WO2001032036A1 - Compositions de stanol reduisant le cholesterol, preparation et procede d'utilisation - Google Patents

Compositions de stanol reduisant le cholesterol, preparation et procede d'utilisation Download PDF

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Publication number
WO2001032036A1
WO2001032036A1 PCT/US2000/030417 US0030417W WO0132036A1 WO 2001032036 A1 WO2001032036 A1 WO 2001032036A1 US 0030417 W US0030417 W US 0030417W WO 0132036 A1 WO0132036 A1 WO 0132036A1
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Prior art keywords
phytostanol
weight percent
group
surfactant
mixtures
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PCT/US2000/030417
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English (en)
Inventor
Vinod P. Menon
Patrick J. Kinlen
Vinod Pirakitikulr
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Monsanto Technology Llc
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Priority to CA002389605A priority Critical patent/CA2389605A1/fr
Priority to EP00976929A priority patent/EP1225813A1/fr
Priority to JP2001534252A priority patent/JP2003520204A/ja
Priority to BR0015302-8A priority patent/BR0015302A/pt
Priority to CNA008180806A priority patent/CN1479581A/zh
Priority to AU14636/01A priority patent/AU1463601A/en
Priority to MXPA02004511A priority patent/MXPA02004511A/es
Publication of WO2001032036A1 publication Critical patent/WO2001032036A1/fr

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    • 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
    • A23L33/20—Reducing nutritive value; Dietetic products with reduced nutritive value
    • A23L33/21—Addition of substantially indigestible substances, e.g. dietary fibres
    • A23L33/25—Synthetic polymers, e.g. vinylic or acrylic polymers
    • A23L33/26—Polyol polyesters, e.g. sucrose polyesters; Synthetic sugar polymers, e.g. polydextrose
    • 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
    • A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
    • A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs

Definitions

  • This invention relates to plant stanol compositions and its derivatives for reduction of cholesterol absorption. More particularly, the invention provides compositions containing a phytostanol and/or a phytostanol ester and surfactant(s) that are useful for reducing cholesterol absorption. The invention also relates to methods of preparing such compositions for reducing cholesterol absorption.
  • Cholesterol while an essential nutrient for humans, is well known to be a leading cause of death in the United States and most countries around the world. Many foods consumed today have high cholesterol content. Once the cholesterol reaches the small intestine it can be absorbed which results in an increase in serum cholesterol levels .
  • the serum cholesterol is well-known to be deposited in various parts of the circulatory system, for example, in soft tissues. The long-term accumulation or build-up of cholesterol deposits leads to atherosclerotic disease. By reducing cholesterol content of food, as well as inhibiting the absorption of cholesterol, it has been possible to reduce serum levels of cholesterol.
  • Plant sterols have been found to be particularly effective at reducing serum cholesterol levels. In particular, studies conducted employing beta-sitosterol were found to produce significant reductions (17%) in the amounts of cholesterol in the blood (Farquhar, J.W. et al., Circulation, 14, 77-82 (1956)). However, large doses of beta-sitosterol were required, 12-18 grams per day. This is a major impediment to the use of beta-sitosterol for cholesterol reduction.
  • a related class of compounds, plant stanols saturated plant sterols
  • plant stanols block cholesterol absorption by competing with cholesterol for bile acid micellerization. As a result of this competition between plant stanols and cholesterol, it is believed that plant stanols displace cholesterol from the micellar phase and thereby prevent its absorption in the small intestine.
  • Plant stanols and sterols have represented particularly attractive classes of compounds for use in lowering serum cholesterol levels, since they are natural components of vegetable fats and oils. Additionally, plant stanols and sterols are absorbed in very small quantities compared to the absorption of bile and dietary cholesterol. In fact, sitostanol is considered to be practically unabsorable, i.e., less than 5%. Although, plant sterols and stanols are attractive as cholesterol absorption inhibitors, they have proven to be difficult to formulate. A major factor in these difficulties has been the fact that plant stanols are virtually insoluble in water. Considerable efforts have been made to develop plant sterol or stanol preparations that can easily be formulated with consumer food products.
  • U.S. Patent No. 5,244,887 is directed to plant stanol food additives for reducing the absorption of cholesterol in the gastro-intestinal tract.
  • the greatest effectiveness was obtained when the stanols were evenly distributed in finely divided form throughout the food product or beverage to which it is added. This was accomplished by dissolution of the stanols or by suspension of the stanols in an emulsion.
  • Solubilizing agents listed for the stanols include vegetable oil, monoglycerides, diglycerides, triglycerides, tocopherols, and the like and mixtures thereof.
  • Suspensions or emulsions of stanols include water, alchohols, polyols, and other edible compounds.
  • Dispersing agents may be used to aid in the formation of suspensions, such as lecithin, polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, polysorbate 85, sodium lauryl sulfate, and the like.
  • the stanol food additives are used with cholesterol containing foods, such as meats, eggs and dairy products.
  • EP 0 897 671 discloses aqueous dispersions of high melting lipids, such as plant sterols, with non-sterol emulsifiers.
  • Emulsifiers used to disperse the high melting lipids include polyglycerol esters and tweens, especially polysorbate 60. Mono- and diglycerides are also mentioned as suitable emulsifiers.
  • the dispersions have reduced size on the order of 15 microns or lower. The dispersions are said to be useful in spreads and other food products. Additionally, the dispersions provide structure to the food products and their use can apparently permit minimization or elimination of saturated fats and trans fatty acids.
  • formulations which lower serum cholesterol levels by preventing or significantly reducing the absorption of cholesterol.
  • Such formulations would desirably be able to be delivered in a variety of ways to individuals, e.g., as an additive to food products or as a pill for oral administration.
  • the formulation in order for the formulations to be most effective in lowering cholesterol absorption, the formulation must reach the gastrointestinal tract so that they can be rapidly and efficiently solublized in the micellar phase thereby preventing the absorption of cholesterol. It has now been discovered that formulations comprising a plant stanol or a plant stanol ester and a surfactant(s) are effective at inhibiting the absorption of cholesterol.
  • compositions for inhibiting the absorption of cholesterol comprise a plant stanol and/or a plant stanol ester and a surfactant(s) .
  • the surfactant(s) is selected from the group consisting of anionic, cationic, nonionic and zwitterionic surfactants.
  • plant stanols examples include sitostanol, campestanol, 22, 23 dihydorbrassicastanol, and clionastanol.
  • the compositions of the present invention provide an effective method of reducing cholesterol without any adverse side-effects.
  • compositions of the present invention can be used as food additive compositions for reducing cholesterol absorption from foods.
  • the food additive composition may be employed in small quantities making it convenient for use and also an inexpensive method to reduce cholesterol absorption.
  • the food additive compositions of the present invention are storage-stable for extended periods of time.
  • the food additive compositions may be added before, during or after cooking with foods.
  • the food additive compositions may be added to food products during production prior to sale to the consumer.
  • the compositions of the present invention can be used in non-fat containing foods .
  • the present invention also contemplates various combinations of the foregoing surfactant(s) and a phytostanol and/or a phytostanol ester being administered orally in any of the usual solid forms such as pills, tablets, capsules or powders, including sustained release preparations.
  • the present invention relates to the use of plant stanol and/or plant stanol ester compositions that inhibit the absorption of cholesterol. More particularly, the invention relates to the formation of water soluble/dispersible stanol and/or stanol "ester systems comprising a plant stanol and/or a plant stanol ester and anionic, cationic, nonionic, or zwitterionic surfactant systems, which reduce cholesterol absorption.
  • stanols refers to plant sterol derivatives in which all carbon-carbon bonds in the rings are saturated.
  • the principal stanols of the present invention are those which are composed of 28 or 29 carbon atoms.
  • Four major plant stanols are beta-sitostanol, campestanol, 22,23 dihydrobrassicastanol, and clionastanol.
  • R is CH 3 for campestanol and its epimer, 22,23 dihydrobrassicastanol and where R is C 2 H 5 for sitostanol and its epimer, clionastanol .
  • the C 28 stanols campestanol and 22, 23 dihydrobrassicastanol differ only by their steric configuration at C 24 .
  • the C 29 stanols likewise, differ only by the steric configuration at C 24 .
  • clionastanol is (3 beta, 5 alpha, 24S)-Stigmast- 5an-3-ol; sitostanol is (3 beta, 5 alpha, 24R)-Stigmast- 5an-3-ol; campestanol is (3 beta, 5 alpha, 24R)-Ergost-5an- 3-ol; 22, 23 dihydrobrassicastanol is (3 beta, 5 alpha, 24S)-Ergost-5an-3-ol. It will also be appreciated that modifications of the plant stanols are also well within the scope of the present invention, for example, small side chains.
  • stanol ester refers to plant stanols that has been modified to form a plant stanol ester derivative. These derivatives are well known in the art and are described in U.S. Pat. Nos. 4,588,717, 5,270,041, and 5,958,913, International applications WO 98/06405, and WO 99/25362, European Application EP 911385, and H. Gylling et al., Journal of Lipid Research, 40, 593-600 (1999), the disclosures which are hereby incorporated by reference.
  • Stanols are found in small quantities in nature in many plants, e.g., wheat, rye, and corn. As a result, this is not a particularly good source of large quantities of stanols due to the large cost associated with extraction of sufficient quantities of stanols.
  • a more cost effective method to obtain large quantities of stanols is by hydrogenation of the much more abundant plant sterols .
  • Many hydrogenation methods for plant sterols are well-known by those of ordinary skill in the art. For example, plant sterols can be converted into stanols by hydrogenation techniques that employ Pd/C catalyst in organic solvents (Augustine, R.L. et al., Org. Prep, and Proc. 1: 107-109, (1969)).
  • a larger number of inexpensive sources of plant sterols are known. These include, vegetable oils, vegetable oil sludge, vegetable oil distillates, and other plant oil sources such as tall oils.
  • vegetable oils vegetable oil sludge, vegetable oil distillates, and other plant oil sources such as tall oils.
  • a preparation of sterols from vegetable oil sludge by using solvents such as methanol is taught in U.S. Pat. No. 4,420,427.
  • Sterols isolated from plant sources are usually mixtures of several different sterols, hydrogenation leads to a mixture the corresponding stanols.
  • Sterols, which differ only by the degree of unsaturation in the carbon bonds of the ring or side chains, upon hydrogenation usually produce stanols which differ only in epimeric centers such as the C 24 carbon.
  • sitostanol may be obtained by hydrogenation of sitosterol.
  • Sitosterol may be obtained from cold pressed wheat germ oil, soy extract, or rice extract.
  • natural sitosterol contains about 40% alpha-sitosterol and about 60% beta- sitosterol. Both the alpha and beta forms of sitosterol may be used to form sitostanol for use in the present invention.
  • Particularly preferred stanol comprises a minimum of 63 weight percent sitostanol, a maximum of 35 weight percent campestanol and a minimum of 93 weight percent of sitostanol and campestanol.
  • hydrogenation of plant sterols may leave some amounts of unreacted sterols. Although, the hydrogenation results in a majority of stanol production. For the purposes of the present invention, it is acceptable to have small residual amounts of unreacted sterols, generally less than about 10%. It will be readily apparent to those of ordinary skill in the art that amount of residual sterol present may be substantially reduced ( ⁇ 1.5%) depending on the solvents and reaction conditions employed. However, if it is desired to have a stanol free of unreacted sterols, then a pure sterol preparation may be employed.
  • the surfactants to be employed according to the invention can be anionic, cationic, nonionic, zwitterionic and mixtures thereof.
  • Suitable anionic surfactants include AOT, also known as sodium dioctylsulfosuccinate or sodium docusate, ammoniated glycyrrhizin, and sodium stearoyl lactylate.
  • Nonionic surfactants include, polyoxyethylene castor oil (cremophor EL polyoxyl 35 castor oil), polyethylene glycol "PEG” (low molecular weight 1000 to 4000), diacetyl lactic acid of esters of mono- and diglycerides, diacetyl tartaric acid esters of mono- and diglycerides , monosodium phosphate derivatives of mono- and diglycerides, ethoxylated mono- and diglycerides, polyethylene glycol (8) stearate, polyethylene glycol (40) stearate, sorbitan esters of fatty acids, quillaja saponin, ethylene oxide propylene oxide block copolymers, vitamin E
  • TPGS d-alpha tocopheryl poyethylene glycol 1000 succinate
  • fatty alcohols fatty alcohols
  • sucrose fatty acid esters such as sucrose stearate, sucrose distearate, sucrose palmitate.
  • Preferred fatty alcohols include but are not limited to the following, 1-decanol (CH 3 (CH 2 ) 8 CH 2 OH) also known as n-decyl alcohol, 1-dodecanol (CH 3 (CH 2 ) 10 CH 2 OH) also known as dodecyl or lauryl alcohol, 1-tetradecanol (CH 3 (CH 2 ) 12 CH 2 OH) also known as myristyl alcohol, 1-hexadecanol (CH 3 (CH 2 ) 14 CH 2 OH) also known as cetyl or palmityl alcohol, 1-octadecanol
  • Zwitterionic surfactants include, hydroxylated lecithin and the like.
  • anionic surfactants such as sodium stearate, sodium palmitate, sodium laurate, sodium myristate, sodium linoleate, and potassium oleate may also be employed.
  • Additional nonionic surfactants that may be included in the compositions of the present invention include polyglycerol esters and tweens, polysorbate 20 (tween 20), polysorbate 40 (tween 40), polysorbate 60 (tween 60), polysorbate 80
  • tween 80 polysorbate 85 (tween 85), fatty acids such as oleic acid (C 17 H 33 COOH) , stearic acid (C 17 H 36 COOH) , and palmitic acid (C 15 H 31 COOH) , triglycerides CH 3 (CH 2 ) 6 COOH and CH 3 (CH 2 ) 8 COOH and mixtures thereof (e.g., MCT oil).
  • fatty acids such as oleic acid (C 17 H 33 COOH) , stearic acid (C 17 H 36 COOH) , and palmitic acid (C 15 H 31 COOH)
  • triglycerides CH 3 (CH 2 ) 6 COOH and CH 3 (CH 2 ) 8 COOH and mixtures thereof e.g., MCT oil
  • Naturally occurring polymers such as guar gum, karaya gum, gum arabic, carrageenan, xanthan gum, dextran, maltodextrin, chondroitin sulfate, polyglycerol esters of fatty acids commercially known as Polyaldo, succinoglucan and hyaluronic acid may also be employed in the compositions of the present invention.
  • Synthetic polymers such as poly(vinyl alcohol), poly(vinyl pyrrolidone), hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose may also be employed in the compositions of the present invention.
  • fatty acids that may be employed in the present invention, include caprylic, capric, lauric, myristic, myristoleic, palmitoleic, oleic, ricinoleic, linoleic, linolenic, eleostearic, arachidic, arachidonic, behenic and erucic acid.
  • the fatty acids of the present invention can be derived from naturally occurring or synthetic fatty acids; they can be saturated or unsaturated, including positional and geometric isomers, depending on the desired physical properties, for example liquid or solid.
  • the composition of the present invention comprises a mixture of a phytostanol and/or a phytostanol ester and a surfactant selected from the group consisting of sodium docusate, ammoniated glycyrrhizin, polyoxyethylene castor oil, polyethylene glycol, diacetyl lactic acid esters of mono- and diglycerides, diacetyl tartaric acid esters of mono- and diglycerides, monosodium phosphate derivatives of mono- and diglycerides, ethoxylated mono- and diglycerides, quillaja saponin, ethylene oxide propylene oxide block copolymers, vitamin E TPGS, hydroxylated lecithin and mixtures thereof.
  • a surfactant selected from the group consisting of sodium docusate, ammoniated glycyrrhizin, polyoxyethylene castor oil, polyethylene glycol, diacetyl lactic acid esters of mono- and diglycerides, diacetyl
  • composition of the present invention may further comprise a surfactant selected from the group consisting of sodium salts of fatty acids, fatty alcohols, polyethylene glycol (8) stearate, polyethylene glycol (40) stearate, sucrose fatty acid esters, tween and mixtures thereof.
  • a surfactant selected from the group consisting of sodium salts of fatty acids, fatty alcohols, polyethylene glycol (8) stearate, polyethylene glycol (40) stearate, sucrose fatty acid esters, tween and mixtures thereof.
  • One preferred embodiment of the present invention comprises a mixture of a phytostanol and/or a phytostanol ester and fatty acid alcohol, preferably, octadecanol.
  • Another preferred embodiment of the present invention comprises a mixture a phytostanol and/or a phytostanol ester, Tween 60 and PEG.
  • Other preferred embodiments include a phytostanol and/or a phytostanol ester, fatty acid alcohol and sucrose fatty acid ester, such as Crodesta.
  • One preferred embodiment of the present invention provides a method of reducing cholesterol absorption in humans which comprises orally administering an effective amount of a composition of the present invention.
  • the invention also provides for a method for reducing serum cholesterol levels comprising administering a mixture of a phytostanol and/or a phytostanol ester and a surfactant(s) .
  • emulsifiers may be used in the formulation of dispersible stanol and/or stanol ester systems.
  • Preferred emulsifiers include a variety of phosphoiipids, phosphatidyl choline (PC), phosphatidyl ethanolamine (PE), N-acylphosphatidyl ethanolamine (NAPE), phosphatidyl serine (PS), phosphatidyl inositol (PI), phosphatidyl glycerol (PG), diphosphatidyl glycerol (DPG), phosphatidic acid (PA) and plasmalogen.
  • PC phosphatidyl choline
  • PE phosphatidyl ethanolamine
  • NAPE N-acylphosphatidyl ethanolamine
  • PS phosphatidyl serine
  • PS phosphatidyl serine
  • PS phosphatidyl inositol
  • PG phosphatidyl glycerol
  • the phosphoiipids may be used individually or in various combinations, and may be obtained from "natural" sources (e.g., soybean lecithin) or from chemical synthesis.
  • the phospholipids may be in the form of relatively unpurified mixtures of phosphoiipids and other constituents (e.g., crude commercial lecithins obtained from the refining of soybean oil and other vegetable oils such as sunflower and canola), or may be purified to various degrees.
  • phosphoiipids including those found in crude soybean lecithins or other crude commercial lecithins may be chemically modified.
  • Lecithins, other phospholipid preparations, or individual phosphoiipids purified from natural sources or obtained by chemical synthesis contain one or more functional groups susceptible to chemical modification, e.g., carbon-carbon double bonds, esters, phosphonate esters , amines and hydroxyl groups . Chemical modification of phosphoiipids can be compatible with the present methods.
  • phosphoiipids that have been acetylated, hydroxylated, hydrolyzed (e.g., to produce lysophospholipids ) , hydrogenated, halogenated, phosphorylated, sulfated epoxidated, ethoxylated, or otherwise modified are potentially useful in the present methods and are included within the meaning of the term "phospholipid” as used herein.
  • Various natural and synthetic phosphoiipids, including various types of lecithins may be obtained commercially, for example Ultralec from ADM Corp., and other lecithins may be obtained from CALBIOCHEM®, La Jolla, Calif., USA and from SIGMA® Chemical Company, St. Louis, Mo., USA.
  • lecithin refers to the entire phospholipid fraction obtained from natural sources such as soybean, cotton seed, corn, wheat germ, oat, barley, sunflower, rapeseed, canola, linseed, peanut, palm kernel, egg yolk, milk and brain. Generally these fractions include a mixture of polar and neutral lipids with a polar lipid content (as defined by insolubility in acetone) of at least 50%.
  • the art has also used the term “lecithin” as the common name for phosphatidyl choline.
  • lecithin refers to the first usage, i.e., the entire phospholipid fraction obtained from selected vegetable oils or other appropriate sources. See, Chapter 2 of Szuhaj and List. It is to be noted, however, that phosphatidyl choline is an appropriate phospholipid for use in the present methods, either alone or in combination with other phosphoiipids .
  • soybean lecithin a preferred source of phosphoiipids
  • Crude soybean oil generally contains about 1.0 to 3.0 weight percent phosphoiipids.
  • the first step generally is to remove the phosphoiipids . This step, often called “degumming,” is accomplished by first adding water to the crude oil . The water hydrates the phosphoiipids and makes them less soluble in the oil. The denser phosphoiipids and water are then separated from the less-dense oil, typically by centrifugation.
  • phosphatidyl choline phosphatidyl ethanolamine
  • inositol phosphatides Partially refined soybean oil is commonly added back to produce a liquid product that is flowable at room temperature (sometimes called "fluidized lecithin").
  • Commercial fluid soybean lecithin contains about 50 to about 65 weight percent phosphoiipids and a small amount (generally less than about 5 weight percent) of various carbohydrates, mineral salts, protein materials, free fatty acids, sterols, and water. The remainder of commercial soybean lecithin is soybean oil.
  • lecithin powders enriched for phospholipid content are available commercially and may also be used in the present methods. Such lecithin powders are also within the scope of the term "lecithin” as used herein.
  • the powders are typically derived by fractionation, for example acetone fractionation, of crude lecithins such as commercial soybean lecithin, and may contain from about 60% to over 95% phospholipid.
  • soybean lecithin may be chemically or ezymatically modified, e.g., via reaction with maleic anhydride. Certain components may be removed from commercial soybean lecithin.
  • another approach is to add various components, for example nonionic emulsifiers, to the commercial soybean lecithin.
  • emulsifiers include, without limitation, polyoxyalkylene monoglyceride, polyoxyalkylene diglycerides, and the polyoxyethylene derivatives of partial fatty acid esters.
  • Hydroxylated lecithin is a preferred embodiment of the phosphoiipids used in the invention.
  • Hydroxylated lecithin is prepared by hydroxylating the double bonds in the fatty acids attached to the phosphoiipids and glycolipids of lecithin, which can be carried out by reaction with hydrogen peroxide and a weak acid such as lactic acid.
  • hydrogen peroxide and a weak acid such as lactic acid.
  • hydroxylation is not specific and can occur at any double bond within any of the lipids .
  • the degree of hydroxylation is typically about 10% but can be varied by methods known to those of ordinary skill in the art.
  • compositions of the present invention are preferably formed into a fine dispersion using melt processing.
  • melt processing comprises dry-mixing a phytostanol and/or a phytostanol ester and a surfactant(s) together with a stirring device such as a mechanical stirrer, shear mixer, vibrational mixer or sonicator. The mixture is then heated to a temperature sufficient to melt same, but not so high as to degrade the phytostanol, phytostanol ester or surfactant(s) . The resulting mixture is then rapidly cooled, e.g., liquid nitrogen, to form a salt like material.
  • the step of melt blending the phytostanol and/or phytostanol ester and surfactant(s) prior to rapid cooling facilitates the formation of a composition that is in a finely dispersed state that is able to reach the small intestine thereby being able to inhibit the absorption of cholesterol.
  • An alternative variation on the melt processing described above comprises the addition of a surfactant(s) to a phytostanol and/or phytostanol ester melt. This may be desirable in cases where the surfactant(s) is thermally unstable and would not survive prolonged heating at high temperatures, i.e., thus the residence time for the surfactant(s) is reduced by its later addition to phytostanol melt. Once the surfactant(s) has been added to the melt, the mixture can be treated in a fashion similar to that described previously.
  • a further alternative procedure to melt blending for forming the compositions of the present invention is high pressure melting. This procedure is also desirable for blending heat sensitive surfactant(s) and phytostanol and/or phytostanol esters . It has been discovered that by using a mixing or compression means allowing for increasing the pressure on the ingredients, the surfactant(s) phytostanol and/or phytostanol esters will melt blend at ambient temperatures. Homogenous mixtures of heat sensitive surfactant(s) and phytostanol and/or phytostanol esters can therefore be formed while avoiding temperatures at which thermal decomposition of ingredients will occur.
  • high pressure melting is roller compaction, where the surfactant(s) and phytostanol and/or phytostanol ester are mixed together as described previously. The mixture is then compressed together using a roller such that the pressure exerted on the mixture is high enough to result in the flow of the ingredients and surface sintering of the mixture results.
  • An additional embodiment of high pressure melting is extrusion.
  • a loosely packed powder mixture of surfactant(s) and phytostanol and/or phytostanol ester is propelled continuously along a screw through regions of high pressure and controlled temperature. Shear forces from the screw melt and mix the material into a continuous stream of molten material, which is then forced through a die.
  • the mixture resulting from the high pressure melting process is typically a soft, pliable solid material that can be further processed by cooling to solidify followed by breaking into chips or milling to form a uniform powder for use in the formation of products as described herein.
  • Mixtures of a phytostanol and/or a phytostanol ester and surfactant( s) may also be processed using solution processing or steric stabilization.
  • Use of solution processing is particularly effective for use with surfactant(s) that are thermally stable.
  • the phytostanol and/or phytostanol ester and surfactant(s) are generally dry mixed together, although this is not always necessary, the resulting solid mixture is then dissolved in an organic solvent, such as methylene chloride. The solvent is then removed to provide an amorphous/dispersible solid form.
  • Steric stabilization provides an effective method to form a dispersible solid form of a phytostanol and/or phytostanol ester and surfactant(s ) .
  • a fine dispersion of a phytostanol and/or phytostanol ester is added to water containing the surfactant(s) .
  • the surfactant(s) in the water help to keep the stanol(s) in suspension. Once a finely divided suspension has formed the water is evaporated off leaving a more readily dispersible solid form.
  • Preferred embodiments of the present invention include a mixture of from about 10 to about 99.99 weight percent of a phytostanol and/or phytostanol ester and from about 0.01 to about 90 weight percent of a surfactant(s ) , preferably from about 40 to about 95 weight percent of a phytostanol and/or phytostanol ester and from about 5 to about 60 weight percent of a surfactant( s) , and more preferably about 95 weight percent of a phytostanol and/or phytostanol ester and about 5 percent by weight percent of a surfactant(s) .
  • the compositions of the present invention comprise a phytostanol and/or phytostanol ester and at least two surfactants .
  • a mixture comprises from about 10 to about 99.99 weight percent of a phytostanol and/or phytostanol ester and the sum of the at least two surfactants is from about 0.01 to about 90 weight percent, preferably such a mixture comprises from about 40 to about 95 weight percent of a phytostanol and/or phytostanol ester and the sum of at least two surfactants is from about 5 to about 60 weight percent, and more preferably about 95 weight percent of a phytostanol and/or phytostanol ester and the sum of at least two surfactants is about 5 weight percent.
  • Desirable characteristics of food additive compositions for reducing cholesterol absorption include absence of side effects, efficacy without absorption of the compound, stability at cooking temperatures, stability in storage and in oxidizing environments, low cost, availability, and small dose requirements.
  • compositions of the present invention may be orally administered in a variety of forms: uncoated tablets, coated tablets such as film, sugar or gelatin coated, chewable tablets, swallowable tablets (capsules), effervescent tablets, immediate release tablets, sustained (controlled or modified) release tablets; soft gelatin capsules either liquid (non-aqueous) or paste (slurry); hard gelatin capsules in powder (granulation), bead, tablet, liquid, semi-solid, sprinkle (immediate or controlled release) forms; oral liquids such as aqueous, emulsions or suspension; sachets (packages) in powder, granule or sprinkle (immediate or controlled release) forms.
  • Other forms for administering the compositions of the present invention include syrup, fruit beverages, or fruit gelatines.
  • compositions of the invention may be used in various embodiments it may be said, one preferred embodiment is when the compositions of the present invention are evenly distributed in finely divided form throughout the food product or beverage to which it is added.
  • the compositions of the present invention may be added to food products or beverages prior to purchase by the consumer for consumption.
  • the compositions of the present invention may be purchased in bulk form or individually wrapped packages, e.g., 8 oz. servings.
  • a serving from the bulk form, e.g., 8 oz., or the contents of a package may be added to a glass of cold or hot water or other beverage, stirred to dissolve the contents, prior to consumption.
  • Typical beverages include the following, instant ice tea in Orange Pekoe, English Breakfast, Passion Fruit and Hisbiscus Flavors, powdered soft drinks such as Crystal Light and Contry Time Lemonade, Instant Iced Coffee in flavors such as Mocchacchino, Hazelnut, French Vanilla, and Hot Chocolate and Fruit Smoothies.
  • compositions of the present invention may also be included in mini-sweets.
  • the mini-sweets will typically be consumed after any and all meals of each day.
  • the mini- sweets will typically contain between 25 and 60 calories and 1 to 3 grams of fat.
  • Mini-sweets include the following varieties: chocolate chews; caramel chews; hard candies such as cinnamon, butterscotch, coffee and fruit flavors; chocolate truffles such as hard dark chocolate on the outside filled with hazelnut creme, irish creme or cappucinno creme; brownie bites; cookie chews in peanut butter, chocolate chip or ginger snaps; granola/nutrition bar miniatures such as chocolate covered oat and peanut butter; chewy breath mints; mint meltaways; and mini- pudding.
  • Mini-sweets may be prepared in individually wrapped packages or in larger containers for multiple uses.
  • the method by which the novel food additive composition, i.e., the stanol and/or stanol ester and surfactant(s) , is used to reduce cholesterol absorption from foods and beverages includes the step of commingling the food additive composition with foods and beverages, mixing until uniformly blended.
  • the food additive is added such that the amount of stanols in the food additive is in the ratio of about 1 : 1 by weight to the cholesterol contained in the foods and beverages .
  • the ratio of food additive to food product is about 1:250 by weight.
  • the food additive composition of the invention can be commingled with foods by a step selected from the group of infusion, injection, mixing, kneading, blending, immersion, spraying, surface application (for example, brushing and basting), cooking in oils which contain the food additive-invention, and combinations thereof.
  • Preferred steps for commingling the food additive-invention with ground meat are kneading and mixing; for meat pieces such as steaks, chicken breasts, and chopped, diced or sliced meat, the preferred steps are injection, infusion, spraying, immersion, and surface applications such as basting and marinating.
  • Two preferred steps for commingling the food additive-invention with beverages are mixing and blending.
  • compositions of the present invention will be used as food additives to foods such as meats, eggs and dairy products. Generally, when used as food additives, the compositions of the present invention will not contribute substantially to the taste of the food product. Accordingly, the compositions of the present invention can be used in food products without compromising the food products taste and flavor.
  • compositions of the present invention may also be formulated into fine particles which may be sprinkled on to other food products, i.e., dairy products such as ice cream or candy.
  • compositions of the invention may be administered to any animal.
  • animals are mammals, e.g., humans, although the invention is not intended to be so limited.
  • the dosage administered will be dependent upon the age, health, and weight of the recipient, kind of concurrent treatment, if any, frequency of treatment, and the nature of the effect desired.
  • compositions of the present invention may be administered orally in any of the usual solid forms such as pills, tablets, capsules or powders, including sustained release preparations.
  • unit dosage form as used in this specification and the claims refer to physically discrete units to be administered in single or multiple dosage to animals, each unit containing a predetermined quantity of active material, i.e., phytostanol and/or phytostanol ester, in association with a surfactant(s) and a carrier.
  • the quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.
  • active material i.e., phytostanol and/or phytostanol ester
  • the quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of such units.
  • the exact treatment level will depend upon the case history of the animal, e.g., human being, that is treated. The precise treatment level can be determined by one of ordinary skill in the art without undue experimentation.
  • the require dosage of the phytostanol and/or phytostanol ester will vary with the severity of the condition and the duration of the treatment.
  • Unit dosages can range from about 0.01 mg/kg to about 500 mg/kg (the unit designated "mg/kg” as used herein refers to mg of phytostanol and/or phytostanol ester per kilogram of body weight), preferably from about 0.1 mg/kg to about 125 mg/kg with up to six doses daily, preferably four dosages daily. Most preferably, the doses are administered at meal times .
  • the dosages may be administered orally in any suitable unit dosage form such as pills, tablets, and capsules. Preferred are capsules made from gelatin.
  • carrier denotes a solid or liquid filler, diluent, or encapsulating substance.
  • substances that can act as carriers are sugars such as lactose, glucose, and sucrose; starches such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, cellulose acetate; powdered tragacanth; malt; gelatin; talc; stearic acid; magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil and of the broma; polyols such as propylene glycol, glcerin, sorbitol, mannitol, and polyethylene glycol; agar, alginic acid; pyrogen-free water; isotonic saline; ethyl alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in
  • wetting agents and lubricants such as sodium lauryl sulfate, as well as coloring agents, flavoring agents, and preservatives can also be present.
  • Dye stuffs or pigments may be added to the tablets, for example, for identification or in order to characterize combinations of active doses
  • compositions that can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer such as glycerol or sorbitol.
  • the push-fit capsules can contain the active compounds in the form of granules, which may be mixed with fillers such as lactose, binders such as starches, and/or lubricants such as talc or magnesium stearate and, optionally, stabilizers.
  • the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin.
  • stabilizers may be added.
  • Powders are prepared by comminuting the compositions of the present invention to a suitable fine size and mixing with a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch. Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • a similarly comminuted diluent pharmaceutical carrier such as an edible carbohydrate material as for example, starch.
  • Sweetening, flavoring, preservative, dispersing and coloring agents can also be present.
  • Capsules are made by preparing a powder mixture as described above and filling formed gelatin sheaths.
  • a lubricant such as talc, magnesium stearate and calcium stearate can be added to the powder mixture as an adjuvant before the filling operation;
  • a glidant such as colloidal silica may be added to improve flow properties;
  • a disintegrating or solubilizing agent may be added improve the availability of the medicament when the capsule is ingested.
  • Tablets are made by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets.
  • a powder mixture is prepared by mixing the compositions of the present invention, suitable comminuted, with a diluent or base such as starch, sucrose, kaolin, dicalcium phosphate and the like.
  • the powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • a binder such as syrup, starch paste, acacia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen.
  • the powder mixture can be run through the tablet machine and the resulting imperfectly formed slugs broken into granules.
  • the granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil.
  • the lubricated ixture is then compressed into tablets.
  • the medicaments can also be combined with free flowing inert carriers and compressed into tablets directly without going through the granulating or slugging steps.
  • a protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided.
  • Dye stuffs or pigments may be added to the tablets, for example, for identification or in order to characterize combinations of active doses.
  • the carrier comprises from about 0.1% to 99% by weight of the total composition.
  • Soy sitostanol (AC Humko, NF00114) (lg) was physically mixed with an equal weight of sodium dioctylsulfosuccinate (Aldrich Chemicals). The blend was melted at 170°C to form a clear solution. The clear solution was rapidly cooled by pouring it into liquid nitrogen. A crystalline transparent salt was obtained. The salt (2g) was added to water (8g) to give a milky-white emulsion with no visible particles. The solubility of the crystalline was found to be 1200 micrograms per ml using the dissolution assay described below. (Maximum solubility of cryground beta-sitostanol in the dissolution assay was found to be 300 icrograms per ml. )
  • Dissolution Assay A stock dissolution solution (5X) was prepared comprising taurocholic acid, Na 2+ (500 mM, Sigma, cat# T4009), 2- monoolein (10 mM, Nu-Check Prep, cat# M-239), oleic acid, free (10 mM, Sigma cat# O1008) in cholorform:MeOH (1:1).
  • a buffer solution was prepared comprising 0.01M sodium phosphate buffer with 3 mM sodium azide, pH 7.4.
  • the vial with the dried down dissolution solution was rehydrated with 5 ml of the sodium phosphate buffer. Nitrogen was bubbled through the solution for 5 minutes to ensure complete removal of ether.
  • the final concentrations of the dissolution constituents were taurocholic acid (100 mM) , 2-monoolein (2 mM), oleic acid (2 mM) in sodium phosphate (0.01 M, pH 7.4) with 3 mM NaN 3 .
  • a sample of the blend having an equivalent of 100 mg sitostanol was added to the vial with the 5 ml of the rehydrated dissolution solution.
  • the contents of the vial were gently swirled and then placed in rotating incubator.
  • a 100 mg cholesterol sample was prepared for assaying in the same manner as the blend of the present Example, as well as a 100 mg sample of cryoground stanol.
  • the amount of stanol dissolved in the filtered dissolution solution was determined according to the following protocol. Note that the concentration of stanol is given as the amount of unesterified stanol.
  • a 2X color reagent was prepared by adding only one-half the recommended buffer solution to the supplied lyophilized color reagent.
  • a 0.2 mg/ml sitostanol standard was prepared by aliquoting sitostanol from a 1:1 CHCl 3 /MEOH stock and adding triton-X 100 for a final rehydrated concentration of 2.0% Triton, 0.2 mg/ml sitostanol. This solution was vortexed and dried down under a N 2 stream at 50°C, followed by redrying twice from ethyl ether. The sample was rehydrated in of 0.01 M sodium phosphate buffer with 3 mM NaN 3 , pH 7.4. The mixture was then vortexed. 4. A 96 well plate was setup. The first two columns were used for the standard. Each sample was run in quadruplicate.
  • the 2X color reagent was added to each of the wells using a multi-pipettor. Care should be taken to avoid contact with the solutions by touching the pipet tips at the top edges of the well wall. 8. The reagents were then mixed by shaking on a plate shaker (cover with plate sealing plastic). The plates were incubated at 37°C for 15 min.
  • the plate was removed from the incubator and an ELISA reader at 500 nm (within 1 hour of plates removal from the incubator) was used to read the plate and thereby determine the solubility of the sample in the dissolution solution.
  • Example 1 The formulation (20g) of Example 1 was dispersed in water (100 mL) in a high speed blender prior to mixing with hamster chow containing 10% by weight corn oil (0.24% cholesterol). The dispersion was added to the hamster chow to give 2% by weight stanol equivalent. Hamsters were fed diet for 7 days and fecal cholesterol levels were determined on the last 48 hours pooled samples. Fecal cholesterol ratio ("FC Ratio") for each sample, formulated stanol and unformulated stanol (control), is determined by dividing their cholesterol measurement by the cholesterol measurement for hamsters fed hamster chow with 10% by weight corn oil and 0.24% cholesterol (containing chow only).
  • FC Ratio Fecal cholesterol ratio
  • the dogs were fed certified canine diet #5007 (PMI Feeds, Inc.). During the testing period, days 1-4, the dogs were fed certified canine diet #5007, supplemented with 0.25% cholesterol made by Ed Uhlman at Research Diets, Inc. New Brunswick, NJ. All diets were offered for approximately 2 to 4 hours daily at approximately the same time each day. Water was provided ad libitum. The animal room's environment was maintained at a temperature of 18° to 29°C, a relative humidity of 50% ⁇ 20%, and a 12-hour light/12-hour dark cycle.
  • a control sample of stanol in a push-fit gelatin capsule and a 50 weight % cremophor/50 weight % soy stanol blend which was prepared by co-melting the cremophor and stanol together at 180°C and rapidly quenching the melt in liquid nitrogen to afford a transparent crystalline salt.
  • the salt was ground to a fine powder using a cryo-mill and placed in a push-fit gelatin capsule for administration.
  • a 9% AOT/9% PEG/72% soy sitostanol blend formulation by solution blending in chloroform. The chloroform was then evaporated to give an amorphous material, which was cryo-milled into a fine powder.
  • the powder was placed in a push-fit gelatin capsule for administration. Animals were dosed at 63 mg/kg stanol equivalence. Each animal received the cholesterol-supplemented diet and the formulations of the present invention in gelatin capsule form daily for 4 days . The gelatine capsules and controls were offered at approximately the same time each day, before the animals were fed in on each day.
  • Pre-test fecal samples were collected for 72 hours before test formulation administration and on test days 3, 4 and 5. Samples were collected before feed in (and before administration of the samples and control) each day, transferred to plastic containers, and pooled at 3-day intervals. The fecal cholesterol level in each of the collected samples was then determined using liquid chromatography mass-spectrometry ("LC-MS").
  • LC-MS liquid chromatography mass-spectrometry
  • the compacted material was then passed through a Comil (Model No. 197.5, Quadro Engineering Inc., Waterloo, Canada).
  • the powder was then mixed with the reminder of the Ac-Di-Sol and Crodesta F-160 (sucrose stearate, Croda, Inc., Mill Hall, PA), followed by blending with the V-blender for 5 minutes.
  • the stearic acid triple pressed, Mallinckrodt Baker, Inc., Phillipsbury, NJ, which was first passed through a 40 mesh sieve, was added to the blend in the V-blender and mixed for 3 minutes .
  • the resulting mixture is then tableted by compression in a standard tablet press.
  • Push-fit capsules comprising a unit dosage form of a stanol were prepared as described in Example 4 , having the following composition,
  • Avicel PH-102 is microcrystalline cellulose and is available from FMC Corp., Newark, Delaware.
  • Benecol is a spread that incorporates plant stanol esters, as a method to promote healthy cholesterol levels and is available from McNeil Consumer Healthcare, Ft. Washington PA. The results are shown in the following table:
  • Deoiled Hydroxylated lecithin (lOg, Central Soya) was dispersed in water (30g) using a high speed blender. Hammer-milled stanol (20g) was added to the dispersion and the mixture was once again blended under high shear. The resulting mixture was dried at 70°C at reduced pressure (6 inches, Hg) overnight in a vacuum oven. The resulting mixture was hammer-milled to obtain a fine powder. The solubility of the powder was found to be 750 mg per mL using the dissolution assay described in Example 1.
  • a push-fit gelatin capsule was prepared using the powder having a dosage of 63 mg stanol per kg of dog weight.
  • the efficacy of the prepared gelatin capsule containing the powder was compared to a benecol at the same stanol dosage level.
  • the benecol was delivered to the dog in liquid form using a syringe.
  • the FC ratio for the dog dosed with powder prepared in this Example was determined and compared to the FC ratio for a control dog dosed with benecol. The results are shown in Table 8.
  • EXAMPLE 9 A formulation containing lecithin in place of hydroxylated lecithin was formulated as in Example 8.
  • the FC rations determined for the formulation compared to Benecol from a dog study administered in the same manner as Example 8 are shown below:
  • EXAMPLE 10 Compressed tablets comprising a unit dosage form of a stanol were prepared as described in Example 4 , having the following composition,
  • stanol powder (AC Humko NF00114) was combined with stanol powder (AC Humko NF00114) to give a mixture containing 70% w/w stanol and 30% w/w hydroxylated lecithin.
  • the mixture was extruded using a Prism twin screw which allows for temperature control over four zones and the die end. For this example zone temperatures 1 through 4 were set to 65°C.
  • the die temperature was set to 90°C and the screw speed set to 200 rpm. Approximately 100 grams of this material was extruded in long spaghetti like rods which were too soft and brittle to be processed through a chopper. The rods were hammer milled into a free flowing powder under liquid nitrogen.
  • Hard gelatin capsules were filled with the powdered lecithin/stanol product and tested for cholesterol absorption inhibition in the standard dog model described above in Example 3. Dose-response results are shown in Table 12, indicating performance statistically better than control at 30, 120 and 360 mg/Kg.
  • Example 14 Sodium stearate (Witco) was added to a 70:30 mixture of stanol: hydroxylated lecithin powder prepared as in Example 12 to give 16.7% w/w stearate.
  • the powders were fed into a Prism twin screw extruder using a vibrating feeder. Temperatures of zones 1 to 4 were set at 50, 57, 68 and 91°C respectively (the actual temperatures measured in zones 2-4 were 57, 69 and 99°C, respectively). The die temperature was set to 110°C (actual temperature 102°C). The screw speed was set to 100 RPM. As in Example 12, spaghetti-like rods were extruded and hammer milled to yield a free-flowing powder. The powder was incorporated into gelatin capsules and tested for cholesterol absorption in the dog model discussed in Example 3.
  • Example 14 Example 14
  • stanol 62% (w/w) (AC Humko), hydroxylated lecithin 30% (w/w) (Precept 8120, Central Soya) and Ac-Di- Sol 8% (w/w) (croscarmellose sodium NF Type A, FMS Corp.,

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Abstract

L'invention concerne une composition contenant un mélange de phytostanol et/ou d'ester de phytostanol et un ou des tensioactifs. Les tensioactifs sont sélectionnés dans le groupe formé par des tensioactifs anioniques, cationiques, non ioniques et bipolaires. Le phytostanol est sélectionné dans le groupe formé par le sitostanol, le campestanol, le 22,23 dihydrobrassicastanol et des mélanges de ceux-ci. Les esters de phytostanol sont des dérivés des phytostanols mentionnés précédemment. L'invention a également trait à un procédé de fabrication des compositions décrites, à des produits alimentaires exempts de graisse et qui contiennent les compositions décrites.
PCT/US2000/030417 1999-11-04 2000-11-03 Compositions de stanol reduisant le cholesterol, preparation et procede d'utilisation WO2001032036A1 (fr)

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CA002389605A CA2389605A1 (fr) 1999-11-04 2000-11-03 Compositions de stanol diminuant le cholesterol, preparation et procede d'utilisation
EP00976929A EP1225813A1 (fr) 1999-11-04 2000-11-03 Compositions de stanol reduisant le cholesterol, preparation et procede d'utilisation
JP2001534252A JP2003520204A (ja) 1999-11-04 2000-11-03 コレステロール低下用スタノール組成物、調製および使用法
BR0015302-8A BR0015302A (pt) 1999-11-04 2000-11-03 Composições de estanol redutoras de colesterol, preparação e método de uso
CNA008180806A CN1479581A (zh) 2000-11-03 2000-11-03 降低胆固醇的甾烷醇组合物、制备和使用方法
AU14636/01A AU1463601A (en) 1999-11-04 2000-11-03 Cholesterol reducing stanol compositions, preparation and method of use
MXPA02004511A MXPA02004511A (es) 1999-11-04 2000-11-03 Composiciones de estanol reductoras de colesterol, preparacion y metodo de uso.

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Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1108364A2 (fr) * 1999-12-15 2001-06-20 McNEIL-PPC, INC. Alcools à chaine longue en mélange dans des composés stéroliques
WO2002034238A2 (fr) * 2000-10-24 2002-05-02 Banner Pharmacaps, Inc. Procede et formulations a base de gelatine coloree
US6623780B1 (en) 2002-03-26 2003-09-23 Cargill, Inc. Aqueous dispersible sterol product
WO2005009144A1 (fr) * 2002-11-13 2005-02-03 Basf Aktiengesellschaft Formulations pulverulentes a base de phytosterols
EP1538929A1 (fr) * 2002-03-20 2005-06-15 Eugene Science Inc. Melange poudreux de sterol vegetal et d'emulsifiant, et procede de preparation associe
WO2006074752A1 (fr) * 2005-01-14 2006-07-20 Unilever N.V. Sachets comprenant un phytosterol
EP1695634A1 (fr) * 2005-02-24 2006-08-30 Cognis IP Management GmbH Dispersion solide de sterol contenant du sucre
WO2009098475A1 (fr) * 2008-02-06 2009-08-13 Biosuspensions Limited Systèmes tensioactifs structurés et leurs utilisations
EP2398476A1 (fr) * 2009-02-23 2011-12-28 Nanorx, Inc. Nanoparticules de policosanol
US9808426B2 (en) 2010-10-29 2017-11-07 Western University Of Health Sciences Ternary mixture formulations

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060035009A1 (en) * 2004-08-10 2006-02-16 Kraft Foods Holdings, Inc. Compositions and processes for water-dispersible phytosterols and phytostanols
US8360990B2 (en) 2004-12-16 2013-01-29 Senorx, Inc. Biopsy device with aperture orientation and improved tip

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289636A1 (fr) * 1986-02-13 1988-11-09 Asahi Denka Kogyo Kabushiki Kaisha Composition émulsifiée ou solubilisée de stérol
US5244887A (en) * 1992-02-14 1993-09-14 Straub Carl D Stanols to reduce cholesterol absorption from foods and methods of preparation and use thereof
EP0897671A1 (fr) * 1997-08-22 1999-02-24 Unilever N.V. Dispersions ou suspensions aqueuses
EP0986962A1 (fr) * 1998-08-31 2000-03-22 McNEIL-PPC, INC. Assaisonnements stables pour salade
WO2000045648A1 (fr) * 1999-02-03 2000-08-10 Forbes Medi-Tech Inc. Procede de preparation de microparticules constituees de phytosterols ou de phytostanols
WO2000047213A1 (fr) * 1999-02-15 2000-08-17 Washington University Formulation de sitostanol contenant un emulsifiant utile pour reduire l'absorption du cholesterol, procede de preparation et d'utilisation de cette derniere

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0289636A1 (fr) * 1986-02-13 1988-11-09 Asahi Denka Kogyo Kabushiki Kaisha Composition émulsifiée ou solubilisée de stérol
US5244887A (en) * 1992-02-14 1993-09-14 Straub Carl D Stanols to reduce cholesterol absorption from foods and methods of preparation and use thereof
EP0897671A1 (fr) * 1997-08-22 1999-02-24 Unilever N.V. Dispersions ou suspensions aqueuses
EP0986962A1 (fr) * 1998-08-31 2000-03-22 McNEIL-PPC, INC. Assaisonnements stables pour salade
WO2000045648A1 (fr) * 1999-02-03 2000-08-10 Forbes Medi-Tech Inc. Procede de preparation de microparticules constituees de phytosterols ou de phytostanols
WO2000047213A1 (fr) * 1999-02-15 2000-08-17 Washington University Formulation de sitostanol contenant un emulsifiant utile pour reduire l'absorption du cholesterol, procede de preparation et d'utilisation de cette derniere

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1108364A3 (fr) * 1999-12-15 2002-05-29 McNEIL-PPC, INC. Alcools à chaine longue en mélange dans des composés stéroliques
EP1108364A2 (fr) * 1999-12-15 2001-06-20 McNEIL-PPC, INC. Alcools à chaine longue en mélange dans des composés stéroliques
WO2002034238A2 (fr) * 2000-10-24 2002-05-02 Banner Pharmacaps, Inc. Procede et formulations a base de gelatine coloree
WO2002034238A3 (fr) * 2000-10-24 2003-01-16 Banner Pharmacaps Inc Procede et formulations a base de gelatine coloree
US6685961B1 (en) 2000-10-24 2004-02-03 Banner Pharmacaps, Inc. Colored gelatin-based formulations and method
EP1538929A4 (fr) * 2002-03-20 2009-03-11 Eugene Science Inc Melange poudreux de sterol vegetal et d'emulsifiant, et procede de preparation associe
EP1538929A1 (fr) * 2002-03-20 2005-06-15 Eugene Science Inc. Melange poudreux de sterol vegetal et d'emulsifiant, et procede de preparation associe
US6623780B1 (en) 2002-03-26 2003-09-23 Cargill, Inc. Aqueous dispersible sterol product
WO2005009144A1 (fr) * 2002-11-13 2005-02-03 Basf Aktiengesellschaft Formulations pulverulentes a base de phytosterols
WO2006074752A1 (fr) * 2005-01-14 2006-07-20 Unilever N.V. Sachets comprenant un phytosterol
EP1695634A1 (fr) * 2005-02-24 2006-08-30 Cognis IP Management GmbH Dispersion solide de sterol contenant du sucre
US8029845B2 (en) 2005-02-24 2011-10-04 Cognis Ip Management Gmbh Compositions of sugar-containing sterol solids dispersions
WO2009098475A1 (fr) * 2008-02-06 2009-08-13 Biosuspensions Limited Systèmes tensioactifs structurés et leurs utilisations
WO2009098469A1 (fr) * 2008-02-06 2009-08-13 Biosuspensions Limited Nouvelles compositions et leurs utilisations
US9254264B2 (en) 2008-02-06 2016-02-09 Biosuspensions Limited Compositions and uses thereof
EP2398476A1 (fr) * 2009-02-23 2011-12-28 Nanorx, Inc. Nanoparticules de policosanol
EP2398476A4 (fr) * 2009-02-23 2013-09-11 Nanorx Inc Nanoparticules de policosanol
US9808426B2 (en) 2010-10-29 2017-11-07 Western University Of Health Sciences Ternary mixture formulations

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AU1463601A (en) 2001-05-14
JP2003520204A (ja) 2003-07-02
BR0015302A (pt) 2003-02-25
EP1225813A1 (fr) 2002-07-31
CA2389605A1 (fr) 2001-05-10
MXPA02004511A (es) 2002-10-11

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