MXPA99010678A - Phytosterol and / or phytostate derivatives - Google Patents
Phytosterol and / or phytostate derivativesInfo
- Publication number
- MXPA99010678A MXPA99010678A MXPA/A/1999/010678A MX9910678A MXPA99010678A MX PA99010678 A MXPA99010678 A MX PA99010678A MX 9910678 A MX9910678 A MX 9910678A MX PA99010678 A MXPA99010678 A MX PA99010678A
- Authority
- MX
- Mexico
- Prior art keywords
- esters
- mixture
- phytosterol
- phytosterols
- polyunsaturated fatty
- Prior art date
Links
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol 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 claims abstract description 54
- 150000002148 esters Chemical class 0.000 claims abstract description 54
- 235000020777 polyunsaturated fatty acids Nutrition 0.000 claims abstract description 24
- 150000003626 triacylglycerols Chemical class 0.000 claims abstract description 21
- 125000004432 carbon atoms Chemical group C* 0.000 claims abstract description 10
- 239000000203 mixture Substances 0.000 claims description 74
- 229940068065 Phytosterols Drugs 0.000 claims description 29
- MBMBGCFOFBJSGT-KUBAVDMBSA-N Docosahexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 21
- JAZBEHYOTPTENJ-JLNKQSITSA-N Eicosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O JAZBEHYOTPTENJ-JLNKQSITSA-N 0.000 claims description 20
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 20
- 235000005911 diet Nutrition 0.000 claims description 18
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 17
- 239000000194 fatty acid Substances 0.000 claims description 17
- 229960005135 Eicosapentaenoic Acid Drugs 0.000 claims description 16
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 16
- 150000004665 fatty acids Chemical class 0.000 claims description 16
- 229950005143 sitosterol Drugs 0.000 claims description 16
- KZJWDPNRJALLNS-VJSFXXLFSA-N β-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 description 16
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 15
- 229960004363 doconexent Drugs 0.000 claims description 14
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 14
- 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 description 12
- 235000013305 food Nutrition 0.000 claims description 11
- -1 sodium alkoxide Chemical class 0.000 claims description 11
- LGJMUZUPVCAVPU-HRJGVYIJSA-N Stigmastanol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]2(C)CC1 LGJMUZUPVCAVPU-HRJGVYIJSA-N 0.000 claims description 9
- LGJMUZUPVCAVPU-JFBKYFIKSA-N Sitostanol Natural products O[C@@H]1C[C@H]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)CC2)CC1 LGJMUZUPVCAVPU-JFBKYFIKSA-N 0.000 claims description 8
- 229940076810 beta Sitosterol Drugs 0.000 claims description 8
- 150000002194 fatty esters Chemical class 0.000 claims description 8
- 210000002966 Serum Anatomy 0.000 claims description 7
- 238000006243 chemical reaction Methods 0.000 claims 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 description 6
- 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 description 6
- 235000000431 campesterol Nutrition 0.000 claims description 6
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 5
- 230000000378 dietary Effects 0.000 claims description 5
- 238000010438 heat treatment Methods 0.000 claims description 5
- 238000009884 interesterification Methods 0.000 claims description 5
- ARYTXMNEANMLMU-ATEDBJNTSA-N Campestanol Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@H](C)CC[C@@H](C)C(C)C)[C@@]2(C)CC1 ARYTXMNEANMLMU-ATEDBJNTSA-N 0.000 claims description 4
- 239000002775 capsule Substances 0.000 claims description 3
- 235000015872 dietary supplement Nutrition 0.000 claims description 3
- 125000005456 glyceride group Chemical group 0.000 claims description 3
- 239000004615 ingredient Substances 0.000 claims description 3
- 241000282412 Homo Species 0.000 claims description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 claims description 2
- 238000005886 esterification reaction Methods 0.000 claims description 2
- 235000006486 human diet Nutrition 0.000 claims description 2
- 238000000034 method Methods 0.000 claims description 2
- 238000002360 preparation method Methods 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- 125000004429 atoms Chemical group 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 229940107161 Cholesterol Drugs 0.000 abstract description 25
- 235000012000 cholesterol Nutrition 0.000 abstract description 18
- 230000001603 reducing Effects 0.000 abstract description 7
- 238000006722 reduction reaction Methods 0.000 abstract description 5
- 239000011203 carbon fibre reinforced carbon Substances 0.000 abstract 1
- 235000003702 sterols Nutrition 0.000 description 17
- 230000037213 diet Effects 0.000 description 13
- 239000003921 oil Substances 0.000 description 13
- 235000019198 oils Nutrition 0.000 description 13
- 150000003432 sterols Chemical class 0.000 description 12
- 210000002381 Plasma Anatomy 0.000 description 10
- 241000700159 Rattus Species 0.000 description 10
- 239000007788 liquid Substances 0.000 description 9
- 239000007787 solid Substances 0.000 description 9
- 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 description 8
- 229940032091 Stigmasterol Drugs 0.000 description 8
- HCXVJBMSMIARIN-MFBJGPNFSA-N Stigmasterol 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)CC)C)CC4)CC3)CC=2)CC1 HCXVJBMSMIARIN-MFBJGPNFSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- 235000015500 sitosterol Nutrition 0.000 description 8
- 235000016831 stigmasterol Nutrition 0.000 description 8
- 239000000463 material Substances 0.000 description 7
- 229940075999 phytosterol esters Drugs 0.000 description 7
- 235000015112 vegetable and seed oil Nutrition 0.000 description 7
- 229940000640 Docosahexaenoate Drugs 0.000 description 6
- 239000002253 acid Substances 0.000 description 6
- 239000008157 edible vegetable oil Substances 0.000 description 6
- 230000037406 food intake Effects 0.000 description 6
- DTOSIQBPPRVQHS-PDBXOOCHSA-N α-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 6
- 210000004369 Blood Anatomy 0.000 description 5
- 108060003412 GRP Proteins 0.000 description 5
- 102000015779 HDL Lipoproteins Human genes 0.000 description 5
- 239000008280 blood Substances 0.000 description 5
- 239000012230 colorless oil Substances 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003925 fat Substances 0.000 description 5
- 235000019197 fats Nutrition 0.000 description 5
- 239000008158 vegetable oil Substances 0.000 description 5
- 208000008787 Cardiovascular Disease Diseases 0.000 description 4
- 229940066279 Eicosapentaenoate Drugs 0.000 description 4
- 235000019484 Rapeseed oil Nutrition 0.000 description 4
- 150000007513 acids Chemical class 0.000 description 4
- 230000003247 decreasing Effects 0.000 description 4
- YMWUJEATGCHHMB-UHFFFAOYSA-N methylene dichloride Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 4
- 238000008214 LDL Cholesterol Methods 0.000 description 3
- OYHQOLUKZRVURQ-IXWMQOLASA-N Linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 3
- 229960004488 Linolenic Acid Drugs 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N Oleic acid Natural products CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 3
- QTBSBXVTEAMEQO-UHFFFAOYSA-N acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 3
- 230000005587 bubbling Effects 0.000 description 3
- 235000005687 corn oil Nutrition 0.000 description 3
- 239000002285 corn oil Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 235000012631 food intake Nutrition 0.000 description 3
- 239000011261 inert gas Substances 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 235000013310 margarine Nutrition 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 229940045348 Brown mixture Drugs 0.000 description 2
- 240000007170 Cocos nucifera Species 0.000 description 2
- 235000013162 Cocos nucifera Nutrition 0.000 description 2
- 102000007330 LDL Lipoproteins Human genes 0.000 description 2
- 108010007622 LDL Lipoproteins Proteins 0.000 description 2
- QDRKDTQENPPHOJ-UHFFFAOYSA-N Sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 230000000875 corresponding Effects 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 235000009200 high fat diet Nutrition 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- OKKJLVBELUTLKV-UHFFFAOYSA-N methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 2
- 230000035764 nutrition Effects 0.000 description 2
- 235000016709 nutrition Nutrition 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000019587 texture Nutrition 0.000 description 2
- 235000021122 unsaturated fatty acids Nutrition 0.000 description 2
- 150000004670 unsaturated fatty acids Chemical class 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- GJJVAFUKOBZPCB-ZGRPYONQSA-N (R)-3,4-Dihydro-2-methyl-2-(4,8,12-trimethyl-3,7,11-tridecatrienyl)-2H-1-benzopyran-6-ol Chemical compound OC1=CC=C2OC(CC/C=C(C)/CC/C=C(C)/CCC=C(C)C)(C)CCC2=C1 GJJVAFUKOBZPCB-ZGRPYONQSA-N 0.000 description 1
- BVDRUCCQKHGCRX-UHFFFAOYSA-N 2,3-dihydroxypropyl formate Chemical compound OCC(O)COC=O BVDRUCCQKHGCRX-UHFFFAOYSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 235000011437 Amygdalus communis Nutrition 0.000 description 1
- 206010002091 Anaesthesia Diseases 0.000 description 1
- 229940114079 Arachidonic Acid Drugs 0.000 description 1
- YZXBAPSDXZZRGB-DOFZRALJSA-N Arachidonic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/C\C=C/CCCC(O)=O YZXBAPSDXZZRGB-DOFZRALJSA-N 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 210000000941 Bile Anatomy 0.000 description 1
- 240000002791 Brassica napus Species 0.000 description 1
- 235000004977 Brassica sinapistrum Nutrition 0.000 description 1
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Carbodicyclohexylimide Chemical compound C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 description 1
- 206010071234 Combined hyperlipidaemia Diseases 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- SSQPWTVBQMWLSZ-AAQCHOMXSA-N Ethyl eicosapentaenoic acid Chemical compound CCOC(=O)CCC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CC SSQPWTVBQMWLSZ-AAQCHOMXSA-N 0.000 description 1
- 229920000064 Ethyl eicosapentaenoic acid Polymers 0.000 description 1
- 240000006669 Helianthus annuus Species 0.000 description 1
- 235000003222 Helianthus annuus Nutrition 0.000 description 1
- 238000004566 IR spectroscopy Methods 0.000 description 1
- PIWKPBJCKXDKJR-UHFFFAOYSA-N Isoflurane Chemical compound FC(F)OC(Cl)C(F)(F)F PIWKPBJCKXDKJR-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-UHFFFAOYSA-N Linoleic acid Chemical compound CCCCCC=CCC=CCCCCCCCC(O)=O OYHQOLUKZRVURQ-UHFFFAOYSA-N 0.000 description 1
- 102000004895 Lipoproteins Human genes 0.000 description 1
- 108090001030 Lipoproteins Proteins 0.000 description 1
- 239000004165 Methyl ester of fatty acids Substances 0.000 description 1
- PSHKMPUSSFXUIA-UHFFFAOYSA-N N,N-dimethylpyridin-2-amine Chemical compound CN(C)C1=CC=CC=N1 PSHKMPUSSFXUIA-UHFFFAOYSA-N 0.000 description 1
- ZIWPYEIAPMTNTE-WRABICDASA-N Oryzanol Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)O[C@@H]2C([C@@H]3CC[C@@]4(C)[C@@H]5CC[C@@H]([C@@]5(C)CC[C@@]54C[C@@]53CC2)[C@H](C)CCC(=C)C(C)C)(C)C)=C1 ZIWPYEIAPMTNTE-WRABICDASA-N 0.000 description 1
- 206010033799 Paralysis Diseases 0.000 description 1
- 108010069201 VLDL Cholesterol Proteins 0.000 description 1
- 229940088594 Vitamin Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000020224 almond Nutrition 0.000 description 1
- 230000037005 anaesthesia Effects 0.000 description 1
- 230000002429 anti-coagulation Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 238000004166 bioassay Methods 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 235000019994 cava Nutrition 0.000 description 1
- 238000005119 centrifugation Methods 0.000 description 1
- 230000001906 cholesterol absorption Effects 0.000 description 1
- 235000019864 coconut oil Nutrition 0.000 description 1
- 239000003240 coconut oil Substances 0.000 description 1
- 235000020940 control diet Nutrition 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 235000021004 dietary regimen Nutrition 0.000 description 1
- 230000003467 diminishing Effects 0.000 description 1
- 238000006073 displacement reaction Methods 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N edta Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 230000001278 effect on cholesterol Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 235000019387 fatty acid methyl ester Nutrition 0.000 description 1
- 235000021323 fish oil Nutrition 0.000 description 1
- 238000003818 flash chromatography Methods 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 238000004817 gas chromatography Methods 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 150000002338 glycosides Chemical class 0.000 description 1
- 201000010238 heart disease Diseases 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 229960002600 icosapent ethyl Drugs 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 230000000968 intestinal Effects 0.000 description 1
- 229960002725 isoflurane Drugs 0.000 description 1
- 229960004232 linoleic acid Drugs 0.000 description 1
- 108010022197 lipoprotein cholesterol Proteins 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000002894 organic compounds Chemical class 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000002378 plant sterols Nutrition 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- NRHMKIHPTBHXPF-TUJRSCDTSA-M sodium cholate Chemical compound [Na+].C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC([O-])=O)C)[C@@]2(C)[C@@H](O)C1 NRHMKIHPTBHXPF-TUJRSCDTSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000007619 statistical method Methods 0.000 description 1
- 239000011731 tocotrienol Substances 0.000 description 1
- 229930003802 tocotrienols Natural products 0.000 description 1
- 235000019148 tocotrienols Nutrition 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 150000003722 vitamin derivatives Chemical class 0.000 description 1
- 235000019195 vitamin supplement Nutrition 0.000 description 1
- 229930003231 vitamins Natural products 0.000 description 1
Abstract
The phytosterol and / or phytostanol esters of polyunsaturated fatty acids from 18 to 22 carbon atoms and at least three carbon-carbon double bonds are effective for the reduction of both cholesterol and triglycerides of the dream
Description
DERIVATIVES OF FTTOESTEROL AND / OR FTTOESTANOL
FIELD OF THE INVENTION
The present invention relates to polyunsaturated fatty acid esters of phytosterols and / or phytostanols and to their use.
BACKGROUND OF THE INVENTION Phytosterols are found among plant sterols, for example in small amounts in vegetable oils such as corn oil, seed oil or oils from other oily plants, where they are found as free sterols, esters of fatty acids and glycosides. Phytosterols are structurally similar to cholesterol, with the main differences in the carbon skeleton of their side chains. In nature you will find a good number of different phytosterol structures. The most common are campesterol, beta-sitosterol and stigmaesterol. The reduction of phytosterols provides saturated phytosterols, called phytostanols, such as campestanol or sitostanol, which are also found in nature in small amounts. A normal human diet
R E P. : 3200? it typically leads to the ingestion of less than half a gram per day of said substances in various forms.
It is known that the ingestion of phytosterols and / or phytostanols in defined amounts, for example of several grams per day or more, can reduce cholesterol levels in blood serum. It is assumed that free phytosterols and phytostanols inhibit the absorption of dietary cholesterol and bile cholesterol through the displacement of cholesterol. However, only modest reductions in serum cholesterol levels have been generally observed by adding phytosterols or free phytostanols to the diet.
Arteriosclerosis is a cause that causes death in many parts of the Western world. It has been shown that low density lipoprotein (LDL) cholesterol is directly associated with the development of cardiovascular diseases, while high density lipoprotein (HDL) cholesterol has an inverse relationship with the development of cardiovascular diseases. People with combined hyperlipidemia are even more at risk for heart disease. High levels of cholesterol in blood serum and high levels of triglycerides are generally accepted, both as causes and as indicators of the progression of cardiovascular diseases. Thus, the decrease of cholesterol and the decrease of triglycerides are considered as desirable targets as main strategies for intervention. Many methods have been proposed to lower serum cholesterol, among which are the use of certain pharmaceutical agents and the ingestion of phytosterols in various forms. Similarly, many methods have been proposed to decrease serum triglycerides, among which are the ingestion of polyunsaturated fatty acids (PUFA) in various forms.
Physical properties are especially important in food applications. The properties of the ingredients allow and limit the ways in which the products can be supplied, for example in oils or shortenings. In addition, properties such as solubility and melting point can affect the acceptability of a food product by changing texture, taste or mouth taste, by complicated, unpredictable ways. A problem with the use of free phytosterols has been its crystalline nature and its limited solubility in oils. Generally, large amounts have been used to achieve an effect on cholesterol levels, but as a consequence, resulting physical problems have appeared. So, other forms have been sought.
WO 96/38047 discloses a food product based on fats, which contains natural fatty components that have a diminishing effect on blood cholesterol and where at least one component of tocotrienol is physically present., oryzanol and phytosterol, preferably mixed with at least one PUFA triglyceride component. The phytosterols present are mainly in the form of free phytosterol at low, defined, and relatively insoluble concentrations. The resulting products are semi-solid. Much higher proportions of PUFA triglycerides are used than phytosterols. The effects of mixtures on triglyceride levels are not described.
US Patent 4,588,717 describes phytosterol fatty acid esters as vitamin supplements or as diet pills, said esters being obtained from a phytosterol and a fatty acid of 18 to 20 carbon atoms. Included among these fatty acids are also unsaturated acids, linolenic acid, linoleic acid and arachidonic acid. It is generally known that these acids have almost no effect on triglyceride levels.
The patent WO 97/42830 describes the preparation and use of gels consisting of partially crystallized mixtures of natural edible oils with low concentrations of sterols and esters of sterol (especially sitosterol and aryzanol) and optionally monoglycerides, in certain proportions as a means to give firmness to liquid edible fats. Because of the low content of sterol and sterol ester, said necessity products require considerable volumes and an additional caloric content, to supply phytosterols and phytosterol esters in sufficient quantities to effectively lower cholesterol.
Patent WO / 98/06405 describes a method for reducing cholesterol in the bloodstream by administering beta-sitostanol with campestanol in certain proportions, such as esters of fatty acids derived from vegetable oils.
Patent US 5,502,045 describes the reduction of cholesterol absorption in the bloodstream by the administration of beta-sitostanol esters of acids of 2 to 22 carbon atoms derived from vegetable oils.
In the Journal of Lipid Research (1933, 34, 1535-1544), experiments are described and referenced experiments with feed mixtures of human subjects, of esters of sitostanol obtained from fatty acids of rapeseed oil. It was found that phytostanol esters reduced serum LDL cholesterol more effectively than free phytosterols, even though they were hydrolyzed during the intestinal passage.
In the European Journal of Clinical Nutrition
("European Journal of Clinical Nutrition") 1998, 52, 334-343, results of human trials with margarines enriched with phytosterols and phytosterol esters. It was shown that plasma concentrations of total cholesterol and LDL cholesterol had been reduced by sterol esters mixed with margarines, compared to controls with similar fatty acid profiles. All materials contained esters of unsaturated fatty acids, especially those of oleic, linoleic or linolenic acid. No effect on the concentration of triglycerides in plasma was seen, with the margarines enriched with sterol.
DESCRIPTION OF THE INVENTION It has now been discovered that phytosterol and / or phytostanol esters obtained from phytosterols and / or phytostanols with certain omega-3 polyunsaturated fatty acids (n-3 fatty acids) are surprisingly effective in reducing both cholesterol and cholesterol. serum triglycerides. Said polyunsaturated fatty acids are, for example, eicosapentaenoic acid (EPA) with five unsaturated carbon-carbon double bonds, or docosahexaenoic acid (DHA) with six unsaturated carbon-carbon double bonds. These esters significantly decreased both plasma cholesterol and triglyceride levels, whereas phytosterol combined with vegetable oil only decreased plasma cholesterol levels. Consequently, these esters can be used as a combined agent for cholesterol reduction and as an agent to lower triglycerides, and thus positively affect two of the major risk factors for cardiovascular diseases.
The effects described above have been shown in rats and the methods employed and the results obtained are described summarized below.
Animal treatment
Thirty male Fischer rats, with a weight of 177 ± 14 g, they were kept on a high fat diet (table 1) during the two weeks preceding the treatment. They were randomly divided into five experimental groups of six animals each. The control group (group 1) continued with the high fat diet used during the two weeks of the pretreatment period. For the other experimental diets, in order to have isocaloric diets and an equal amount of fat in all the experimental diets, 2% (p /?) Of the fat content of the control diet was replaced (1% oil). coconut and 1% corn oil) for 2% (w / w) of the following lipids:
Group 2: 2% mixture of sitosterol / oleic oil rich in sunflower (TRISUN 80) (in the ratio 1: 1);
Group 3: 2% of the ester sitostanol-DHA;
Group 4: 2% of the ester stigmaesterol-EPA:
Group 5: 2% mixture of sitosterol + EPA / DHA ester (in the ratio 1: 1).
The fatty acid compositions of the experimental diets are shown in Table 2. The rats were given free access to water and diet, and were kept in a 12 hour light / dark cycle. The diet of the cages was renewed daily, all unconsumed material was discarded and the food intake was measured. Blood samples (1 ml) were collected by retro-orbital puncture at the beginning of the experimental period (week 0) and after 2 weeks of treatment (week 2). After 4 weeks, the animals were sacrificed by withdrawing blood from the vena cava, with isoflurane anesthesia. The blood was collected in tubes containing EDTA as an anticoagulant.
Lipid analysis __
Plasma was prepared from heparinized blood by immediate centrifugation at 1600 g for 10 minutes at 4 ° C. The plasma cholesterol, triglycerides and HDL cholesterol assays (precipitation method) were determined enzymatically on a COBASFARA analyzer (Roche Diagnostica, Switzerland). Non-HDL cholesterol was calculated by difference. The fatty acid composition of the diets was analyzed by gas chromatography.
Statistical analysis All data are expressed as means ± SD for the animals of each diet group. Differences in the means between dietary groups were analyzed by one-way analysis of the covariance (ANCOVA) with the subsequent Dunnet test for multiple comparison against the control group (group 1 and / or group 2). The adjusted covariant was the value of the corresponding parameter at the beginning of the treatment period (week 0). All trials were performed at the 5% level and the 95% confidence intervals were calculated.
Results
The growth of the rats was similar in all the dietary groups during the 4 weeks of the feeding period. The average food intake during the 4-week period of the five dietary regimens was 12 g / day / rat. Dietary treatment had no significant effect on body weight and food consumption.
Plasma cholesterol was significantly lower from 28% to 46% in all four groups treated with phytosterols compared to control and 46% to 66% with respect to the pretreatment period (week 0) (Table 3) .
HDL cholesterol levels were almost unaffected by the phytosterol treatment (table 4). Therefore, non-HDL cholesterol (VLDL cholesterol + LDL cholesterol) was decreased mainly by phytosterol treatment.
Plasma triglyceride levels were significantly decreased from 18% to 39% in the groups treated with phytosterol combined with n-3 fatty acids compared to the control group and from 15% to 41% compared to the period of pretreatment (week 0) (table 5), while phytosterol combined with vegetable oil (group 2) did not significantly decrease plasma triglycerides.
Table 1
Composition of the diet3 rich in fats of rats.
The diet contained 0.5% by weight of cholesterol, 1% by weight of sodium cholate and the standard mixture of vitamin and mineral standard, according to the specifications for the rats.
aThe main fats consisted of coconut almond (18% by weight), coconut oil (2.5% by weight) and corn oil (2.5% by weight).
r f in s (_p O i
abla 2
Fatty acid composition of experimental diets (* molar)
Group 1 Group 2 Group 3 Group 4 Group 5 Fatty acids Control 2% (mixture of 2% of ester sito- 2% of ester stig- 2% of mixture of esters sitoesterol + Trisun) eswnol-DH? maesterol-EPA sitoesterol EPA / DHA?
Saturated 57.73 56.57 57.62 56.16 56.86 Monoenos 18.84 25.35 15.59 15.62 16.34 PUFAs 23.43 18.08 26.79 27.98 26.81 Sum n -6 22,08 16,76 16,85 16,92 17,47 Sum n-3 1,21 1,15 9,91 10,89 9,20 C 14 33,91 33,63 34,99 34,05 34.04 C 15 17.84 16.84 16.76 16.58 16.66 C 18 5.38 5.64 5.33 5.26 5.42
•
C 18: 1-9 17.99 24.39 15,08 15,02 15.16
C 18: 1-7 0.55 0.67 0.41 0.42 0.56
C 18: 2-6 21.91 16.54 16.31 16.56 16.74
C 18: 3-3 1.21 1.15 1.17 1.21 1.25
C 20: 5-3 0.00 0.00 0.11 9.52 4.56
C 22: 6-3 0.00 0.00 8.58 0.13 2.76
The results are expressed as percent methyl esters of fatty acids (molar I).
I-1 Lp O Ol O in
Tt la 3 Effects of phytosterol esters on total cholesterol in plasma, in rats
in
Change in percent of pretreatment. Significantly different from the control at week 2 or week 4 (P <0.05). Significantly different from group 2 (mixture of sitosterol + trisun) at week 2 or week 4 (P <0.05).
t in in or in or TPblfl 4
Effects of phytosterol esters on lipoproteins in rats
* Significantly different from the control at week 2 or week 4 (P <0.05). Significantly different from group 2 (mixture of sitosterol + trisun) at week 2 or week 4 (P <0.05).
to t in or in or in
Table 5
Effects of phytosterol esters on plasma triglycerides in rats
l- >
Change in percent of pretreatment. Significantly different from the control at week 2 or week 4 (P <0.05). Significantly different from group 2 (mixture of sitosterol + trieun) at week 2 or week 4 (P <0.05).
The physical properties of organic compounds such as physical state, melting point and solubility can not be predicted with certainty, from chemical structures. These properties significantly influence the acceptability of the food product since they affect the texture, taste or taste of mouth by complex and unpredictable pathways. In the context of the present invention, EPA and DHA esters were synthesized with sitoesterol, sitostanol and stigmaesterol in pure form as well as mixtures of these sterols with other sterols and with mixtures of said acids with other fatty acids. Some of the compounds and mixtures were liquid while others were partially solid at room temperature or lower. All were significantly more soluble in edible oil than the corresponding phytosterols or phytostanols. For comparison, sitoestanol esters were also synthesized with mixtures of fatty acids containing significant levels of unsaturated fatty acids of 16 to 20 carbon atoms, especially the linolenic acid obtained from rapeseed oil, and it was found that the mixtures obtained were very crystalline. ambient and lower temperature. Much more edible oil was needed to completely dissolve these esters compared to esters prepared with EPA or DHA.
It was further discovered that the compounds of the present invention offer unique physical advantages. The compounds have a higher solubility in edible oils than other phytosterol esters described so far, which is an advantage for their incorporation into a wide variety of food products. These materials allow the supply of phytosterols and / or phytostanols and selected PUFAs, in their ester form in the highest possible concentration per unit volume. This is advantageous for incorporation into products where small volumes are important, such as dispersible formulations in water or when additional non-essential edible oils are not desirable. This presents physical advantages over simple mixtures or formulations of other phytosterols / phytostanols and / or their fatty esters with PUFAs and their ester or triglyceride forms normally available.
Accordingly, an object of the present invention are phytosterol and / or phytostanol esters obtained from phytosterols and / or phytostanols with PUFAs having 18 to 22 carbon atoms and at least three unsaturated carbon-carbon double bonds. Another object of the present invention is the use of said phytosterol and / or phytostanol esters or mixtures thereof in the diet and human dietetic food for the purpose of lowering serum cholesterol levels and serum triglyceride levels., in humans. The compounds according to the present invention are preferably used in a total amount with a content of 1 to 10 grams per day of phytosterol ester and / or phytostanol ester. Still another object of the present invention is the use of these phytosterol esters and / or phytostanol or mixtures thereof, in formulations in suitable physical forms such as capsules, etc., as dietary supplements or as ingredients in foods as well as also these formulations per se.
The preferred phytosterols are beta-sitosterol or stigmasterol and campesterol or mixtures thereof.
More preferred are beta-sitosterol and stigmasterol or mixtures thereof. The most preferred is beta-sitosterol. The preferred phytostanols are beta-sitostanol and campestanol or mixtures thereof. The most preferred is beta-sitostanol. Preferred PUFAs are EPA and DHA.
It is readily understood that the esters of the present invention do not need to be used in the pure state. The mixture of these esters can be used. Mixtures of these esters with other fatty esters of phytosterol / phytostanols can also be used. The proportions of phytosterol and / or phytostanols used can vary with the origin thereof. Likewise, the proportions of PUFA and other fatty acids may vary. It is also understood that the products may contain some free phytosterols / phytostanols and / or glycerides or PUFA esters. The physical properties can vary as a consequence, from those having a high proportion of phytosterol / stanol polyunsaturated esters and then they are perfectly soluble liquids in edible oils, up to those of the mixture having lower ratios of unsaturation, and then they are semi-solid or waxy
The compounds according to the present invention can be prepared according to known methods. For example they can be obtained by esterification of a phytosterol / phytostanol with an n-3 PUFA in a known manner. Alternatively, they can be prepared preferably by interesterification of free phytosterols / phytostanols with n-3 PUFAs esters, heating in the presence of an interesterification catalyst, wherein (i) the interestinication is effected solvent-free, (ii) the fatty esters they include suitable esters and triglycerides of 1 to 4 carbon atoms, (iii) the catalyst is a sodium alkoxide of an alcohol of 1 to 4 carbon atoms. The reaction is suitably carried out by heating the mixture to 80-140 ° C at a pressure of 133-6650 Pa and carrying out the reaction preferably with a stoichiometric amount to an excess of PUFA ester. The following examples illustrate the invention in more detail:
Example 1
To a mixture of 0.91 g of docosahexaenoic acid (purity: 90%), 1.03 g of stigmaterol (purity: 95%) and dimethylaminopyridine (50 mg) in 18 ml of anhydrous dichloromethane, a solution of dicyclohexylcarbodiimide was added.
(0.63 g) in 5 ml of dichloromethane. After 4 hours of stirring at room temperature, the reaction was terminated. Then, methanol (0.5 g) and acetic acid were added
(0.25 g), and the mixture was stirred for an additional hour. The mixture was cooled to 0 ° C, filtered and the solids were washed with exano (3 x 25 mL). The solvent was removed under reduced pressure and the residue subjected to flash chromatography on silica gel obtaining a pure fraction of 1.0 g of docosahexaenoate of stigmaterol in the form of a colorless oil consistent with the NMR and IR data. This substance was kept in oil form when stored for several weeks at room temperature and when cooling for several weeks at -20 ° C.
Example 2
Analogously to example 1, stigmaesterol eicosapentaenoate was prepared from eicosapentaenoic acid (purity: 90%) and stigmaterol. The stigmasterol eicosapentaenoate (1.46 g) was obtained in the form of a colorless oil that remained liquid at a temperature between 20 ° C and -20 ° C.
Example 3
Analogously to Example 1, a mixture of eicosapentaenoic acid-docosahexaenoic acid esters of stigmaterol was prepared from stigmasterol with a mixture of 49% eicosapentaenoic acid and 27% docosahexaenoic acid. The mixture of stigmasterol esters was obtained in the form of a colorless oil that remained liquid in the temperature range of 20 ° C to -20 ° C.
Example 4
Analogously to example 1, docosahexaenoate of stigma-ethanol was prepared from stigma-ethanol (purity: 95%) and docosahexaenoic acid (purity: 90%). The docosahexaenoate of stigma-ethanol was obtained as a lightly colored oil, which remained liquid between 20 ° C and -20 ° C.
Example 5
Analogously to Example 1, the stigma-ethanol eicosapentaenoate was prepared from stigma-ethanol and eicosapentaenoic acid. Eicosapentaenoate of stigma-ethanol was obtained as a slightly yellowish oil, which remained liquid in the temperature range between 20 ° C and -20 ° C.
Example 6
Analogously to example 1, a mixture of stigma-ethanol esters of eicosapentaenoic acid and docosahexaenoic acid was prepared from stigma-ethanol and a mixture of 49% eicosapentaenoic acid with 27% docosahexaenoic acid. A mixture of stigmaestanol esters of eicosapentaenoic acid and docosahexaenoic acid was obtained in the form of a colorless oil which became turbid when stored at 20 ° C and partially solid at -20 ° C.
Example 7
Analogously to example 1, a mixture of sterol esters of PUFA was prepared from a mixture of beta-sitosterol, campesterol and stigmasterol and a mixture of 49% eicosapentaenoic acid with 27% docosahexaenoic acid. A mixture of sterol PUFA esters was obtained in the form of a turbid oil containing some solids at 20 ° C and partially solid at -20 ° C.
Example 8
Analogously to example 1, a mixture of unsaturated fatty esters of stigma-ethanol was prepared from the stigma-ethanol and a mixture of fatty acids obtained from the basic hydrolysis of a sample of a commercial food of Swiss rapeseed oil (9% of saturated, 61% monounsaturated, 30% polyunsaturated triglycerides). A mixture of unsaturated fatty esters of stigma-ethanol was obtained in the form of a colorless oil which crystallized slowly at room temperature. At -20 ° C the material was essentially solid.
Example 9
A mixture of phytosterols (20.6 g of a commercial mixture of 43% sitosterol, 23 stigmasterol, campesterol 24% with other minor sterols) and 75% ethyl esters of DHA-EPA (16.8 g of a commercial mixture of 43% docosahexaenoate of ethyl and 32% ethyl eicosapentaenoate with other fatty esters), dried at 120 ° C while bubbling with an inert gas stream. To the liquid mixture was added sodium ethoxide (1.03 ml of 21% solution in ethanol). The mixture was stirred at 120 ° C at 15 mbar vacuum for two hours. The light brown mixture was cooled to 80 ° C and the catalyst was paralyzed with dilute acid. The separated oily phase was dehydrated by heating under reduced pressure while bubbling with an inert gas stream. 35.0 g of crude phytosterol sters were obtained, in the form of a turbid, light brown oil, which remained fluid at room temperature. HPLC showed that the conversion to sterol esters was 95%.
Example 10
A mixture of phytosterols (148 g of a commercial mixture of 43% sitosterol, 23 stigmaterol, campesterol 24% with other minor sterols) and fish oil glycerides (141 g of a commercial glyceride mixture with a fatty acid composition of 17% EPA- and 11% DHA), was dehydrated by bubbling at 120 ° C with an inert gas. To the liquid mixture, sodium ethoxide (11.9 ml of 21% solution in ethanol) was added. The mixture was stirred at 120 ° C at 15 mbars vacuum for one hour.
The light brown mixture was quenched with dilute acid, and the separated oil phase was dehydrated under reduced pressure to obtain 249 g of a light brown oil which crystallized slowly in a semi-solid mass. HPLC showed that the conversion was 93%.
'Example 11
The solubilities of the materials obtained according to the procedures described in examples 1-8, as well as the original sterols, were determined in a commercial sample of Swiss rapeseed oil, by the alternative addition of small increments of oil at room temperature. to heavy amounts of sterol esters and stirring for periods of 5 minutes until the solution was achieved. The minimum starting ratio was around 1: 1 and discontinuous tests were carried out until reaching 10: 1.
Material Solubility g of oil / g of material
Docosahexaenoate of miscible stigma sterol > 1
Eicosapentao miscible stigmasterol> 1
Esters Mixture EPA-DHA miscible stigma sterol > 1
Docosahexaenoate of miscible stigma-ethanol > 1 Eicosapenta in miscible stigma-ethanoate > 1
Esters blend EPA-DHA of soluble stigma-ethanol > 4
Esters blend EPA-DHA of miscible sitoesterol mixture sterols > 1 Mix of rapeseed esters of Insoluble stigma-ethanol > 10
Insoluble stigma sterol > 10
Insoluble stigma-ethanol > 10
Ethyl ester of docosahexaenoic acid 90% miscible > 1 EPA miscible 90% ethyl ester > 1
It is noted that in relation to this date, the best method known to the applicant, to implement said invention is that which is clear from the manufacture of the objects to which it refers.
Having described the invention as above, the content of the following is claimed as property:
Claims (10)
1. Phytosterol and / or phytostanol esters obtained from phytosterols and / or phytostanols with polyunsaturated fatty acids, characterized in that the polyunsaturated fatty acid has from 18 to 22 carbon atoms and at least three unsaturated carbon-carbon double bonds.
2. Esters according to claim 1, characterized in that the phytosterol is beta-sitosterol, stigmasterol or campesterol or a mixture thereof, preferably beta-sitosterol or stigmaterol or a mixture thereof, more preferably beta-sitosterol.
3. Esters according to claim 1 or claim 2, characterized in that the phytostanol is campestanol or beta-sitostanol or a mixture thereof, preferably beta-sitostanol.
Esters according to any one of claims 1 to 3, characterized in that the polyunsaturated fatty acid is eicosapentaenoic acid or docosahexaenoic acid.
5. Esters according to any one of claims 1 to 4, characterized in that they further comprise in admixture therewith, phytosterol and / or phytostanol esters with fatty acids or the polyunsaturated fatty acids specified in claim 1 or claim 4, and / or which further comprise in admixture therewith, free phytosterols / phytostanols and / or glycerides or PUFA esters.
6. The use of esters according to any one of claims 1 to 5, characterized in that the human diet and dietetic food, in order to decrease serum cholesterol levels and serum triglyceride levels, in humans.
7. The use of esters according to any one of claims 1 to 5, characterized in that in formulations, in suitable physical forms, preferably in capsules, as dietary supplements or as ingredients in foods.
8. Formulations in suitable physical forms, preferably in capsules, of dietary supplements or foods characterized in that they contain esters as claimed in any one of claims 1 to 5.
9. A process for the preparation of esters according to any one of claims 1 to 5, characterized in that it comprises the esterification of a free phytosterol / phytostanol to a mixture thereof, with a polyunsaturated fatty acid n-3 with 18 to 22 atoms carbon and at least three unsaturated carbon-carbon double bonds to a mixture thereof, in a manner known per se.
10. Esters according to any one of claims 1 to 5, characterized in that they have been obtained by interesterification of phytosterols / phytostanols with fatty esters of n-3 polyunsaturated fatty acids, heating in the presence of an interesterification catalyst, wherein (i) the interesterification is effected solvent-free, (ii) the fatty esters include suitable simple triglycerides and esters of 1 to 4 carbon atoms, (iii) the catalyst is a sodium alkoxide of an alcohol of 1 to 4 carbon atoms, wherein the reaction is conveniently carried out by heating the mixture to 80-140 ° C at a pressure of 133-6650 Pa and wherein the reaction is carried out with a stoichiometric amount to an excess of the PUFA ester.
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WO2004091603A1 (en) * | 2003-04-07 | 2004-10-28 | Clinigenetics | Use of an ester of dha for the treatment of cardiovascular diseases |
KR101054913B1 (en) * | 2003-12-31 | 2011-08-05 | 주식회사 삼양제넥스 | Composition for preventing and treating hyperlipidemia, arteriosclerosis and liver disease, including phytosterol, hesperidin and rutin |
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US20070298079A1 (en) * | 2006-06-26 | 2007-12-27 | Tropicana Products, Inc. | Food fortified with omega-3 fatty acids |
EP2076142B1 (en) | 2006-06-29 | 2019-10-30 | Intercontinental Great Brands LLC | Improved chain cutter for continuously forming center-filled gum pieces |
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US9352025B2 (en) | 2009-06-05 | 2016-05-31 | Veroscience Llc | Combination of dopamine agonists plus first phase insulin secretagogues for the treatment of metabolic disorders |
CN101919537B (en) * | 2010-09-09 | 2012-08-08 | 浙江大学 | Application of phytosterol ester and conjugated linoleate in functional meat product |
FI123374B (en) * | 2011-03-25 | 2013-03-15 | Ravintoraisio Oy | New edible composition |
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CN103242407A (en) * | 2013-05-15 | 2013-08-14 | 张雅茹 | Polyunsaturated fatty acyl group-containing phosphatidyl sterol and/or phosphatidyl stanol, and preparation method and application of same |
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