WO2002072035A2

WO2002072035A2 - Novel anti-inflammatory compositions and methods of use

Info

Publication number: WO2002072035A2
Application number: PCT/US2002/008191
Authority: WO
Inventors: Ronald H. Lane
Original assignee: Lipogenics, Inc.
Priority date: 2001-03-14
Filing date: 2002-03-14
Publication date: 2002-09-19
Also published as: WO2002072035A3; AU2002252387A1

Abstract

This invention relates to novel anti-inflammatory compositions comprising chromanols and sterols. The compositions of this invention may be used in pharmaceutical compositions, foodstuffs, food additives and dietary supplements. The use of the anti-inflammatory formulations to treat disorders associated with inflammation is also disclosed.

Description

NOVEL ANTI-INFLAMMATORY COMPOSITIONS AND METHODS OF USE

FIELD OF THE INVENTION

This invention relates to novel anti-inflammatory compositions comprising chromanols and phytosterols.

BACKGROUND OF THE INVENTION

Tocotrienols and other chromanols have many well-recognized health benefits, including cholesterol reduction, antioxidant, anti-platelet aggregation and anti-cancer properties (U.S. Pat. No. 5,591 ,712; Lipids, 2000, 35(2):171-80; J. Nutr., 2001 , 31 (2):369S-373S; and Biosci. Biotechnol. Biochem., 1999, 63(3):575 - 576). Tocopherols (such as Vitamin E (d-α-tocopherol)) are well-known anti-inflammatory agents, and have been shown to reduce the production of cytokines in a variety of experimental cell culture and animal studies (J. Nutr., 1998, 128:1657-1660; Biofactors, 1998, 7:15-19; BBS, 1998, 1404:427-34; and, J. Clin. Invest, 1996, 98:756-753). Cytokines (such as tumor necrosis factor (TNF) and interleukins (e.g., IL-1 and IL-6)) are cellular peptide mediators that regulate inflammatory response. Tocotrienols have been shown to reduce elevated levels of TNF (Brit. J. Nutr., 1993, 69:159-16 7). Although the anti-inflammatory properties of tocotrienols have been noted elsewhere (U.S. Pat. No. 5,591 ,772), these are not well- recognized and are generally considered secondary to other activities.

Mixed chromanol preparations rich in tocotrienols are available commercially from a number of different vendors (e.g., Evolve®, from Bionutrics, NuTriene™ from Eastman Chemical Company and Tocovid™ from Carotech, Inc.). In these products, tocotrienols are formulated with other ingredients that provide additional beneficial properties to the composition. Some tocotrienol formulations (including the three commercial products mentioned above) incorporate plant sterols (or phytosterols). In addition to their antioxidant capabilities, phytosterols have been shown to inhibit inflammation, modulate the effects of the immune system, and block cholesterol absorption {Biol. Pharm. Bull., 1995, 18(11 ):1617-1619); and Nahrϋng, 2000, 44(5):373-374). Phytosterols and phytosterol-like compounds reduce the number and chemotaxis of neutrophils (neutrophilia) associated with inflammatory responses (Z. Naturforsch., 1999, 54(11 ):93741 ). This results in lower superoxide levels (a principle activated neutrophil product) with its sequential impact on the cytokine cascade.

As a result of focusing on cholesterol reduction and anti-oxidation, the relative amount of tocotrienols (and other chromanols) to phytosterols (and phytosterol-like compounds) in currently available commercial preparations do not optimize the anti- inflammatory benefits. Accordingly, there remains a need for new formulations comprising tocotrienols (and other chromanols) and phytosterols (and phytosterol-like compounds) present in relative amounts that provide improved anti-inflammatory activity.

SUMMARY OF THE INVENTION

Thus, it is an object of this invention to provide a formulation comprising sterols (and sterol-like compounds) and chromanols, wherein the sterols (and sterol- tike compounds) to chromanols ratio is at least about 1.1 :1.

It is another object of this invention to provide a formulation comprising sterols (and sterol-like compounds) and tocotrienols, wherein the sterols (and sterol-like compounds) to tocotrienols ratio is at least about 2:1.

It is yet another object of this invention to provide methods for using these formulations to inhibit inflammation and to treat and prevent disorders associated with inflammation.

DETAILED DESCRIPTION OF THE INVENTION

The term "chromanol" refers to a class of chemical compounds which possesses a chromane ring "head" attached to a saturated, partially unsaturated, or fully unsaturated hydrocarbon "tail". Chromanols may be synthetic or natural. Naturally occurring chromanols are presently preferred. Presently preferred tails are saturated, partially unsaturated, and unsaturated pyhtyl groups (comprising a 16- carbon isoprenoid chain). Particularly preferred chromanols are the eight vitamin E isomers shown below:

The relative amounts of tocopherols and tocotrienols in chromanol mixtures of this invention may be varied with regard to the total amount of tocopherol or tocotrienol or with regard to individual tocopherols or tocotrienols. Such different relative amounts are within the scope of this invention. In general, chromanol mixtures having higher tocopherol content tend to be more cost effective. However, under any circumstance, the mixture should comprise at least about 5%, preferably at least about 15%, more preferably at least about 20%, and most preferably at least about 25% tocotrienols for maximum anti-inflammatory activity.

As used herein, the term "effective amount" refers to an amount sufficient to inhibit oxidative stress, to inhibit inflammation, or to treat or prevent a disorder associated with oxidative stress or inflammation. An effective amount of an anti- inflammatory agent of this invention may be considered in combination with other anti-inflammatory agents included in a particular formulation herein.

As used herein, the term "about" means within ± 20% of the indicated amount.

The term "formulation," as used herein, refers to a composition prepared in a manner for administration by any acceptable route known to those of ordinary skill in the art. Such routes include, but are not limited to, oral, parenteral, transdermal, intravenous, inhalation or topical administration. "Formulation" encompasses pharmaceutical compositions as well as dietary supplements, foodstuffs, food additives, inhalers, cosmetic preparations and the like. Although in general, the term "composition" refers to a crude mixture of component ingredients, while "formulation" refers to a finished material, the terms "composition" and "formulation" are sometimes used interchangeably herein.

The terms "sterol" and "phytosterol" are used interchangeably herein to refer to natural or synthetic oligoglycosylsterols, sterylglycosides, sterylglucosides, sterolins or lupane-type triterpene derivatives. In nature, these compounds are typically found in the unsponifiable fraction of hexane or methanol extracts of plants and are sometimes included within the saponin family. Preferred sterols include brassicasterol, campesterol, stigmasterol, β-sitosterol, campostanol, 9,19- cycloanosterol, delta 5-avenasterol, delta 5,24-stigmastadienol and delta 7- avenasterol, oxygenated stigmastane-type sterols, stigmastane-3β, 6α-diol, stigmastane-3β, 6β-diol, 7α-hydroxysitosterol and its diacetyl derivative, 7β- hydroxysitosterol and its diacetyl derivative, 7-oxositosterol, 4-β-hydroxysitosterol, and stigmast-4-ene-3β, 6β-diol, sitosterol ferulate, 24-methylcholesterol ferulate, cycloartenol ferulate and 24-methylenecycloartanol ferulate, ergosterol, 7- dehydroporiferasterol, ergosterol peroxide, 7-dehydroporiferasterol peroxide, and 7- oxocholesterol.

"Sterol-like" or "phytosterol-like" compounds include stable analogs such as stanols, sterolins (or any glycated sterol), dienes, trienes, esters, epoxides or similar substitution or addition products thereof. Presently preferred sterols are campesterol, stigmasterol and β-sitosterol. Presently preferred sterol-like compounds are stanol, sterolin (or any glycated sterol), diene, and triene analogs of campesterol, stigmasterol and β-sitosterol.

The term "tocotrienol" refers to a compound possessing the following structural characteristics: (1 ) a hydrogen donor group (or a group that can be hydrolyzed to a hydrogen donor group) attached to an aromatic ring system; (2) a side chain attached to the aromatic ring system comprising one or more isoprenoid or isoprenoid-like groups; and, (3) a group, or atom having at least one lone pair of electrons, in or attached to the non-aromatic ring adjacent to the atom to which the side chain is attached. The electrons are preferably conjugated with the π-electron system of the aromatic ring. Presently preferred groups and atoms include, CH₂, C=O, CH₂OH, O, S or NH). Presently preferred tocotrienols for use in this invention are the naturally occurring α-, β-, γ- and δ-tocotrienol. The term "tocotrienol" may refer to a single tocotrienol or a mixture of tocotrienols. Naturally occurring tocotrienols may be conveniently isolated from biological materials or synthesized from commercially available starting material. The tocotrienols for use in the methods of this invention may be obtained from biological materials that have been stabilized and extracted by the processes described in PCT publication WO 91/17985 and U.S. Patent No. 5,908,940, both of which area incorporated by reference, including any drawings, as if fully set forth herein. Examples of biological materials from which naturally- occurring tocotrienols can be obtained and examples of synthetic tocotrienols and how to make them are described in U.S. Pat. Nos. 5,591 ,772 and 5,821 ,264 and PCT publication WO 91/17985, each of which is likewise incorporated by reference, including any drawing, as if fully set forth herein. Presently preferred biological materials from which tocotrienols can be isloated are stabilized brans, particularly stabilized rice bran.

This invention expressly encompasses prodrugs of tocotrienols and other ingredients included in the formulations of this invention. Upon administration, a prodrug undergoes biotransformation to its active form. Prodrugs include salts and esters of the tocotrienols and other ingredients that may be included in the formulations of this invention.

Tocotrienols, tocopherols and other ingredients in the formulations of this invention that have at least one chiral center may be used in an isomerically pure form or as a mixture of isomers. For example, tocotrienols exist and may be used as an enantiomerically pure d- or l-isomer or a d,l-racemate. The naturally occurring isomer (usually the d-isomer) and the d,l-racemic mixture are preferred.

Without wishing to be bound to any particular theory, it is thought that the compositions of this invention may enhance anti-inflammatory activity through a synergy between the various components of the compositions. For example,, by reducing the level of inflammatory cytokines (such as TNF and IL-1 ) with tocotrienols and/or other chromanols while simultaneously reducing the number and activity of neutrophils with phytosterols and sterol-like compounds, a synergy is created that reduces chronic elevations of inflammatory factors of the autoimmune system. Inhibition of superoxide may also play a critical role in the synergistic, anti- inflammatory effect between sterols and chromanols. By reducing superoxide and other undesirably factors such as those mentioned above, the compositions herein are suitable for inhibiting oxidative stress and treating diseases associated therewith, and treating pathological inflammation and autoimmune diseases. Because phytosterols tend to be somewhat more active than chromanols in eliciting an anti- inflammatory response, a ratio of sterol (and sterol-like compounds) to chromanols of at least about 1.1 :1 and a ratio of sterol (and sterol-like compounds) to tocotrienols of at least about 2:1 has been determined to optimize the anti-inflammatory activity of compositions herein. These component ratios represent substantially greater amounts of sterols (and sterol-like compounds) compared to commercially available products. In a presently preferred embodiment, the ratio of sterol (and sterol-tike compounds) to chromanols is from about 1 :1 to about 6:1 , more preferably from about 1 :1 to about 4:1 , and most preferably from about 1.1 to 2.5:1. In another presently preferred embodiment, the ratio of sterol (and sterol-like compounds) to tocotrienols is from about 2:1 to about 200:1. More preferably it is from about 2:1 to about 100:1. Even more preferably, it is from about 2:1 to about 20:1. At present, it is most preferably from about 2:1 to about 4:1.

Compositions and formulations of this invention are prepared by providing an effective amount of tocotrienols and/or other chromanols, sterols and sterol-like compounds in the proportions recited herein. These compositions and formulations may be prepared by combining individual components (which may be purchased commercially or obtained by extraction or other techniques known to those of skill in the art). The compositions according to this invention are preferably prepared from natural extracts of biological materials. Presently preferred biological materials include those obtained from conifers, legumes, asteraceae, poaceae and palmae. More specifically, they include, without limitation, tocotrienol-rich extracts from stabilized brans (stabilized rice bran in particular), psyllium seed, barley, pine nut, sunflower, peanut, palm fruit, millet, avocado, olive, juniper berries, cedar leaves, mango, cranberry seeds, pine needles, rubber tree leaves, tomato, amatto, and amaranth.

Acceptable carriers for use in the formulations of this invention are non-toxic for the mode, and at the level, of administration and do not destroy the activity of the active components of the formulation. Such carriers are well known to those of ordinary skill in the art.

The compositions and formulations according to this invention may be used alone, in combination with other inflammatory agents, or with other agents that have other complementary activities. The additional agents may be formulated with the compositions described herein or may be administered separately. For example, immunonutrition agents may be administered in combination with the compositions of this invention. Immunonutrition agents that may be used with the formulations of this invention include: cell membrane modeling fatty acids (including, but not limited to, omega-3 eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), omega-6 gamma-linolenic acid (GLA), alpha-linolenic acid (ALA), and conjugated linoleic acid (OLA)), immunosuppressant flavonoids (including, but not limited to, luteolin, luteolin- 7-glucoside, flavopiridol, catechins, genistein, fisetin, rutin, epigallocatechin 3- gallate.quercetin, eriodictyol and hesperetin), and peroxisome proliferator-activated receptor-gamma (PPAR-δ) binding agents (including, but not limited to, troglitazone). These compounds have been shown to inhibit both LPS-stimulated TNF-alpha and interleukin-6 release, and production of proinflammatory eicosanoids. Proinflammatory icosanoids, prostaglandin E(2) (PGE(2)) and leukotriene B(4) (LTB(4)) are derived from arachidonic acid (AA), which is maintained at high cellular concentrations by the high n-6 and low n-3 polyunsatu rated fatty acid content of the modern Western diet. As an example of an immunonutritonal additive, flaxseed oil, which contains alpha-linolenic acid, can be converted after ingestion to eicosapentaenoic acid (EPA). Fish oils contain both 20- and 22-carbon n-3 fatty acids, EPA and docosahexaenoic acid. EPA can act as a competitive inhibitor of AA conversion to PGE(2) and LTB(4), and decreased synthesis of one or both of these eicosanoids has been observed after inclusion of flaxseed oil or fish oil in the diet. Analogous to the effect of n-3 fatty acids, inclusion of the 20-carbon n-9 fatty acid eicosatrienoic acid in the diet also results in decreased synthesis of LTB(4). Regarding proinflammatory cytokines, TNF-α and IL-1 β, studies of healthy volunteers and rheumatoid arthritis patients have shown a 90% or greater inhibition of cytokine production after dietary supplementation with fish oil (J. Investig. Med., 1999, 47(5):246-250; Am. J. Clin. Nutr., 2000, 71 (1 Suppl):343S-348S). Excess production of PGE2 is linked to osteoporosis and arthritis and is associated with bone and proteoglycan loss. Therefore, administration of immunonutrition agents (including without limitation the cell membrane modeling fatty acids, immunosuppressant flavonoids, and peroxisome proliferator-activated receptor-gamma binding agents listed above) in combination with the compositions of this invention, may provide additional benefits and/or enhanced anti-inflammatory effects.

The formulations of this invention may be used to inhibit inflammation in a patient and to treat or prevent disorders associated with inflammation. Presently preferred disorders associated with inflammation that may benefit from the compositions of this invention include, but are not limited to, those described in U.S. Pat. No. 5,591 ,772, which is incorporated by reference, including any drawings, as if fully set forth herein. These disease and disorders include, but are not limited to inflammatory and autoimmune diseases of endocrine, hematopoietic, neuromuscular, cardiopulmonary systems, systemic, cardiovascular and diabetic diseases, and the inflammatory disorders of the skin (such as psoriasis, eczema and pathology or damage associated with burns, UV exposure, and aging). Presently preferred disorders associated with inflammation that may be treated according to this invention include gastrointestinal disorders such as, inflammatory bowel disease and acute pancreatitis; rheumatic conditions such as osteoarthritis, systemic lupus erythematosis, panarteriitis, spondylarthritis, and gout; cardiovascular disorders such as atherosclerosis and thrombophlebitis; neurological disorders such as Alzheimer's disease and nephrological disorders such as interstitial nephritis. In a presently preferred embodiment of this invention, the disease associated with inflammation is an autoimmune disorder. More preferably, the autoimmune disorder is selected from the group consisting ofi alopecia areata; ankylosing spondylitis, antiphospholipid syndrome, autoimmune Addison's disease, autoimmune hemolytic anemia, autoimmune hepatitis, autoimmune neutropenia, autoimmune oophoritis, autoimmune orchitis, autoimmune polyneuritis, autoimmune thrombocytopenia, Behcet's disease, bullous pemphigoid, cardiomyopathy, celiac sprue-dermatitis, chronic fatigue immune dysfunction syndrome (OFIDS), chronic inflammatory demyelinating polyneuropathy, Churg-Strauss syndrome, cicatricial pemphigoid, circulating anticoagulants, CREST syndrome, cold agglutinin disease, Crohn's disease, discoid L upus, Dressler's syndrome, essential mixed cryoglobulinemia, experimental allergic encephalomyelitis, fibromyalgia-fibromyositis, Graves' disease, Guillain-Barr6 disease, Hashimoto's thyroiditis, idiopathic pulmonary fibrosis, idiopathic thrombocytopenia purpura (ITP), IgA nephropathy, insulin dependent diabetes, juvenile arthritis, Lichen Planus lupus, M6ni&e's disease, mixed connective tissue disease, multiple sclerosis, myasthenia gravis, paroxysmal cold hemoglobinuria, pemphigus vulgaris, pernicious anemia, polyarteritis nodosa, polychondritis, polyglandular syndromes, polymyalgia rheumatica, polymyositis, dermatomyositis, primary Agammag-lobulinemia, primary biliary cirrhosis, psoriasis, pulmonary hemorrhage and nephritis, pure red cell anemia, Raynaud's phenomenon, Reiter's syndrome, rheumatic carditis, rheumatic fever, rheumatoid arthritis, sarcoidosis, scleroderma, Sjdgren's syndrome, stiff-man syndrome, Takayasu arteritis, remporal arteritis/giant cell arteritis, ulcerative colitis, uveitis, vasculitis, vitiligo, and Wegener's granulomatosis.

Anti-inflammatory activity may be measured using techniques well known to those of ordinary skill in the art. For example, anti-inflammatory activity may be measured in vivo by treating an animal, such as a mouse, rat or pig, with a test composition, then stimulating an inflammatory response with a cytokine-inducing agent, such as liposaccharide (LPS), that increases production of inflammatory cytokines such as IL-1 or TNFα, which can then be measured in plasma (plasma normally does not contain detectable amounts of these substances). Alternatively, cell culture systems provide a broad selection of cell types for study, including those cells primarily involved in cytokine release (including monocytes, neutrophils, macrophages, endothelial cells, and B and T lymphocytes). These cells can either be harvested from animals that had been pretreated with the test composition or exposed to the test composition in culture. Cultures that may be particularly useful (due to their susceptibility to chromanol modulation of cytosine production) include human monocytes and neutrophils, human aortic endothelial cells, human umbilical vein endothelial cells, human leukemia cells, rat peritoneal macrophages and mouse splenocytes. The formulations of this invention may be administered by any acceptable means to inhibit inflammation and to treat or prevent disorders associated with inflammation. For example, formulations of this invention may be administered orally, topically, transdermally, parenterally, intravenously or by inhalation. The formulations of this invention may be used in pharmaceutical compositions, foodstuffs, food additives and dietary supplements. Formulations may be also be produced so as to impart a timed-release benefit. Oral compositions may be formulated as tablets, capsules, caplets, emulsions, liposomes, suspensions, powders, drinks, drink mixes, snack bars, other foodstuffs, dietary supplements or in any other orally acceptable administration form which, based on the disclosures herein, will become apparent to those skilled in the art. Any such oral administrative approach is within the scope of this invention.

Topical compositions include, but are not limited to, gels, lotions and creams.

Parenteral compositions may be formulated as sterile solutions, emulsions and the like.

Inhalation compositions may be either dry or liquid and may be adminstered using a mechanical inhaler device.

Intravenous compositions include, but are not limited, to sterile solutions.

Presently preferred route of administration of the compositions herein is oral or, in the case of treatment of the skin, topical.

The dosage levels for each of the components (within the relative ranges disclosed) may be determined by methods known to those of skill in the art. In some cases, guidance may be gleaned from published recommended daily allowances. Presently preferred formulations are designed for once a day, oral administration. The dosage form may, if desired, be devided up for more than once a day dosing. Preferred dosage levels are between about I and about 1000 mg, more preferably between about 10 and 500 mg, and most preferably between 10 and 100 mg of tocotrienol per dose. Tocopherols are administered in about the same general dosage levels as the tocotrienols. The relative amounts of tocopherols and tocotrienols may be varied and formulations having more or either or of individual tocopherols or tocotrienols are within the scope of this invention. For phytosterols, dosage levels are between about 2 and about 2000 mg, more preferably between about 20 and 2000 mg, and most preferably between 40 and 400 mg per dose. In all cases, the actual amounts of each individual ingredients is subject to the previously expressed ratio of sterols (and sterol-like compounds) to chromanols of at least about 1.1 :1 or the ratio of sterols (and sterol-like compounds) to tocotrienols of at least about 2:1. Multiple doses may be required to obtain the maximum anti-inflammatory benefit. Specific dosage and treatment regimens will depend upon factors such as the patient's overall health status, the severity and course of the patient's disorder or disposition thereto and the judgment of the treating physician. Higher or lower doses may be employed as needed. EXAMPLES

The following examples are provided for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way. Example 1 : Preparation of Sterol/Chromanol Composition

Rice bran (approx. 1 ,000 tons) was heated and extracted with hexanes according to the method described in U.S. Pat. No. 5,908,940, which is incorporated by reference, including any drawings, as if fully set forth herein. The hexanes were removed by evaporation. The concentrated rice bran extract was degummed, dewaxed and deodorized using the process described in US patent 5,908,940. The material (approx. 400,000 pounds) was distilled in a three-stage molecular still to strip off free fatty acids and vegetable oil residue (VaR). The second stage, middle cut (approx. 20,000 pounds) was isolated and characterized by an acid value (AV) of 20 mg of KOH/g of fat; a saponification number (SN) of 180 mg of KOH/g of fat and a total of 40 mg of actives/g of fat.

The above fraction was saponifed with sodium hydroxide (2572 pounds) in 40,000 pounds of water, then neutralized with 5480 pounds of 50% aqueous H₂SO . Anti-foaming agent was added as needed. The reaction was carried out by charging a clean reactor with water and the the rice bran fraction at room temperature. The mixture was agitated and degassed under vacuum while heating to 70° C. As soon as the temperature reached 70° C, the vacuum was release with N₂. A reflux condenser was added to the vessel and aqueous NaOH was added to saponify the glycerides. The infrared (IR) spectrum of the mixture was checked every hour until the ester band has disappeared. The reaction mixture was then washed twice with hot water (2 x 600 lbs.). The aqueous layer was then separated. The pH of the residue was adjusted to 6.0 with cold aqueous sulfuric acid and washed a final time with hot water (600 lbs). The saponified material was then esterified by refluxing it with anhydrous MeOH (7000 pounds) and a catalytic amount (40 pounds) of H₂SO₄. Excess MeOH was distilled off and the remaining material was washed with water (600 lbs.) followed by addition of 5% aqueous NaHCO₃ (600 lbs.) until a pH of 7.0 was obtained. A vacuum was then applied to the tank until the material was fully dehydrated. Approximately 19,000 pounds of esterified distillate was recovered.

Fatty acid methyl esters were removed under the following conditions: evaporator temperature 160° C, evaporator pressure 0.1 mm, condenser temperature 25°C, distillate 60 - 65%, residue 35 - 40%. Then, the chromanol/sterol fraction was recovered under the following conditions: evaporator temperature 240° C, evaporator pressure 30 mm, condenser temperature 25° C, distillate 60 - 80%, residue 20-40%. Approx. 5,000 pounds of sterol/chromanol composition was obtained.

The composition was analyzed by Intertek Testing Services (New Orleans, LA):

Tocotrienols 6.8%

Tocopherols 16.8 %

Phytosterols 46.1 %

Other 30.3% While a number of specific embodiments of this invention have been described herein, it is apparent that the basic constructions may be altered to provide other embodiments that utilize the formulations and methods of this invention. Such alterations are within the scope of this invention. Other embodiments of this invention are provided in the claims that follow.

Claims

WHAT IS CLAIMED:

1. A composition, comprising sterols (and sterol-like compounds) and chromanols, wherein the sterols (and sterol-like compounds) to chromanols ratio is at least about 1.1 :1.

2. A composition, comprising sterols (and sterol-like compounds) and tocotrienols, wherein the sterols (and sterol-like compounds) to chromanols ratio is at least about 2:1.

3. The composition according to claim 1 or 2, wherein the composition comprises from about 10 to about 500 mg of tocotrienol.

4. The composition according to claim 1 or 2, wherein the composition comprises from about 20 to about 2000 mg of sterol and sterol-like compounds.

5. The composition according to claim 1 or 2, where the sterol-like compounds are selected from the group consisting of: stanols, sterolins (or a glycated sterol), dienes, trienes, and esters and epoxies of any of the preceding.

6. The composition according to claim 1 or 2, wherein the composition is formulated as a capsule.

7. The composition according to claim 1 or 2, wherein the composition is formulated as a drink mix.

8. A method for inhibiting inflammation, comprising administering to a patient in need thereof a composition according to claim 1 or 2

9. A method for treating or preventing a condition, disease or disorder associated with inflammation, comprising administering to a patient in need thereof an effective amount of a composition according to claim 1 or 2.

10. A method for inhibiting oxidative stress, comprising administering to a patient in need thereof an effective amount of a composition according to claim 1 or

2.

11. A method for treating a disease associated with oxidative stress, comprising administering to a patient in need thereof an effective amount of a composition according to claim 1 or 2.