EP1370148A1 - Cholesterinspiegelsenkendes speiseöl - Google Patents

Cholesterinspiegelsenkendes speiseöl

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Publication number
EP1370148A1
EP1370148A1 EP01908744A EP01908744A EP1370148A1 EP 1370148 A1 EP1370148 A1 EP 1370148A1 EP 01908744 A EP01908744 A EP 01908744A EP 01908744 A EP01908744 A EP 01908744A EP 1370148 A1 EP1370148 A1 EP 1370148A1
Authority
EP
European Patent Office
Prior art keywords
oil
cholesterol
edible oil
human patient
blood
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP01908744A
Other languages
English (en)
French (fr)
Other versions
EP1370148A4 (de
Inventor
Christopher J. Berry
Marvin L. Bierenbaum
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
MLB Enterprises LLC
Redeem Inc
Original Assignee
MLB Enterprises LLC
Redeem Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by MLB Enterprises LLC, Redeem Inc filed Critical MLB Enterprises LLC
Publication of EP1370148A1 publication Critical patent/EP1370148A1/de
Publication of EP1370148A4 publication Critical patent/EP1370148A4/de
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
    • A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
    • A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/105—Plant extracts, their artificial duplicates or their derivatives
    • A23L33/11—Plant sterols or derivatives thereof, e.g. phytosterols
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/115—Fatty acids or derivatives thereof; Fats or oils
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the present invention relates to an edible oil that is useful in improving blood lipid levels in a human patient, and to methods for making and using the oil.
  • cholesterol levels are the major predictors of cardiovascular disease.
  • Cholesterol a soft, waxy substance found among the lipids in the blood stream, is an important part of a healthy body because it is used to form cell membranes, some hormones and other needed tissues.
  • a high level of cholesterol in the blood hyper- cholesterolemia
  • coronary heart disease which leads to heart attack.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • Low-density lipoprotein is the major cholesterol carrier in the blood. Excess LDL cholesterol circulating in the blood can slowly build up within the walls of the arteries feeding the heart and brain. Together with other substances it can form plaque, a thick, hard deposit that can clog those arteries. This condition is known as atherosclerosis. The formation of a clot (or thrombus) in the region of this plaque can block the flow of blood to part of the heart muscle and cause a heart attack. If a clot blocks the flow of blood to part of the brain, the result is a stroke. A high level of LDL cholesterol reflects an increased risk of heart disease. Thus, LDL cholesterol is often called "bad cholesterol. "
  • High density lipoprotein (“HDL”) carries about one-third to one-fourth of blood cholesterol. It is believed that HDL carries cholesterol away from the arteries and back to the liver, from which it is ultimately passed from the body. Some experts believe HDL removes excess cholesterol from atherosclerotic plaques and thus slows their growth. HDL is known as "good cholesterol” because a high level of HDL seems to protect against heart attack. The opposite is also true: a low HDL level indicates a greater risk.
  • Cholesterol comes from two sources. It is produced in the body, mostly in the liver (about 1 ,000 milligrams a day), and is also found in foods that come from animals, such as meat, poultry, fish, seafood and dairy products. Foods from plants (fruits, vegetables, grains, nuts and seeds) do not contain cholesterol.
  • Saturated fatty acids are the chief culprit in raising blood cholesterol, which increases the risk of heart disease. But dietary cholesterol also plays a part.
  • the average American man consumes about 360 milligrams of cholesterol a day; the average American woman, between 220 and 260 milligrams.
  • LDL low-density lipoprotein
  • HDL high-density lipoprotein
  • triglycerides in the blood.
  • Cholesterol and triglyceride levels can be reduced through medical intervention and/or dietary modification, such as reduction of the dietary intake of cholesterol and saturated fats.
  • some dietary modifications have given rise to new problems.
  • the substitution of margarine for butter has been promoted. Butter is high in cholesterol and saturated fats.
  • Stick margarine has a semi-solid consistency based on their content of hydrogenated oils. The hydrogenation process, however, forms trans fats.
  • Clinical studies have demonstrated that trans fats are atherogenic, causing two to three times the cardiovascular risk of the naturally saturated fats which give butter its stability.
  • the health advantage of margarine over butter is now suspect in that margarine, particularly stick margarine, can contain 20% to 30% of trans fats.
  • plant sterols particularly beta-sitosterol
  • beta-sitosterol have been reported to have anticholesterolemic effects, and are believed to inhibit cholesterol absorption in the small intestine.
  • Plant sterols are thought to displace cholesterol in bile salt micelles. Approximately half of the dietary cholesterol ingested is absorbed whereas less than 5 % of beta-sitosterol is absorbed. When the plant sterols displace cholesterol of the bile salt micelles, the cholesterol is fecally excreted.
  • Plant sterols exist naturally in saturated and unsaturated forms, as free alcohols and as esters. The unsaturated forms dominate. It is known that natural sitosterols may be converted to sitostanols by hydrogenation, and it has been reported that stands are more effective per unit weight than sterols in blocking cholesterol absorption and that stanols are not absorbed. Further, the amount of beta-sitosterol absorbed appears to be relatively constant even when doses administered vary by an order of magnitude. Both sterols and stanols have been used as relative markers of cholesterol absorption because of their unabsorbability. However, it seems clear that while sitostanol is completely unabsorbed, some sitosterol is.
  • sitostanol to the diet reduces not only cholesterol absorption but also sitosterol and vitamin absorption. Some have characterized this as an advantage, but the fact that sitostanols block the normal absorption of micronutrients may be problematic.
  • sitostanols alone as an anti-cholesterolemic thus may increase the risk of BPH.
  • tocotrienols which are natural forms of vitamin E found in wheat germ, rice bran, oats and palm.
  • HMGCoA reductase 3-hydoxy- 3-methyl-glutaryl coenzyme A reductase
  • statins also sometimes cause liver dysfunction.
  • statins 80% of patients taking statins as a monotherapy failed to reach treatment goals. With respect to statins, increasing the dosage to the levels frequently required to overcome compensatory increase in cholesterol absorption, produces an 1 1 - fold increase in the incidence of liver complications as noted above. Because of the risk of liver complications, statins must be taken under a doctor's supervision. Similarly, while tocotrienols have shown promise in vitro, the results of clinical trials have been equivocal. Qureshi, Am. J Clin. Nutr. 53: Suppl.
  • Benecol that contains hydrogenated plant sterols extracted from pulp and paper waste, has been found to achieve a 10-1 5% reduction in cholesterol levels in patients substituting Benecol margarine for standard margarine in their diets. This reduction corresponds to a twenty to thirty percent decrease in cardiovascular risk.
  • Benecol suffers from the disadvantage that the plant sterol extracts require regulatory approval in the United States and other countries as a new food additive.
  • Toxic forms of oxygen have been associated with many chronic, debilitating diseases. These include cardiovascular, neoplastic, arthritic, age related macular degenerative and progeria, among others. As tissue levels of these toxic forms of oxygen rise, tissue levels of protective antioxidants, such as antioxidants of the vitamin E family, decline. These risk factors have been confirmed in the case of cardiovascular disease by Gey, who showed that as blood vitamin E values decrease in a population, the incidence of ischemic heart disease rises. To assess the blood levels of peroxides, many researchers have measured adducts of thiobarbituric acid (a.k.a TBARS, thiobarbituric acid reactive substances, also called malonaldehyde modified material), or peroxides.
  • thiobarbituric acid a.k.a TBARS, thiobarbituric acid reactive substances, also called malonaldehyde modified material
  • malonaldehyde- modified LDL as a marker of acute coronary syndromes.
  • TBARS malonaldehyde
  • Other commonly used indices such as troponin I.
  • TBARS material decreased significantly from pre-study values. See: Tomeo, A. C, el al. Antioxidant effects of tocotrienols in patients with hyperlipidemia and carotid stenosis.
  • an edible oil that is trans-free, low in saturated fats and suitable for use in the manufacture of margarine.
  • the edible oil does not require additives that must be chemically processed (e. g., hydrogenated).
  • an edible oil that reduces the synthesis and absorption of cholesterol by the human patient and promotes the excretion of cholesterol from the human patient.
  • the edible oil is substantially free of trans fatty acids.
  • the inventive oils are vegetable oil or mixtures of vegetable oils.
  • the inventive oils are refined rice bran oils or mixtures of rice bran and palm oils.
  • a method of making an anticholesterolemic edible oil includes the steps of providing an edible oil, and adjusting the content of tocopherols, tocotrienols, free sterols * , stejyl esters and cycloartols of the edible oil such that the oil, when consumed at a pre-selected dosage and in a pre-selected dosage form, provides on a daily basis about 25 to 750 mg of tocopherols, tocotrienols or combinations thereof, about 5 to about 500 mg of steryl esters, and about 5 to about 500 mg of cycloartols.
  • a crude vegetable oil (“Oil A”), in particular a crude rice bran oil, is dewaxed and degummed, and held under vacuum at elevated temperature. Free fatty acids are then removed from Oil A at mild pH using an alkaline hydrous sodium silicate and small quantities of potassium hydroxide so that the free fatty acids are converted to soap (saponified) at conditions which minimize the loss of esters of sterols and cycloartenols to the soap stock.
  • a tocotrienol-rich distillate preferably a rice bran or palm oil deodorizer distillate
  • is substantially saponified preferably in isopropanol
  • the non-saponifiable fraction is extracted, preferably with hexane and water to yield an extract ("Oil B" ).
  • Oil A and Oil B are mixed to produce a product having the desired concentration of tocopherols, tocotrienols, free sterols, steryl esters and cycloartenols.
  • Cholesterol levels in the human body are regulated by three concurrent mechanisms, namely synthesis, absorption and excretion. Most known anticholesterolemic compounds and compositions target only one of these mechanisms, and thus must have a relatively large impact on the targeted mechanism in order to function. Edible oils according to the present invention reduce the synthesis and absorption of cholesterol while increasing the excretion of cholesterol. All three mechanisms are affected simultaneously, resulting in a gentle, balanced improvement in LDL, HDL and triglyceride levels.
  • Reductions and increases in cholesterol synthesis, absorption and excretion in human patients are determined by comparison with the same quantities measured in human patients before and after administration of edible oils according to the invention.
  • the edible oils can be characterized as "functional foods," as opposed to drugs or nutraceuticals.
  • Functional foods have been defined by the European Union as “ordinary foods processed or modified in such a way that they have scientifically documented health promoting effects and can be marketed with a health claim.”
  • “functional foods” are defined as ordinary foods that are derived only from naturally occurring ingredients and that are consumed as part of the diet and not in supplement form (i.e., not as tablets or capsules).
  • the edible oil according to the invention includes at least one compound that reduces cholesterol synthesis in a human patient, such as at least one tocotrienol.
  • compounds that reduces cholesterol synthesis in a human patient such as at least one tocotrienol.
  • tocotrienol include ⁇ -tocotrienol, ⁇ - tocotrienol, ⁇ -tocotrienol and ⁇ -tocotrienol.
  • the edible oil also preferably includes at least one compound that reduces cholesterol absorption in a human patient, for example, at least one free sterol or steryl ester.
  • Specific compounds useful according to the invention include ferulic and fatty acid esters of campesterol, ⁇ -sitosterol and other sterols and stanols.
  • At least one compound that promotes cholesterol excretion in a human patient is at least one compound that promotes cholesterol excretion in a human patient.
  • Such compounds include cycloartol esters of ferulic acid (C 10 H 10 0 4 ), variously referred to as 3-(4- hydroxy-3-methoxyphenyl)-2-propanoic acid, 4hydroxy-3-methoxy-cinnarnic acid or 3-methoxy-4-hydroxy-cinnamic acid.
  • Specific examples of these compounds include ferulic esters of 24-methylene-cylcoartenol and cycloartenol.
  • the edible oil preferably attenuates the accumulation in and blood level of peroxidized lipid ⁇ and other substrates, such as protein, carbohydrate and nucleic acid-called peroxides, but also called on analysis TBARS (thiobarbituric acid reactive substances) and malonaldehyde-like compounds (i.e., TBA), known cardiovascular risk factors.
  • peroxidized lipid ⁇ and other substrates such as protein, carbohydrate and nucleic acid-called peroxides, but also called on analysis TBARS (thiobarbituric acid reactive substances) and malonaldehyde-like compounds (i.e., TBA), known cardiovascular risk factors.
  • the edible oil provides at least one compound which limits the formation and accumulation of TBARS, and similar peroxidation adducts, in a human patient.
  • the edible oil also provides vitamin-E like activity, whether derived from the tocotrienol or tocopherol family, which confers antioxidant activity to tissues, such as the blood, which can be measured as tocotrienol or tocopherol.
  • At least one compound in the oil is derived from the tocotrienol or tocopherol family (as described in detail herein), which results in elevated serum tocopherol or tocotrienol levels in the blood of a human patient at risk of cardiovascular disease.
  • the tocopherols, tocotrienols, sterols, steryl esters and cycloartols employed according to the invention are preferably derived from natural sources, but can also be synthetically produced, if desired.
  • one or more of the ingredients can be synthetic or can be derived from a source other than the vegetable oil base.
  • the inventive oil is substantially free of trans fatty acids.
  • substantially free as used herein means less than about 2% (weight/weight).
  • the inventive oil includes no trans fatty acids. It has been discovered in clinical trials that the optimal ratio of (i) tocotrienols and/or tocopherols to (ii) free sterols and/or steryl esters to (iii) cycloartols ranges from about 1 :0.5:0.05 to 1 :5 :0.5, and very preferably is about 1 : 1 :0.05. Thus, in a preferred embodiment, the ratio of the foregoing ingredients in the inventive oil falls within this preferred range, and optimally is about 1 : 1 :0.05.
  • the amount of tocopherols and tocotrienols administered to a human patient preferably ranges from about 50 to 500 mg per day, or alternatively, about 1 0 to 200 mg/dosage unit.
  • the amount of sterols and steryl esters likewise preferably ranges from about 50 to 500 mg/day.
  • the amount of cycloartols preferably ranges from about 2.5 to 25 mg per day.
  • a human patient is administered about 400 milligrams of tocopherols and tocotrienols, 400 milligrams of sterols and steryl esters and 20 milligrams of cycloartols. This corresponds to the preferred ratio of ingredients of about 1 : 1 :0.05.
  • the percentages of the various ingredients in the inventive oil can vary within a wide range, so long as the proportions of the ingredients are within the stated ranges and the patient consumes a total amount of each ingredient within the stated ranges each day.
  • the edible oil according to the invention is a vegetable oil, in particular a refined rice bran oil or a mixture of refined rice bran oil and palm oil.
  • the edible oil is a refined rice bran oil.
  • Crude rice bran oil contains the highest percentage of non-saponifiables of any commercial vegetable oil. Total non-saponifiables often exceed 4% (by weight), approximately four times more than the oils currently used in margarine manufacture.
  • Crude rice bran oil is preferably refined for use according to the invention.
  • a particularly active lipase enzyme is activated which causes a very rapid increase in free fatty acids.
  • free fatty acid (FFA) levels of 5 to 10% are common; industrial rice bran oils may have FFA levels as high as 30% .
  • FFA levels are also high and generally related to the temperature at which the bran is extracted with solvent.
  • Rice bran oil thus is among the most challenging of oils to refine.
  • Industrially, rice bran oil is processed by chemical refining.
  • Palm oil another useful source of tocotrienols, also has high FFA levels because palm fruit releases a lipase enzyme when bruised. FFA levels of palm oil range from 2% to 5 %. Most commercial production of palm oil uses physical refining processes. However, such refining methods produce low-grade distillates of low tocopherol/tocotrienol concentration, typically 3,000 - 5,000 ppm. Deodorizer distillates obtained from chemical refineries are of higher concentration, typically 1 to 3% tocopherol/tocotrienol. However, during the chemical refining process, the ferulic and fatty acid esters of sterols and cycloartols are ionized and lost to the soap stock.
  • Free sterols, and triterpene alcohols are soluble to various extents in both polar and non-polar solvents, whereas non-polar solvents are selective with respect to their esters of fatty acids and ferulic acids. These molecules are structurally similar to cholesterol. In the ester form they more readily displace cholesterol from the micelles in the digestive tract, but are themselves not absorbed, or if absorbed, quickly excreted.
  • Known processes for production of tocopherol and tocotrienol-rich fractions from deodorizer distillates include processes such as ion exchange, saponif ication and extraction from hard soap, methyl esterification, esterification of free fatty acids and molecular distillation, and desterolization.
  • the method of separation of tocotrienol-rich concentrates purposely or incidentally removes the natural steryl esters of ferulates and cycloartenols.
  • tocotrienol content ranged between 72 ppm and 1 1 57 ppm, with an average of 500 ppm. More than 95% of the oryzanols and 60% of the tocotrienols are lost in conventional refining processes. To obtain effective amounts of the anticholesterolemic active principles, a patient could be required to consume more than a kilogram of oil per day.
  • the invention thus meets the need for a new process in which the optimal proportions of tocotrienols, steryl esters and cycloartols are retained in the product and the sterols present are substantially in the form of steryl esters whose increased solubility in lipids underlies the efficacy of the compound in decreasing the absorption of dietary cholesterol.
  • the inventive method begins with crude rice bran oil (“Oil A”), which is dewaxed and degummed, and free sterols and triterpene alcohols esterified with free fatty acids.
  • Oil A crude rice bran oil
  • the remaining free fatty acids are then removed under conditions that preserve the esterified state of the sterols and cycloartols, by distillation or at mild pH using an alkaline hydrous sodium silicate and small quantities of potassium hydroxide so that the free fatty acids are converted to soap (saponified) at conditions which minimize the loss of esters of sterols and cycloartols to the soap stock.
  • a tocotrienol-rich deodorizer distillate preferably of rice bran or palm oil
  • isopropanol is substantially saponified in isopropanol and the non-saponifiable fraction is extracted with hexane and water to produce and extract ("Oil B").
  • Oil A and Oil B are mixed to form a product having the required concentration of tocopherols, tocotrienols, free sterols, steryl esters and cycloartenols.
  • preferred embodiments of the edible oils according to the present invention raise no regulatory issues since they naturally contain suitable steryl and stanyl esters, which, unlike Benecol, do not require hydrogenation and chemical processing with attendant risks of trans fatty acid formation.
  • the edible oils according to the invention can be incorporated into a variety of food products, including, without limitation, butter, margarine, ice cream and mayonnaise- chocolate products; liquid such as soybean milk and rice milk- and water-based drinks such as wines and mineral waters.
  • inventive oils are also suitable for encapsulation in gelatin shells to form soft gels. Regardless of the particular form in which the inventive oil is prepared, the daily dosage of the various ingredients to a human patient should fall within the ranges set forth above.
  • the total amount of the food product per serving, or encapsulated oil, etc. will also vary. Highly concentrated forms, such as soft gels, will be administered in lower total amounts than diluted forms, such as drinks.
  • Example 1 discloses a method for the preparation of an embodiment of the inventive oil.
  • Examples 2, 3, 4 and 5 compare the results of human studies in which patients received the inventive oil or other preparations containing the elements of the inventive oils individually or in proportions which differ substantially from those of the invention.
  • Example 2 compares the administration of palm-derived tocotrienols with the inventive oil.
  • Example 3 compares rice tocotrienols processed by another method with the inventive oil.
  • Example 4 compares a conventionally processed rice oil with the inventive oil.
  • Example 5 compares the performance of the inventive oil against two commercial margarines incorporating high levels of sterols and steryl esters.
  • Oil A One hundred ( 1 00) grams of rice oil (“Oil A”) are analyzed, dewaxed and degummed, and the acid value of the oil is determined by AOAC methods.
  • the oil contains 5 % sterols, stanols, and cycloartols as:
  • 24-methylene- cycloartol 40 and, further, contains 1 1 20 ppm of tocopherols and tocotrienols, 58% as ⁇ -am/ ⁇ a-tocotrienol.
  • Oil A is held overnight at moderate vacuum at 1 25 ° C, so that water generated during esterfication is removed and the reaction driven to the right, accelerating the natural aging process in which fatty acid esters of sterols and cycloartols are formed. Oil A is then cooled to 50° C.
  • a mild, caustic agent is prepared by combining potassium hydroxide and alkaline hydrous sodium silicate (Britesorb ® NC, commercially available from PQ Corporation, Valley Forge, PA) in a slurry, in the ratio of 1 part potassium hydroxide to 4 parts Britesorb ® to 6 parts of water. An amount of slurry equal to 5% stoichiometric excess of the acid value previously measured is added to the cooled Oil A above, and the mixture is stirred at 60° C for one hour, after which the temperature is increased to 80° C and the mixture filtered.
  • potassium hydroxide and alkaline hydrous sodium silicate (Britesorb ® NC, commercially available from PQ Corporation, Valley Forge, PA) in a slurry, in the ratio of 1 part potassium hydroxide to 4 parts Britesorb ® to 6 parts of water.
  • An amount of slurry equal to 5% stoichiometric excess of the acid value previously measured is added to the cooled Oil A above, and the mixture is stirred at 60
  • the refined oil is washed and dried, leaving a neutral oil rich in sterol esters and cycloartol esters of ferulic acids, but substantially free of free fatty acids and free sterols.
  • the distillate is found to contain the following ingredients: 2.0% tocopherols and tocotrienols, including:
  • the resultant refined oil is enriched in tocopherols and tocotrienols, and esters of cycloartols and sterols, but depleted of free fatty acids, mono-, di- and triglycerides and free sterols.
  • the semi-solid resultant phase above can be de-sterolized by precipitating free sterols from methanol in 4° C, and further concentrated by distillation, prior to blending.
  • the yield of tocopherols and tocotrienols ranges between 45 % and 75%, depending upon the degree of saponification of the reaction mixture.
  • the ratio of tocotrienols and tocopherols to cycloartols and ferulic and sterol esters can also be adjusted by the degree of saponification.
  • the ratio of Oil A and Oil B combined can be varied to produce a re- proportioned oil ranging in concentration of tocopherols and tocotrienols between about 0.5% and 25% (weight/weight, based on the total weight of the oil).
  • the oil is suitable for encapsulation into soft gels as a nutraceutical or therapeutic.
  • the oil can be incorporated directly into food products, such as margarine or mayonnaise.
  • the desired concentration is that sufficient to provide between 50 - 500 mg/day (or, alternatively, about 20 - 200 mg/serving) of tocotrienols/tocopherols to a patient consuming the product.
  • a test group was administered a palm oil-derived tocotrienol-rich fraction (TRF), processed in a manner which depletes sterols, steryl esters and cycloartols, in an amount of 1 60 - 240 mg three times per day for one year.
  • TRF palm oil-derived tocotrienol-rich fraction
  • the dosage was increased to 240 mg of tocotrienols three times per day for two additional years.
  • test group was then administered 2.4 grams per day of an oil according to the invention containing 200 mg of tocotrienols three times per day for one year.
  • the blood lipids improved: a 20% decrease in LDL cholesterol, a 20% increase in HDL cholesterol and a 23% decrease in triglycerides was observed. See Table 1 .
  • Example 4 The patients of Example 4 were switched to margarine preparations containing either stanol esters (Benecol) or steryl esters. Both groups received margarine containing approximately 3 grams per day of the stated esters. Decreases of LDL cholesterol concentrations between 8% and 1 3 % were observed, but'no significant changes in HDL cholesterol or triglycerides were found. This study confirms the findings of other studies of sitostanol esters but reported significant depletion of plasma antioxidants.
  • Example 2 The results in Example 2 show that the administration of tocotrienols alone does not affect blood lipid values.
  • Example 2 further demonstrates that administration of an edible oil according to the invention lowers total cholesterol, LDL cholesterol and triglycerides, while increasing HDL cholesterol.
  • Example 3 demonstrates that a rice-derived tocotrienol concentrate depleted in steryl esters and cycloartols is ineffective in increasing HDL levels or decreasing triglycerides.
  • Example 4 shows that a physically refined rice oil poor in tocotrienols is ineffective, and
  • Example 5 shows that administration of sterols and steryl esters without tocotrienols does not result in changes in HDL or triglyceride values.

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EP01908744A 2001-01-29 2001-01-29 Cholesterinspiegelsenkendes speiseöl Withdrawn EP1370148A4 (de)

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/US2001/002953 WO2002060272A1 (en) 2001-01-29 2001-01-29 Anticholesterolemic edible oil

Publications (2)

Publication Number Publication Date
EP1370148A1 true EP1370148A1 (de) 2003-12-17
EP1370148A4 EP1370148A4 (de) 2004-08-04

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EP1796726A2 (de) 2004-08-10 2007-06-20 Enzymotec Ltd. Gemisch aus phytosterolestern und 1,3-diglycerid(en) zur behandlung von medizinischen krankheiten
EP2012598A1 (de) * 2006-04-13 2009-01-14 Naturi LLC Konzentrate mit hohem biowirkstoffgehalt, und nährprodukte und therapeutika, die diese enthalten
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KR100548602B1 (ko) 2006-01-31
CA2430878A1 (en) 2002-08-08
CN1479578A (zh) 2004-03-03
JP2004519228A (ja) 2004-07-02
EP1370148A4 (de) 2004-08-04
WO2002060272A1 (en) 2002-08-08
JP3746270B2 (ja) 2006-02-15

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