid, Sorbitol syrup 35.0 ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, Palmkernel fat 60.0 diosgenin, curcumin and derivatives, Glycyrrhiza foetida and Biscofin N 40.0 white willow bark extract. Lecithin 1.5 2. The composition as in claim 1, wherein at least one Monomuls 90-35-5 (emulsifer) 2.5 Apple dried and cut 63.0 additional component is selected from the group of ligustil Raisins 27.0 ide, oleuropein aglycone (II), magnolol, honokiol, genistein, Cornflakes 100.0 resveratrol, EGCG, boswellic acid, magnolia bark extract, Rice crispies 140.0 Mini Crispini, Wheat 90.0 cashew fruit extract and Glycyrrhiza foetida. Hazelnut, roasted 54.0 3. The composition as in claim 1 comprising hydroxytyro Skim milk powder 45.0 sol, lycopene and resveratrol. Apple flavour 74863-33 2.0 4. The composition as in claim 1, wherein the hydroxyty Citric acid” 5.0 HIDROX (R, 2% spray dried powder 1.85 rosol is in the form of a hydroxytyrosol containing olive Genistein TG 0.34 eXtract. Magnolia bark extract 0.28 5. A use of a composition as in claim 1 as an agent for the É-Carotene 10% B 0.77 treatment, co-treatment or prevention of inflammatory disor Yield 1000.0 ders. *used to support the apple flavour 6. A use of a composition in claim 1 for maintenance of joint health. [0210] 2. Preparation: 7. A use of a composition as in claim 1 as an agent for treatment, co-treatment and prevention of joint disorders. 8. A nutraceutical comprising a composition as in claim 1 2.1 Premix HIDROX, Genistein TG, magnolia bark extract and and a nutraceutically acceptable carrier. É-Carotene 10% B with skim milk powder and place in a 9. The nutraceutical as in claim 8 which is a food product, Kenwood type mixer 2.2 Add cornflakes, ricecrispies and gently mix with 2.1. Then add the foodstuff, dietary supplement, nutritional supplement or a more humid ingredients as dried apples and raisins. All ingredients supplement composition for a food product or a foodstuff. are gently mixed in order to ensure a good distribution of the dry 10. The nutraceutical composition as in claim 8 wherein ingredients the amount of hydroxytyrosol and/or oleuropein (I) is 0.01 to 2.3 The following ingredients are weight into a separate bowl each Sugar, water, salt 1 g, more preferably 0.2 mg to 500 mg per serving. Glucose-inverte and sorbitol syrup 11. The composition as in claim 1 for use as a medicament. Biscofin N, Palmkernel fat, Lecithin and Emulsifier 12. A use of a composition as in claim 1, for the manufac 2.3 Mixture of sugar, water and salt is heated to 110°C. 2.4 Mixture of the different syrups is heated to 113°C. and cooled in ture of a medicament for the treatment, co-treatment or pre a cold water bath in order to stop the cooking process vention of inflammatory disorders. 2.5 Solution 2.3 and 2.4 are combined 13. The use as in claim 12, wherein the inflammatory 2.6 Mixture of Biscofin N, palm kernel fat, lecithin and emulsifier are disorder is arthritis. molten in a water bath at 75° C. 2.7 Mixture (2.6) of fats is added to the combined sugar solution (2.5). 14. The use as in claim 12 wherein the inflammatory dis The later should be still hot order is an inflammation of the skin. 2.8 Flavour and citric acid is added to the liquid mass (2.7) 2.9 The liquid mass is added to the dry ingredients (2.2) in the 15. A pharmaceutical comprising a composition as in claim Kenwood mixer and mixed well with the dry ingredients 1 and a pharmaceutically acceptable carrier. 2.10 The mass is put on a marmor plate and rolled to the desired 16. The pharmaceutical as in claim 15, which is in the form thickness. Then the mass is cooled down at room temperature of a powder, tablet, capsule, gel, liquid or solid. 2.11 Cut into pieces of e.g. one serving size and pack into e.g. 17. The pharmaceutical as in claim 15, which is for derma aluminium bags tological purposes. 18. A cosmetic composition comprising a composition as 1. A composition comprising hydroxytyrosol and/or oleu in claim 1 and a cosmetically acceptable carrier. ropein (I) and at least one additional component selected from 19. The cosmetic composition as in claim 18 which is a skin the group of ligustilide, oleuropein aglycone (II), tyrosol, care preparation. extract from the bark of Magnolia officinalis, magnolol, 20. A method for treatment, co-treatment or prevention of honokiol, genistein, resveratrol, EGCG methylsulfonyl inflammatory disorders in animals said method comprising methane, SAMe, collagen hydrolysate, collagen, ascorbyl the step of administering an effective amount of the compo phosphate, lycopene, lutein, zeaxanthin, fl-cryptoxanthin, sition as in claim 1 to an animal, which are in need of such a Devil’s Claw, milk protein concentrate, solubilized keratin, treatment. US 2010/0056463 A1 Mar. 4, 2010

21. The method as in claim 20, wherein the inflammatory 24. Method of enhancing the efficacy of hydroxytyrosol disorder is arthritis. and/or oleuropein (I) which comprises adding to a composi 22. The method as in claim 20, wherein the inflammatory tion containing hydroxytyrosol and/or oleuropein (I) an disorder is an inflammation of the skin. effective amount of one or several components selected from 23. Use of hydroxytyrosol and/or oleuropein (I) for the group of ligustilide, oleuropein aglycone (II), tyrosol, enhancing the anti-inflammatory activity of one or several extract from the bark of Magnolia officinalis, magnolol, compounds selected from the group of ligustilide, oleuropein honokiol, genistein, resveratrol, EGCG methylsulfonyl aglycone (II), tyrosol, extract from the bark of Magnolia methane, SAMe, collagen hydrolysate, collagen, ascorbyl officinalis, magnolol, honokiol, genistein, resveratrol, EGCG phosphate, lycopene, lutein, zeaxanthin, fl-cryptoxanthin, methylsulfonylmethane, SAMe, collagen hydrolysate, col Devil’s Claw, milk protein concentrate, solubilized keratin, lagen, ascorbyl phosphate, lycopene, lutein, zeaxanthin, celery seed extract, cetylated fatty acids, carnitine, thymo fl-cryptoxanthin, Devil’s Claw, milk protein concentrate, quinone, 2-hydroxy-4-methoxy-3-(2-hydroxy-3-methyl-3 solubilized keratin, celery seed extract, cetylated fatty acids, butenyl)-6-(2-phenylethyl)-benzoic acid (III), Amorfrutin B carnitine, thymoquinone, 2-hydroxy-4-methoxy-3-(2-hy (IV), Amorfrutin A (V), 2-hydroxy-4-methoxy-3-(3-methyl droxy-3-methyl-3-butenyl)-6-(2-phenylethyl)-benzoic acid 2-butenyl)-6-pentyl-benzoic acid (VI), cannabigerolic acid (III), Amorfrutin B (IV), Amorfrutin A (V), 2-hydroxy-4 monomethyl ether (VII), 2-hydroxy-4-methoxy-3-(2-hy methoxy-3-(3-methyl-2-butenyl)-6-pentyl-benzoic acid droxy-3-methyl-3-butenyl)-6-pentyl-benzoic acid (VIII), (VI), cannabigerolic acid monomethyl ether (VII), 2-hy 3-methoxy-2-(3-methyl-2-butenyl)-5-(2-phenylethyl)-phe droxy-4-methoxy-3-(2-hydroxy-3-methyl-3-butenyl)-6-pen nol (IX), the compound of formula (X) and 2-hydroxy-4 tyl-benzoic acid (VIII), 3-methoxy-2-(3-methyl-2-butenyl) methoxy-5-(2-hydroxy-3-methyl-3-butenyl)-6-(2-phenyl 5-(2-phenylethyl)-phenol (IX), the compound offormula (X) ethyl)-benzoic acid (XI), cardol diene (XII), cardol triene and 2-hydroxy-4-methoxy-5-(2-hydroxy-3-methyl-3-bute (XIII), cashew fruit extract, boswellic acid, carnosic acid, nyl)-6-(2-phenylethyl)-benzoic acid (XI), cardol diene (XII), ursolic acid, horse chestnut extract, diosmetin, tryptanthrin, cardol triene (XIII), cashew fruit extract, boswellic acid, car diosgenin, curcumin and derivatives, Glycyrrhiza foetida and nosic acid, ursolic acid, horse chestnut extract, diosmetin, white willow bark extract. tryptanthrin, diosgenin, curcumin and derivatives, Glycyr rhiza foetida and white willow bark extract. sk sk sk sk sk