CA2388339A1 - Cholesterol reducing sterol compositions, preparation and method of use - Google Patents
Cholesterol reducing sterol compositions, preparation and method of use Download PDFInfo
- Publication number
- CA2388339A1 CA2388339A1 CA002388339A CA2388339A CA2388339A1 CA 2388339 A1 CA2388339 A1 CA 2388339A1 CA 002388339 A CA002388339 A CA 002388339A CA 2388339 A CA2388339 A CA 2388339A CA 2388339 A1 CA2388339 A1 CA 2388339A1
- Authority
- CA
- Canada
- Prior art keywords
- phytosterol
- weight percent
- group
- mixtures
- polysorbate
- 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.)
- Abandoned
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 154
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 title claims description 70
- 238000000034 method Methods 0.000 title claims description 53
- 235000012000 cholesterol Nutrition 0.000 title description 30
- 229930182558 Sterol Natural products 0.000 title description 26
- 235000003702 sterols Nutrition 0.000 title description 26
- 150000003432 sterols Chemical class 0.000 title description 21
- 238000002360 preparation method Methods 0.000 title description 8
- 239000004094 surface-active agent Substances 0.000 claims abstract description 65
- 235000013305 food Nutrition 0.000 claims abstract description 42
- 229940075999 phytosterol ester Drugs 0.000 claims abstract description 35
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims abstract description 29
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims abstract description 28
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims abstract description 27
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims abstract description 21
- 229950005143 sitosterol Drugs 0.000 claims abstract description 21
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- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims abstract description 14
- KZJWDPNRJALLNS-FBZNIEFRSA-N clionasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-FBZNIEFRSA-N 0.000 claims abstract description 14
- KZJWDPNRJALLNS-VPUBHVLGSA-N (-)-beta-Sitosterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@@H](C(C)C)CC)C)CC4)CC3)CC=2)CC1 KZJWDPNRJALLNS-VPUBHVLGSA-N 0.000 claims abstract description 13
- CSVWWLUMXNHWSU-UHFFFAOYSA-N (22E)-(24xi)-24-ethyl-5alpha-cholest-22-en-3beta-ol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(CC)C(C)C)C1(C)CC2 CSVWWLUMXNHWSU-UHFFFAOYSA-N 0.000 claims abstract description 13
- KLEXDBGYSOIREE-UHFFFAOYSA-N 24xi-n-propylcholesterol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CCC)C(C)C)C1(C)CC2 KLEXDBGYSOIREE-UHFFFAOYSA-N 0.000 claims abstract description 13
- ARVGMISWLZPBCH-UHFFFAOYSA-N Dehydro-beta-sitosterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(CC)C(C)C)CCC33)C)C3=CC=C21 ARVGMISWLZPBCH-UHFFFAOYSA-N 0.000 claims abstract description 13
- MJVXAPPOFPTTCA-UHFFFAOYSA-N beta-Sistosterol Natural products CCC(CCC(C)C1CCC2C3CC=C4C(C)C(O)CCC4(C)C3CCC12C)C(C)C MJVXAPPOFPTTCA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 235000015500 sitosterol Nutrition 0.000 claims abstract description 13
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims abstract description 7
- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 claims abstract description 7
- SGNBVLSWZMBQTH-FGAXOLDCSA-N Campesterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@@](C)([C@H]([C@H](CC[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 SGNBVLSWZMBQTH-FGAXOLDCSA-N 0.000 claims abstract description 7
- BTEISVKTSQLKST-UHFFFAOYSA-N Haliclonasterol Natural products CC(C=CC(C)C(C)(C)C)C1CCC2C3=CC=C4CC(O)CCC4(C)C3CCC12C BTEISVKTSQLKST-UHFFFAOYSA-N 0.000 claims abstract description 7
- OILXMJHPFNGGTO-ZRUUVFCLSA-N UNPD197407 Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZRUUVFCLSA-N 0.000 claims abstract description 7
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims abstract description 7
- 235000004420 brassicasterol Nutrition 0.000 claims abstract description 7
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 claims abstract description 7
- 235000000431 campesterol Nutrition 0.000 claims abstract description 7
- SGNBVLSWZMBQTH-PODYLUTMSA-N campesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]1(C)CC2 SGNBVLSWZMBQTH-PODYLUTMSA-N 0.000 claims abstract description 7
- 229940032091 stigmasterol Drugs 0.000 claims abstract description 7
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims abstract description 7
- 235000016831 stigmasterol Nutrition 0.000 claims abstract description 7
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims abstract description 7
- -1 polyoxyethylene Polymers 0.000 claims description 35
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 32
- 229920001223 polyethylene glycol Polymers 0.000 claims description 27
- 239000002202 Polyethylene glycol Substances 0.000 claims description 25
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 24
- 239000000194 fatty acid Substances 0.000 claims description 24
- 229930195729 fatty acid Natural products 0.000 claims description 24
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 21
- 150000002191 fatty alcohols Chemical class 0.000 claims description 20
- 229930006000 Sucrose Natural products 0.000 claims description 16
- 238000002156 mixing Methods 0.000 claims description 16
- 229920000136 polysorbate Polymers 0.000 claims description 16
- 239000005720 sucrose Substances 0.000 claims description 16
- 230000001906 cholesterol absorption Effects 0.000 claims description 15
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 15
- MWKFXSUHUHTGQN-UHFFFAOYSA-N decan-1-ol Chemical compound CCCCCCCCCCO MWKFXSUHUHTGQN-UHFFFAOYSA-N 0.000 claims description 14
- NOPFSRXAKWQILS-UHFFFAOYSA-N docosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCO NOPFSRXAKWQILS-UHFFFAOYSA-N 0.000 claims description 14
- BTFJIXJJCSYFAL-UHFFFAOYSA-N icosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCO BTFJIXJJCSYFAL-UHFFFAOYSA-N 0.000 claims description 14
- HLZKNKRTKFSKGZ-UHFFFAOYSA-N tetradecan-1-ol Chemical compound CCCCCCCCCCCCCCO HLZKNKRTKFSKGZ-UHFFFAOYSA-N 0.000 claims description 14
- REZQBEBOWJAQKS-UHFFFAOYSA-N triacontan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCCCO REZQBEBOWJAQKS-UHFFFAOYSA-N 0.000 claims description 14
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims description 13
- 235000013361 beverage Nutrition 0.000 claims description 12
- 239000002775 capsule Substances 0.000 claims description 12
- IRHTZOCLLONTOC-UHFFFAOYSA-N hexacosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCO IRHTZOCLLONTOC-UHFFFAOYSA-N 0.000 claims description 12
- CNNRPFQICPFDPO-UHFFFAOYSA-N octacosan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCCCCCCCCCCCO CNNRPFQICPFDPO-UHFFFAOYSA-N 0.000 claims description 12
- 229920001214 Polysorbate 60 Polymers 0.000 claims description 10
- 229920003171 Poly (ethylene oxide) Polymers 0.000 claims description 9
- 229920000159 gelatin Polymers 0.000 claims description 9
- 235000019322 gelatine Nutrition 0.000 claims description 9
- XSEOYPMPHHCUBN-FGYWBSQSSA-N hydroxylated lecithin Chemical compound CCCCCCCCCCCCCCCCCC(=O)OC(COP([O-])(=O)OCC[N+](C)(C)C)COC(=O)CCCCCCC[C@@H](O)[C@H](O)CCCCCCCC XSEOYPMPHHCUBN-FGYWBSQSSA-N 0.000 claims description 9
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 9
- PIGTXFOGKFOFTO-FVFWYJKVSA-N (2S,3S,4S,5R,6R)-6-[[(3S,4S,4aR,6aR,6bS,8R,8aR,12aS,14aR,14bR)-8a-carboxy-4-formyl-8-hydroxy-4,6a,6b,11,11,14b-hexamethyl-1,2,3,4a,5,6,7,8,9,10,12,12a,14,14a-tetradecahydropicen-3-yl]oxy]-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound O([C@H]1CC[C@]2(C)[C@H]3CC=C4[C@@]([C@@]3(CC[C@H]2[C@@]1(C=O)C)C)(C)C[C@@H](O)[C@]1(CCC(C[C@H]14)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O PIGTXFOGKFOFTO-FVFWYJKVSA-N 0.000 claims description 8
- DUGDSUSSAHQMFH-UHFFFAOYSA-N 2-acetyl-2-hydroxy-4-oxopentanoic acid Chemical class C(C)(=O)CC(C(=O)O)(O)C(C)=O DUGDSUSSAHQMFH-UHFFFAOYSA-N 0.000 claims description 8
- 229920005682 EO-PO block copolymer Polymers 0.000 claims description 8
- 239000001422 FEMA 4092 Substances 0.000 claims description 8
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 claims description 8
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- 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
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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
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/10—Foods or foodstuffs containing additives; Preparation or treatment thereof containing emulsifiers
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
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- 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
Landscapes
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- Chemical & Material Sciences (AREA)
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Abstract
A composition comprising a mixture of a phytosterol and/or phytosterol ester and a surfactant(s). The surfactants are selected from the group consisting of anionic, cationic, nonionic, and zwitterionic surfactants. The phytosterol is selected from the group consisting of sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof. The phytosterol esters are derivatives of the aforementioned phytosterols. The invention is also directed to a method of making the disclosed compositions, and to non-fat containing food products including the disclosed compositions.
Description
Cholesterol Reducing Sterol Compositions, Preparation and Method of Use BACKGROUND
Field of the Invention This invention relates to plant sterol compositions and its derivatives for reduction of cholesterol absorption.
More particularly, the invention provides compositions containing a phytosterol and/or a phytosterol ester and surfactants) that are useful for reducing cholesterol absorption. The invention also relates to methods of preparing such compositions for reducing cholesterol absorption.
Related Background Art 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.
SUBSTITUTE SHEET (RULE 26) By reducing cholesterol content of food, as well as inhibiting the absorption of cholesterol, it has been possible to reduce serum levels of cholesterol. One of the areas that has been explored to control serum cholesterol levels is the use of dietary supplements, such as cholestyramine resin, probucol, colestipol HC1, nicotinic acid, mevinolin, pectin, guar gum, and oat bran. Another area, that has received considerable attention, has been the development of food additives that reduce the absorption of cholesterol in the small intestine. Prevention of the absorption of cholesterol results in lower levels of cholesterol in the blood and thus helps to prevent the formation of atherosclerotic plaques.
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), have also been found to be effective for reducing cholesterol absorption. It has been postulated that plant sterols (stanols) block cholesterol absorption by competing with cholesterol for bile acid micellerization. As a result of this competition between plant sterols and cholesterol, it is believed that plant sterols displace cholesterol from the micellar phase and thereby prevent SUBSTITUTE SHEET (RULE 26) 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 sterols 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 SUBSTITUTE SHEET (RULE 26) 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.
There is a continuing need for 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.
Furthermore, 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 sterol or a plant sterol SUBSTITUTE SHEET (RULE 26) ester and a surfactants) are effective at inhibiting the absorption of cholesterol.
SUMMARY OF THE INVENTION
Compositions for inhibiting the absorption of cholesterol are disclosed. The compositions comprise a plant sterol and/or a plant sterol ester and a surfactant(s). The surfactants) is selected from the group consisting of anionic, cationic, nonionic and zwitterionic surfactants.
Examples of plant sterols that may be employed include sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof. The compositions of the present invention provide an effective method of reducing cholesterol without any adverse side-effects.
The 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.
Advantageously, the compositions of the present invention can be used in non-fat containing foods.
The present invention also contemplates various combinations of the foregoing surfactants) and a SUBSTITUTE SHEET (RULE 26) phytosterol and/or a phytosterol ester being administered orally in any of the usual solid forms such as pills, tablets, capsules or powders, including sustained release preparations.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of plant sterol and/or plant sterol ester compositions that inhibit the absorption of cholesterol. More particularly, the invention relates to the formation of water soluble/dispersible sterol and/or sterol ester systems comprising a plant sterol and/or a plant sterol ester and anionic, cationic, nonionic, or zwitterionic surfactant systems, which reduce cholesterol absorption.
The terms "phytosterols" and "sterols" are used herein interchangeably. The phytosterols used in the present invention typically may include sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof. Generally, the phytosterols in the present invention will be a mixture of two or more of such phytosterols. The phytosterols are preferably present in the free form. However, in some instances, the phytosterols may be in the naturally occurring ester form. It will also be appreciated that modifications of the plant sterols are also well within the scope of the present invention, for example, small side chains.
The terms "phytosterol ester" and "sterol esters" are used herein interchangeably. The term "sterol ester" as used herein refers to plant sterols that has been SUBSTITUTE SHEET (RULE 26) _7_ modified to form a plant sterol ester derivative.
Sterols and their ester derivatives are well known in the art and are described "Analysis of Sterols" by L.J. Goad and T. Akihisa, (published by Blackie Academic &
Professional, in imprint of Chapman and Hall, United Kingdom, 1997) hereby incorporated by reference.
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. For example, 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.
Sitosterol may be obtained from cold pressed wheat germ oil, soy extract, or rice extract. (It will be appreciated that natural sitosterol contains about 40$
alpha-sitosterol and about 60~ beta-sitosterol.) In another embodiment of the present invention, plant stanols and/or plant stanol esters and mixtures may be used in the disclosed formulations of the present invention. Applicants hereby incorporate by reference the entire disclosure of attorney docket 775.4800, U.S.
Serial No. 60/163,382, filed November 4, 1999, and the entire disclosure of attorney docket 775.5100, U.S.
Serial No. 60/198,326, filed April 19, 2000, both entitled "Cholesterol Reducing Stanol Compositions, Preparation and Method of Use".
SUBSTITUTE SHEET (RULE 26) -g-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 and 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 ( CH3 ( CHz ) BCHZOH ) also known as n-decyl alcohol, 1-dodecanol ( CH3 ( CHz ) loCH20H ) also known as dodecyl or lauryl alcohol, 1-tetradecanol ( CH3 ( CHz ) lzCHzOH ) also known as myristyl alcohol, 1-hexadecanol ( CH3 ( CHz ) 14CHZOH ) also known as cetyl or palmityl alcohol, 1-octadecanol ( CH3 ( CHz ) lsCHzOH ) also known as stearyl alcohol, 9-octadecen-1-of ( CH3 ( CHz ),CH=CH ( CHz ),CHZOH ) also known as oleyl alcohol, 1-eicosanol ( CH3 ( CHz ) 18CHZOH ) also known as arachidyl alcohol, 1-docosanol ( CH3 ( CHz ) zoCHzOH ) also known as behenyl alcohol, 1-hexacosanol ( CH3 ( CHz ) z4CHzOH ) , 1-octaCOSariol ( CH3 ( CHz ) zsCHzOH ) also know SUBSTITUTE SHEET (RULE 26) as octacosyl alcohol (wheat leaf wax), 1-triacontanol ( CH3 ( CHz ) zeCHzOH ) also known as melissyl alcohol ( beeswax as stearate). A particularly preferred fatty alcohol is 1-octadecanol.
Zwitterionic surfactants include, hydroxylated lecithin and the like.
Other 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 (C1,H33COOH), stearic acid ( C1,H36COOH ) , and palmitic acid ( C15H31COOH ) , triglycerides CH3 ( CHz ) 6COOH and CH3 ( CHz ) $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 polyvinyl alcohol), polyvinyl pyrrolidone), hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose may also be employed in the compositions of the present invention.
SUBSTITUTE SHEET (RULE 26) Other 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.
In one preferred embodiment the composition of the present invention comprises a mixture of a phytosterol 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. The 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.
One preferred embodiment of the present invention comprises a mixture of a phytosterol and/or a phytosterol ester and fatty acid alcohol, preferably, octadecanol.
Another preferred embodiment of the present invention SUBSTITUTE SHEET (RULE 26) comprises a mixture a phytosterol and/or a phytosterol ester, Tween 60 and PEG. Other preferred embodiments include a phytosterol and/or a phytosterol 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 phytosterol and/or a phytosterol ester and a surf actant ( s ) .
In another embodiment of the present invention, emulsifiers may be used in the formulation of dispersible sterol and/or sterol ester systems. Preferred emulsifiers include a variety of phospholipids, 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. These and other phospholipids are described, for example, in Szuhaj and List (eds.), Lecithins, American Oil Chemists Society (1985) ("Szuhaj and List"), incorporated herein in its entirety by reference.
The phospholipids may be used individually or in various combinations, and may be obtained from "natural" sources (e.g., soybean lecithin) or from chemical synthesis. The SUBSTITUTE SHEET (RULE 26) phospholipids may be in the form of relatively unpurified mixtures of phospholipids 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. In addition, phospholipids including those found in crude soybean lecithins or other crude commercial lecithins may be chemically modified. Lecithins, other phospholipid preparations, or individual phospholipids 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 phospholipids can be compatible with the present methods. Thus, phospholipids 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 phospholipids, 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.
In common usage, the term "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 SUBSTITUTE SHEET (RULE 26) 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.
The term "lecithin"as used herein 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 phospholipids.
Commercial soybean lecithin, a preferred source of phospholipids, is obtained from the refining of soybean oil. Crude soybean oil generally contains about 1.0 to 3.0 weight percent phospholipids. When the crude oil is refined, the first step generally is to remove the phospholipids. This step, often called "degumming," is accomplished by first adding water to the crude oil. The water hydrates the phospholipids and makes them less soluble in the oil. The denser phospholipids and water are then separated from the less-dense oil, typically by centrifugation. Removal of the water from the dense phase results in a product having approximately equal amounts of phosphatidyl choline, phosphatidyl ethanolamine, and 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 phospholipids and a small amount SUBSTITUTE SHEET (RULE 26) (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.
Various 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.
Another commercial source of phospholipids is the class of products, resulting from modification of soybean lecithin to improve its hydrophilic properties. Various approaches have been taken to effect these modifications.
For example, soybean lecithin may be chemically or ezymatically modified, e.g., via reaction with malefic anhydride. Certain components may be removed from commercial soybean lecithin. Alternatively, another approach is to add various components, for example nonionic emulsifiers, to the commercial soybean lecithin.
Such emulsifiers include, without limitation, polyoxyalkylene monoglyceride, polyoxyalkylene diglycerides, and the polyoxyethylene derivatives of partial fatty acid esters. These modified lecithins are also included in the term "lecithin" as used herein.
Hydroxylated lecithin is a preferred embodiment of the phospholipids used in the invention. Hydroxylated SUBSTITUTE SHEET (RULE 26) lecithin is prepared by hydroxylating the double bonds in the fatty acids attached to the phospholipids and glycolipids of lecithin, which can be carried out by reaction with hydrogen peroxide and a weak acid such as lactic acid. Although not wishing to be bound by theory, it is believed that 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.
The compositions of the present invention are preferably formed into a fine dispersion using melt processing. One particular preferred method of melt processing comprises dry-mixing a phytosterol and/or a phytostarol ester and a surfactants) 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 phytosterol, phytosterol ester or surfactant(s). The resulting mixture is then rapidly cooled, e.g., liquid nitrogen, to form a salt like material. While not wishing to be limited by theory, it is believed that the step of melt blending the phytosterol and/or phytosterol ester and surfactants) 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 surfactants) to a SUBSTITUTE SHEET (RULE 26) phytosterol and/or phytosterol ester melt. This may be desirable in cases where the surfactants) is thermally unstable and would not survive prolonged heating at high temperatures, i.e., thus the residence time for the surfactants) is reduced by its later addition to a melt.
Once the surfactants) 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 surfactants) and phytosterol and/or phytosterol esters. It has been discovered that by using a mixing or compression means allowing for increasing the pressure on the ingredients, the surfactant(s), phytosterol and/or phytosterol esters will melt blend at ambient temperatures. Homogenous mixtures of heat sensitive surfactants) and phytosterol and/or phytosterol esters can therefore be formed while avoiding temperatures at which thermal decomposition of ingredients will occur.
One embodiment of high pressure melting is roller compaction. The surfactants) and phytosterol and/or phytosterol ester are mixed together as described previously, the mixture is then compressed together under high pressure using a roller. 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 SUBSTITUTE SHEET (RULE 26) extrusion. For example, in an extrusion process, a loosely packed powder mixture of surfactants) and phytosterol and/or phytosterol 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 phytosterol and/or a phytosterol ester anti surfactants) may also be processed using solution processing or steric stabilization. Use of solution processing is particularly effective for use with surfactants) that are thermally stable. The phytosterol and/or phytosterol ester and surfactants) 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 phytosterol and/or phytosterol ester and surfactant(s). A fine dispersion of a phytosterol and/or phytosterol ester is added to SUBSTITUTE SHEET (RULE 26) water containing the surfactant(s). The surfactants) in the water help to keep the sterols) 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol ester and from about 5 to about 60 weight percent of a surfactan.t(s), and more preferably about 95 weight percent of a phytosterol and/or phytosterol ester and about 5 percent by weight percent of a surfactant ( s ) .
In one preferred embodiment of the present invention, the compositions of the present invention comprise a phytosterol and/or phytosterol ester and at least two surfactants. Such a mixture comprises from about 10 to about 99.99 weight percent of a phytosterol and/or phytosterol 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol ester and the sum of at least two surfactants is about 5 weight percent.
SUBSTITUTE SHEET (RULE 26) 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.
The 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 (granulat.ion), 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.
Although the composition 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.
Alternatively, the compositions of the present invention SUBSTITUTE SHEET (RULE 26) 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.
The 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; brown bites; cookie chews in peanut butter, chocolate chip or ginger snaps;
granola/nutrition bar miniatures such as chocolate covered oat and peanut butter; and chewy breath mints.
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 sterol and/or sterol ester and surfactant(s), is used to reduce cholesterol absorption from foods and beverages includes the step of commingling the food SUBST<TUTE SHEET (RULE 26) additive composition with foods and beverages, mixing until uniformly blended.
In a preferred method of commingling the indicated food additive with foods and beverages which contain cholesterol, the food additive is added such that the amount of sterols in the food additive is in the ratio of about 1:1 by weight to the cholesterol contained in the foods a.nd beverages. Thus, for a food additive composition which comprises 25~ sterols and a food which contains about 0.1~ cholesterol (such as hamburger), 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.
The compositions of the present invention will be used as food additives to foods such as meats, eggs and dairy SUBSTITUTE SHEET (RULE 26) 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.
The 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.
The compositions of the invention may be administered to any animal. Foremost among such animals are mammals, 1.5 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.
The 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. The term 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., phytosterol and/or phytosterol ester, in association with a surfactants) and a carrier. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of SUBSTITUTE SHEET (RULE 26) such units. Of course, it is understood that 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol 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.
As used herein, the term "carrier" denotes a solid or liquid filler, diluent, or encapsulating substance. Some examples of the 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 SUBSTITUTE SHEET (RULE 26) alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in preparation of formulations. 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 Other preparations 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. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, 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.
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 SUBSTITUTE SHEET (RULE 26) 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. As an alternative to granulating, 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 mixture 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. In tablet form the carrier comprises from about 0.1~ to 99~ by SUBSTITUTE SHEET (RULE 26) weight of the total composition.
This invention will be better understood from the Example which follows. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention and no limitation of the invention is implied.
grams of soy sterols was dissolved in 250 ml chloroform with 1.05 grams of octadecanol. The chloroform was evaporated under nitrogen at room 15 temperature yielding a solid mixture containing 5 percent octadecanol. The mixture was cryogro~and into hamster chow and fed to hamsters at 1 percent stanol equivalent ir, their diet. The hamsters who consumed the chow with sterol were found to have absorbed less cholesterol than 20 a control group of hamsters that eat hamster chow without sterol.
Other objects, advantages, features, modifications of this invention will be apparent to those of ordinary skill in this art. This invention is not limited except as set forth in the following claims.
SUBSTITUTE SHEET (RULE 26)
Field of the Invention This invention relates to plant sterol compositions and its derivatives for reduction of cholesterol absorption.
More particularly, the invention provides compositions containing a phytosterol and/or a phytosterol ester and surfactants) that are useful for reducing cholesterol absorption. The invention also relates to methods of preparing such compositions for reducing cholesterol absorption.
Related Background Art 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.
SUBSTITUTE SHEET (RULE 26) By reducing cholesterol content of food, as well as inhibiting the absorption of cholesterol, it has been possible to reduce serum levels of cholesterol. One of the areas that has been explored to control serum cholesterol levels is the use of dietary supplements, such as cholestyramine resin, probucol, colestipol HC1, nicotinic acid, mevinolin, pectin, guar gum, and oat bran. Another area, that has received considerable attention, has been the development of food additives that reduce the absorption of cholesterol in the small intestine. Prevention of the absorption of cholesterol results in lower levels of cholesterol in the blood and thus helps to prevent the formation of atherosclerotic plaques.
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), have also been found to be effective for reducing cholesterol absorption. It has been postulated that plant sterols (stanols) block cholesterol absorption by competing with cholesterol for bile acid micellerization. As a result of this competition between plant sterols and cholesterol, it is believed that plant sterols displace cholesterol from the micellar phase and thereby prevent SUBSTITUTE SHEET (RULE 26) 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 sterols 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 SUBSTITUTE SHEET (RULE 26) 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.
There is a continuing need for 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.
Furthermore, 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 sterol or a plant sterol SUBSTITUTE SHEET (RULE 26) ester and a surfactants) are effective at inhibiting the absorption of cholesterol.
SUMMARY OF THE INVENTION
Compositions for inhibiting the absorption of cholesterol are disclosed. The compositions comprise a plant sterol and/or a plant sterol ester and a surfactant(s). The surfactants) is selected from the group consisting of anionic, cationic, nonionic and zwitterionic surfactants.
Examples of plant sterols that may be employed include sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof. The compositions of the present invention provide an effective method of reducing cholesterol without any adverse side-effects.
The 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.
Advantageously, the compositions of the present invention can be used in non-fat containing foods.
The present invention also contemplates various combinations of the foregoing surfactants) and a SUBSTITUTE SHEET (RULE 26) phytosterol and/or a phytosterol ester being administered orally in any of the usual solid forms such as pills, tablets, capsules or powders, including sustained release preparations.
DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the use of plant sterol and/or plant sterol ester compositions that inhibit the absorption of cholesterol. More particularly, the invention relates to the formation of water soluble/dispersible sterol and/or sterol ester systems comprising a plant sterol and/or a plant sterol ester and anionic, cationic, nonionic, or zwitterionic surfactant systems, which reduce cholesterol absorption.
The terms "phytosterols" and "sterols" are used herein interchangeably. The phytosterols used in the present invention typically may include sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof. Generally, the phytosterols in the present invention will be a mixture of two or more of such phytosterols. The phytosterols are preferably present in the free form. However, in some instances, the phytosterols may be in the naturally occurring ester form. It will also be appreciated that modifications of the plant sterols are also well within the scope of the present invention, for example, small side chains.
The terms "phytosterol ester" and "sterol esters" are used herein interchangeably. The term "sterol ester" as used herein refers to plant sterols that has been SUBSTITUTE SHEET (RULE 26) _7_ modified to form a plant sterol ester derivative.
Sterols and their ester derivatives are well known in the art and are described "Analysis of Sterols" by L.J. Goad and T. Akihisa, (published by Blackie Academic &
Professional, in imprint of Chapman and Hall, United Kingdom, 1997) hereby incorporated by reference.
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. For example, 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.
Sitosterol may be obtained from cold pressed wheat germ oil, soy extract, or rice extract. (It will be appreciated that natural sitosterol contains about 40$
alpha-sitosterol and about 60~ beta-sitosterol.) In another embodiment of the present invention, plant stanols and/or plant stanol esters and mixtures may be used in the disclosed formulations of the present invention. Applicants hereby incorporate by reference the entire disclosure of attorney docket 775.4800, U.S.
Serial No. 60/163,382, filed November 4, 1999, and the entire disclosure of attorney docket 775.5100, U.S.
Serial No. 60/198,326, filed April 19, 2000, both entitled "Cholesterol Reducing Stanol Compositions, Preparation and Method of Use".
SUBSTITUTE SHEET (RULE 26) -g-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 and 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 ( CH3 ( CHz ) BCHZOH ) also known as n-decyl alcohol, 1-dodecanol ( CH3 ( CHz ) loCH20H ) also known as dodecyl or lauryl alcohol, 1-tetradecanol ( CH3 ( CHz ) lzCHzOH ) also known as myristyl alcohol, 1-hexadecanol ( CH3 ( CHz ) 14CHZOH ) also known as cetyl or palmityl alcohol, 1-octadecanol ( CH3 ( CHz ) lsCHzOH ) also known as stearyl alcohol, 9-octadecen-1-of ( CH3 ( CHz ),CH=CH ( CHz ),CHZOH ) also known as oleyl alcohol, 1-eicosanol ( CH3 ( CHz ) 18CHZOH ) also known as arachidyl alcohol, 1-docosanol ( CH3 ( CHz ) zoCHzOH ) also known as behenyl alcohol, 1-hexacosanol ( CH3 ( CHz ) z4CHzOH ) , 1-octaCOSariol ( CH3 ( CHz ) zsCHzOH ) also know SUBSTITUTE SHEET (RULE 26) as octacosyl alcohol (wheat leaf wax), 1-triacontanol ( CH3 ( CHz ) zeCHzOH ) also known as melissyl alcohol ( beeswax as stearate). A particularly preferred fatty alcohol is 1-octadecanol.
Zwitterionic surfactants include, hydroxylated lecithin and the like.
Other 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 (C1,H33COOH), stearic acid ( C1,H36COOH ) , and palmitic acid ( C15H31COOH ) , triglycerides CH3 ( CHz ) 6COOH and CH3 ( CHz ) $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 polyvinyl alcohol), polyvinyl pyrrolidone), hydroxypropyl methyl cellulose, and sodium carboxymethyl cellulose may also be employed in the compositions of the present invention.
SUBSTITUTE SHEET (RULE 26) Other 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.
In one preferred embodiment the composition of the present invention comprises a mixture of a phytosterol 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. The 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.
One preferred embodiment of the present invention comprises a mixture of a phytosterol and/or a phytosterol ester and fatty acid alcohol, preferably, octadecanol.
Another preferred embodiment of the present invention SUBSTITUTE SHEET (RULE 26) comprises a mixture a phytosterol and/or a phytosterol ester, Tween 60 and PEG. Other preferred embodiments include a phytosterol and/or a phytosterol 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 phytosterol and/or a phytosterol ester and a surf actant ( s ) .
In another embodiment of the present invention, emulsifiers may be used in the formulation of dispersible sterol and/or sterol ester systems. Preferred emulsifiers include a variety of phospholipids, 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. These and other phospholipids are described, for example, in Szuhaj and List (eds.), Lecithins, American Oil Chemists Society (1985) ("Szuhaj and List"), incorporated herein in its entirety by reference.
The phospholipids may be used individually or in various combinations, and may be obtained from "natural" sources (e.g., soybean lecithin) or from chemical synthesis. The SUBSTITUTE SHEET (RULE 26) phospholipids may be in the form of relatively unpurified mixtures of phospholipids 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. In addition, phospholipids including those found in crude soybean lecithins or other crude commercial lecithins may be chemically modified. Lecithins, other phospholipid preparations, or individual phospholipids 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 phospholipids can be compatible with the present methods. Thus, phospholipids 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 phospholipids, 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.
In common usage, the term "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 SUBSTITUTE SHEET (RULE 26) 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.
The term "lecithin"as used herein 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 phospholipids.
Commercial soybean lecithin, a preferred source of phospholipids, is obtained from the refining of soybean oil. Crude soybean oil generally contains about 1.0 to 3.0 weight percent phospholipids. When the crude oil is refined, the first step generally is to remove the phospholipids. This step, often called "degumming," is accomplished by first adding water to the crude oil. The water hydrates the phospholipids and makes them less soluble in the oil. The denser phospholipids and water are then separated from the less-dense oil, typically by centrifugation. Removal of the water from the dense phase results in a product having approximately equal amounts of phosphatidyl choline, phosphatidyl ethanolamine, and 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 phospholipids and a small amount SUBSTITUTE SHEET (RULE 26) (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.
Various 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.
Another commercial source of phospholipids is the class of products, resulting from modification of soybean lecithin to improve its hydrophilic properties. Various approaches have been taken to effect these modifications.
For example, soybean lecithin may be chemically or ezymatically modified, e.g., via reaction with malefic anhydride. Certain components may be removed from commercial soybean lecithin. Alternatively, another approach is to add various components, for example nonionic emulsifiers, to the commercial soybean lecithin.
Such emulsifiers include, without limitation, polyoxyalkylene monoglyceride, polyoxyalkylene diglycerides, and the polyoxyethylene derivatives of partial fatty acid esters. These modified lecithins are also included in the term "lecithin" as used herein.
Hydroxylated lecithin is a preferred embodiment of the phospholipids used in the invention. Hydroxylated SUBSTITUTE SHEET (RULE 26) lecithin is prepared by hydroxylating the double bonds in the fatty acids attached to the phospholipids and glycolipids of lecithin, which can be carried out by reaction with hydrogen peroxide and a weak acid such as lactic acid. Although not wishing to be bound by theory, it is believed that 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.
The compositions of the present invention are preferably formed into a fine dispersion using melt processing. One particular preferred method of melt processing comprises dry-mixing a phytosterol and/or a phytostarol ester and a surfactants) 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 phytosterol, phytosterol ester or surfactant(s). The resulting mixture is then rapidly cooled, e.g., liquid nitrogen, to form a salt like material. While not wishing to be limited by theory, it is believed that the step of melt blending the phytosterol and/or phytosterol ester and surfactants) 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 surfactants) to a SUBSTITUTE SHEET (RULE 26) phytosterol and/or phytosterol ester melt. This may be desirable in cases where the surfactants) is thermally unstable and would not survive prolonged heating at high temperatures, i.e., thus the residence time for the surfactants) is reduced by its later addition to a melt.
Once the surfactants) 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 surfactants) and phytosterol and/or phytosterol esters. It has been discovered that by using a mixing or compression means allowing for increasing the pressure on the ingredients, the surfactant(s), phytosterol and/or phytosterol esters will melt blend at ambient temperatures. Homogenous mixtures of heat sensitive surfactants) and phytosterol and/or phytosterol esters can therefore be formed while avoiding temperatures at which thermal decomposition of ingredients will occur.
One embodiment of high pressure melting is roller compaction. The surfactants) and phytosterol and/or phytosterol ester are mixed together as described previously, the mixture is then compressed together under high pressure using a roller. 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 SUBSTITUTE SHEET (RULE 26) extrusion. For example, in an extrusion process, a loosely packed powder mixture of surfactants) and phytosterol and/or phytosterol 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 phytosterol and/or a phytosterol ester anti surfactants) may also be processed using solution processing or steric stabilization. Use of solution processing is particularly effective for use with surfactants) that are thermally stable. The phytosterol and/or phytosterol ester and surfactants) 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 phytosterol and/or phytosterol ester and surfactant(s). A fine dispersion of a phytosterol and/or phytosterol ester is added to SUBSTITUTE SHEET (RULE 26) water containing the surfactant(s). The surfactants) in the water help to keep the sterols) 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol ester and from about 5 to about 60 weight percent of a surfactan.t(s), and more preferably about 95 weight percent of a phytosterol and/or phytosterol ester and about 5 percent by weight percent of a surfactant ( s ) .
In one preferred embodiment of the present invention, the compositions of the present invention comprise a phytosterol and/or phytosterol ester and at least two surfactants. Such a mixture comprises from about 10 to about 99.99 weight percent of a phytosterol and/or phytosterol 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol ester and the sum of at least two surfactants is about 5 weight percent.
SUBSTITUTE SHEET (RULE 26) 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.
The 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 (granulat.ion), 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.
Although the composition 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.
Alternatively, the compositions of the present invention SUBSTITUTE SHEET (RULE 26) 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.
The 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; brown bites; cookie chews in peanut butter, chocolate chip or ginger snaps;
granola/nutrition bar miniatures such as chocolate covered oat and peanut butter; and chewy breath mints.
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 sterol and/or sterol ester and surfactant(s), is used to reduce cholesterol absorption from foods and beverages includes the step of commingling the food SUBST<TUTE SHEET (RULE 26) additive composition with foods and beverages, mixing until uniformly blended.
In a preferred method of commingling the indicated food additive with foods and beverages which contain cholesterol, the food additive is added such that the amount of sterols in the food additive is in the ratio of about 1:1 by weight to the cholesterol contained in the foods a.nd beverages. Thus, for a food additive composition which comprises 25~ sterols and a food which contains about 0.1~ cholesterol (such as hamburger), 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.
The compositions of the present invention will be used as food additives to foods such as meats, eggs and dairy SUBSTITUTE SHEET (RULE 26) 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.
The 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.
The compositions of the invention may be administered to any animal. Foremost among such animals are mammals, 1.5 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.
The 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. The term 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., phytosterol and/or phytosterol ester, in association with a surfactants) and a carrier. The quantity of active material is that calculated to produce the desired therapeutic effect upon administration of one or more of SUBSTITUTE SHEET (RULE 26) such units. Of course, it is understood that 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 phytosterol and/or phytosterol 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 phytosterol and/or phytosterol 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.
As used herein, the term "carrier" denotes a solid or liquid filler, diluent, or encapsulating substance. Some examples of the 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 SUBSTITUTE SHEET (RULE 26) alcohol and phosphate buffer solutions, as well as other non-toxic compatible substances used in preparation of formulations. 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 Other preparations 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. In soft capsules, the active compounds are preferably dissolved or suspended in suitable liquids, such as fatty oils, or liquid paraffin. In addition, 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.
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 SUBSTITUTE SHEET (RULE 26) 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. As an alternative to granulating, 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 mixture 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. In tablet form the carrier comprises from about 0.1~ to 99~ by SUBSTITUTE SHEET (RULE 26) weight of the total composition.
This invention will be better understood from the Example which follows. However, one skilled in the art will readily appreciate that the specific methods and results discussed are merely illustrative of the invention and no limitation of the invention is implied.
grams of soy sterols was dissolved in 250 ml chloroform with 1.05 grams of octadecanol. The chloroform was evaporated under nitrogen at room 15 temperature yielding a solid mixture containing 5 percent octadecanol. The mixture was cryogro~and into hamster chow and fed to hamsters at 1 percent stanol equivalent ir, their diet. The hamsters who consumed the chow with sterol were found to have absorbed less cholesterol than 20 a control group of hamsters that eat hamster chow without sterol.
Other objects, advantages, features, modifications of this invention will be apparent to those of ordinary skill in this art. This invention is not limited except as set forth in the following claims.
SUBSTITUTE SHEET (RULE 26)
Claims (63)
1. A composition comprising a mixture of a phytosterol 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.
2. The composition of claim 1, further comprising 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.
3. The composition of claim 1, wherein the phytosterol is selected from the group consisting of sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof.
4. The composition of claim 3, wherein the sitosterol is alpha-sitosterol or beta-sitosterol.
5. The composition of claim 2, wherein said fatty alcohol is selected from the group consisting of 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol, 9-octadecen-1-ol, 1-eicosanol, 1-docosanol, 1-hexacosanol, 1-octacosanol, 1-triacontanol and mixtures thereof.
6. The composition of claim 5, wherein said fatty alcohol is 1-octadecanol.
7. The composition of claim 2, wherein said sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose distearate, sucrose palmitate and mixtures thereof.
8. The composition of claim 2, wherein said tween is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85.
9. The composition of claim 1, comprising from about 10 to about 99.99 weight percent of said phytosterol and from about 0.01 to about 90 weight percent of said surfactant.
10. The composition of claim 9, comprising from about 40 to about 95 weight percent of said phytosterol and from about 5 to 60 weight percent of said surfactant.
11. The composition of claim 10, comprising about 95 weight percent of said phytosterol and about 5 weight percent of said surfactant.
12. A method of reducing cholesterol absorption in humans which comprises orally administering an effective amount of a mixture of a phytosterol 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.
13. The method of claim 12, further comprising 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.
14. The method of claim 12, wherein the phytosterol is selected from the group consisting of sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof.
15. The method of claim 14, wherein the sitosterol is alpha-sitosterol or beta-sitosterol.
16. The method of claim 13, wherein said fatty alcohol is selected from the group consisting of 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol, 9-octadecen-1-ol, 1-eicosanol, 1-docosanol, 1-hexacosanol, 1-octacosanol, 1-triacontanol and mixtures thereof.
17. The method of claim 16, wherein said fatty alcohol is 1-octadecanol.
18. The method of claim 13, wherein said sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose distearate, sucrose palmitate and mixtures thereof.
19. The method of claim 13, wherein said tween is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85.
20. The method of claim 12, comprising from about 10 to about 99.99 weight percent of said phytosterol and from about 0.01 to about 90 weight percent of said surfactant.
21. The method of claim 20, comprising from about 40 to about 95 weight percent of said phytosterol and from about 5 to 60 weight percent of said surfactant.
22. The method of claim 21, comprising about 95 weight percent of said phytosterol and about 5 weight percent of said surfactant.
23. The method of claim 12, wherein said mixture is orally administered in the form of chewable, effervescent, swallowable and coated tablets, capsules, soft gelatine capsules, syrup, fruit beverages, granule sachets, fruit gelatines, mini-sweets or sweets.
24. A method for reducing serum cholesterol levels comprising administering a mixture of a phytosterol 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.
25. The method of claim 24, further comprising 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.
26. The method of claims 24 or 25, wherein the mixture is administered orally.
27. The method of claim 24, wherein the phytosterol is selected from the group consisting of sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof.
28. The method of claim 27, wherein the sitosterol is alpha-sitosterol or beta-sitosterol.
29. The method of claim 25, wherein said fatty alcohol is selected from the group consisting of 1-decanol, 1-dodecanol, 1-tetradecanol. 1-hexadecanol, 1-octadecanol, 9-octadecen-1-ol, 1-eicosanol, 1-docosanol, 1-hexacosanol, 1-octacosanol, 1-triacontanol and mixtures thereof.
30. The method of claim 29, wherein said fatty alcohol is 1-octadecanol.
31. The method of claim 25, wherein said sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose distearate, sucrose palmitate and mixtures thereof.
32. The method of claim 25, wherein said tween is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85.
33. The method of claim 24, comprising from about 10 to about 99.99 weight percent of said phytosterol and from about 0.01 to about 90 weight percent of said surfactant.
34. The method of claim 33, comprising from about 40 to about 95 weight percent of said phytosterol and from about 5 to 60 weight percent of said surfactant.
35. The method of claim 34, comprising about 95 weight percent of said phytosterol and about 5 weight percent of said surfactant.
36. A method for preparing a composition for the reduction of cholesterol absorption, comprising the step of mixing a phytosterol 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.
37. The method of claim 36, wherein the mixing is conducted under elevated pressure.
38. The method of claim 37, wherein the mixing is conducted by roller compaction.
39. The method of claim 37, wherein the mixing is conducted in an extruder.
40. The method of claim 36, further comprising 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.
41. The method of claim 40, further comprising the step of heating said mixture of said phytosterol and said surfactants to a temperature that results in the formation of a melt.
42. The method of claim 41, further comprising the step of rapidly cooling said melt.
43. The method of claim 42, wherein liquid nitrogen is used for cooling.
44. A food product comprising a mixture of a phytosterol 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.
45. The food product of claim 44, further comprising 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.
46. The food product of claim 44, wherein the phytosterol is selected from the group consisting of sitosterol, campesterol, brassicasterol, stigmasterol, clionasterol and mixtures thereof.
47. The food product of claim 46, wherein the sitosterol is alpha-sitosterol or beta-sitosterol.
48. The food product of claim 45, wherein said fatty alcohol is selected from the group consisting of 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol, 9-octadecen-1-ol, 1-eicosanol, 1-docosanol, 1-hexacosanol, 1-octacosanol, 1-triacontanol and mixtures thereof.
49. The food product of claim 48, wherein said fatty alcohol is 1-octadecanol.
50. The food product of claim 45, wherein said sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose distearate, sucrose palmitate and mixtures thereof.
51. The food product of claim 45, wherein said tween is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85.
52. The food product of claim 44, comprising from about to about 99.99 weight percent of said phytosterol and from about 0.01 to about 90 weight percent of said surfactant.
53. The food product of claim 52, comprising from about 40 to about 95 weight percent of said phytosterol and from about 5 to 60 weight percent of said surfactant.
54. The food product of claim 53, comprising about 95 weight percent of said phytosterol and about 5 weight percent of said surfactant.
55. A composition comprising a mixture of a phytosterol 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.
56. The composition of claim 55, further comprising 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.
57. The composition of claim 55, wherein said fatty alcohol is selected from the group consisting of 1-decanol, 1-dodecanol, 1-tetradecanol, 1-hexadecanol, 1-octadecanol, 9-octadecen-1-ol, 1-eicosanol, 1-docosanol, 1-hexacosanol, 1-octacosanol, 1-triacontanol and mixtures thereof.
58. The composition of claim 56, wherein said fatty alcohol is 1-octadecanol.
59. The composition of claim 56, wherein said sucrose fatty acid ester is selected from the group consisting of sucrose stearate, sucrose distearate, sucrose palmitate and mixtures thereof.
60. The composition of claim 56, wherein said tween is selected from the group consisting of polysorbate 20, polysorbate 40, polysorbate 60, polysorbate 80, and polysorbate 85.
61. The composition of claim 55, comprising from about to about 99.99 weight percent of said phytosterol ester and from about 0.01 to about 90 weight percent of said surfactant.
62. The composition of claim 61, comprising from about 40 to about 95 weight percent of said phytosterol ester and from about 5 to 60 weight percent of said surfactant.
63. The composition of claim 62, comprising about 95 weight percent of said phytosterol ester and about 5 weight percent of said surfactant.
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US16338399P | 1999-11-04 | 1999-11-04 | |
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US60/198,449 | 2000-04-19 | ||
PCT/US2000/030350 WO2001032031A2 (en) | 1999-11-04 | 2000-11-03 | Cholesterol reducing sterol compositions, preparation and method of use |
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JP (1) | JP2004525856A (en) |
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CA (1) | CA2388339A1 (en) |
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CN107594506A (en) * | 2016-09-20 | 2018-01-19 | 福建奥正投资发展有限公司 | The combination of hydrophily lipid composite and water fluid, it is prepared and concocting method and application |
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US6355274B1 (en) * | 1999-12-15 | 2002-03-12 | Mcneil-Ppc, Inc. | Encapsulated long chain alcohols |
NZ508692A (en) * | 1999-12-15 | 2002-10-25 | Mcneil Ppc Inc | Cholesterol lowering comestibles comprising policosanol (predominately octasanol) and sterol |
ATE384446T1 (en) * | 2000-08-03 | 2008-02-15 | Haerting Thomas Francis | PHARMACEUTICAL AND FOOD COMPOSITIONS WITH ßWOOD ALCOHOL AND ßWOOD STEROL FOR LOWERING SERUM CHOLESTEROL |
US6730319B2 (en) * | 2001-06-06 | 2004-05-04 | Hoffmann-La Roche Inc. | Pharmaceutical compositions having depressed melting points |
US6623780B1 (en) | 2002-03-26 | 2003-09-23 | Cargill, Inc. | Aqueous dispersible sterol product |
CN1293882C (en) * | 2003-01-15 | 2007-01-10 | 李安国 | Compound phytosterol with serum cholesterol-reducing action and preparing process thereof |
FI20030610A0 (en) * | 2003-04-22 | 2003-04-22 | Raisio Benecol Oy | Edible product |
US20060035009A1 (en) * | 2004-08-10 | 2006-02-16 | Kraft Foods Holdings, Inc. | Compositions and processes for water-dispersible phytosterols and phytostanols |
JP2007097464A (en) * | 2005-10-04 | 2007-04-19 | Tama Seikagaku Kk | Composition suitable for producing pill |
EP2042180A1 (en) * | 2007-09-28 | 2009-04-01 | Swiss Caps Rechte und Lizenzen AG | Preparations containing phytosterol |
SE532965C2 (en) | 2008-02-06 | 2010-05-25 | Edio Healthcare Ab | Process for the preparation of plant sterol microparticles |
BRPI0909185A2 (en) | 2008-03-20 | 2015-08-25 | Virun Inc | Vitamin E derivative and its uses |
DK2548456T3 (en) | 2008-03-20 | 2015-09-28 | Virun Inc | Emulsions including (comprising) a PEG derivative of tocopherol |
US9320295B2 (en) * | 2010-03-23 | 2016-04-26 | Virun, Inc. | Compositions containing non-polar compounds |
WO2011162802A1 (en) | 2010-06-21 | 2011-12-29 | Virun, Inc. | Compositions containing non-polar compounds |
KR101505064B1 (en) | 2013-05-07 | 2015-03-30 | 한국과학기술연구원 | Discrimination of sitosterolemia in a dried blood spot |
US9132117B2 (en) | 2013-06-17 | 2015-09-15 | Kgk Synergize, Inc | Compositions and methods for glycemic control of subjects with impaired fasting glucose |
US9861611B2 (en) | 2014-09-18 | 2018-01-09 | Virun, Inc. | Formulations of water-soluble derivatives of vitamin E and soft gel compositions, concentrates and powders containing same |
CA3033547C (en) * | 2016-09-27 | 2021-05-18 | Guangxi Jiufu Biotechnology Co., Ltd | Extract effective in treating drug addiction and preparation method therefor |
FR3091706B1 (en) * | 2019-01-10 | 2021-10-01 | Arkema France | COMPOSITION OF VEGETABLE OIL FOR COATING PARTICLES |
CN110236196A (en) * | 2019-07-19 | 2019-09-17 | 陕西益恺生物科技有限公司 | A kind of water-dispersible phytosterols mixing medicinal powder and preparation method thereof |
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JPS62186936A (en) * | 1986-02-13 | 1987-08-15 | Asahi Denka Kogyo Kk | Emulsified or solubilized sterol composition |
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 |
US6423363B1 (en) * | 1997-08-22 | 2002-07-23 | Lipton, Division Of Conopco, Inc. | Aqueous dispersion |
US6063776A (en) * | 1998-05-26 | 2000-05-16 | Washington University | Sitostanol formulation with emulsifier to reduce cholesterol absorption and method for preparing and use of same |
US6123978A (en) * | 1998-08-31 | 2000-09-26 | Mcneil-Ppc, Inc. | Stable salad dressings |
WO2000045648A1 (en) * | 1999-02-03 | 2000-08-10 | Forbes Medi-Tech Inc. | Method of preparing microparticles of phytosterols or phytostanols |
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- 2000-11-03 JP JP2001534247A patent/JP2004525856A/en not_active Withdrawn
- 2000-11-03 CA CA002388339A patent/CA2388339A1/en not_active Abandoned
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- 2000-11-03 MX MXPA02004504A patent/MXPA02004504A/en unknown
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- 2000-11-03 AU AU14608/01A patent/AU1460801A/en not_active Abandoned
- 2000-11-03 EP EP00976899A patent/EP1225812A2/en not_active Withdrawn
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN107594506A (en) * | 2016-09-20 | 2018-01-19 | 福建奥正投资发展有限公司 | The combination of hydrophily lipid composite and water fluid, it is prepared and concocting method and application |
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AU1460801A (en) | 2001-05-14 |
WO2001032031A3 (en) | 2001-12-06 |
EP1225812A2 (en) | 2002-07-31 |
BR0015331A (en) | 2002-07-09 |
MXPA02004504A (en) | 2002-09-02 |
JP2004525856A (en) | 2004-08-26 |
WO2001032031A2 (en) | 2001-05-10 |
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