CA1239587A - Combined fatty acid composition for lowering blood cholestrol and triglyceride levels - Google Patents
Combined fatty acid composition for lowering blood cholestrol and triglyceride levelsInfo
- Publication number
- CA1239587A CA1239587A CA000465531A CA465531A CA1239587A CA 1239587 A CA1239587 A CA 1239587A CA 000465531 A CA000465531 A CA 000465531A CA 465531 A CA465531 A CA 465531A CA 1239587 A CA1239587 A CA 1239587A
- Authority
- CA
- Canada
- Prior art keywords
- acid
- accordance
- cis
- composition
- component
- 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.)
- Expired
Links
- 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 abstract description 37
- 235000014113 dietary fatty acids Nutrition 0.000 title claims abstract description 34
- 239000000194 fatty acid Substances 0.000 title claims abstract description 34
- 229930195729 fatty acid Natural products 0.000 title claims abstract description 34
- 150000004665 fatty acids Chemical class 0.000 title claims abstract description 34
- 239000000203 mixture Substances 0.000 title claims abstract description 30
- 210000004369 blood Anatomy 0.000 title claims abstract description 8
- 239000008280 blood Substances 0.000 title claims abstract description 8
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 title claims abstract description 7
- LEIXEEFBKOMCEQ-AFJQJTPPSA-N (9z,12z)-heptadeca-9,12-dienoic acid Chemical compound CCCC\C=C/C\C=C/CCCCCCCC(O)=O LEIXEEFBKOMCEQ-AFJQJTPPSA-N 0.000 claims abstract description 20
- 235000013305 food Nutrition 0.000 claims abstract description 10
- VZCCETWTMQHEPK-QNEBEIHSSA-N gamma-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCC(O)=O VZCCETWTMQHEPK-QNEBEIHSSA-N 0.000 claims abstract description 9
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic 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 abstract description 4
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 3
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims abstract 5
- HOBAELRKJCKHQD-QNEBEIHSSA-N dihomo-γ-linolenic acid Chemical compound CCCCC\C=C/C\C=C/C\C=C/CCCCCCC(O)=O HOBAELRKJCKHQD-QNEBEIHSSA-N 0.000 claims abstract 3
- 230000009467 reduction Effects 0.000 claims description 8
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims description 6
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims description 6
- 239000000306 component Substances 0.000 claims 12
- SBHCLVQMTBWHCD-METXMMQOSA-N (2e,4e,6e,8e,10e)-icosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C(O)=O SBHCLVQMTBWHCD-METXMMQOSA-N 0.000 claims 4
- HXWJFEZDFPRLBG-UHFFFAOYSA-N Timnodonic acid Natural products CCCC=CC=CCC=CCC=CCC=CCCCC(O)=O HXWJFEZDFPRLBG-UHFFFAOYSA-N 0.000 claims 4
- 229940000425 combination drug Drugs 0.000 claims 1
- MBMBGCFOFBJSGT-SFGLVEFQSA-N docosa-4,7,10,13,16,19-hexaenoic 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-SFGLVEFQSA-N 0.000 claims 1
- 239000000546 pharmaceutical excipient Substances 0.000 claims 1
- 238000004440 column chromatography Methods 0.000 abstract description 9
- 235000013310 margarine Nutrition 0.000 abstract description 6
- 239000003264 margarine Substances 0.000 abstract description 6
- 239000003921 oil Substances 0.000 abstract description 6
- 235000019197 fats Nutrition 0.000 abstract description 4
- 239000008162 cooking oil Substances 0.000 abstract description 3
- 229960005135 eicosapentaenoic acid Drugs 0.000 abstract description 2
- JAZBEHYOTPTENJ-JLNKQSITSA-N all-cis-5,8,11,14,17-icosapentaenoic 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 abstract 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 abstract 1
- 229940090949 docosahexaenoic acid Drugs 0.000 abstract 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 abstract 1
- 230000002083 iodinating effect Effects 0.000 abstract 1
- 230000001035 methylating effect Effects 0.000 abstract 1
- 238000000034 method Methods 0.000 description 14
- 238000011282 treatment Methods 0.000 description 12
- 235000012000 cholesterol Nutrition 0.000 description 10
- 230000026045 iodination Effects 0.000 description 10
- 238000006192 iodination reaction Methods 0.000 description 10
- 230000008569 process Effects 0.000 description 10
- 239000002253 acid Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 7
- 235000021323 fish oil Nutrition 0.000 description 7
- 150000003180 prostaglandins Chemical class 0.000 description 7
- 238000000926 separation method Methods 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 6
- 229940094443 oxytocics prostaglandins Drugs 0.000 description 6
- 239000000243 solution Substances 0.000 description 6
- 235000019198 oils Nutrition 0.000 description 5
- 238000007127 saponification reaction Methods 0.000 description 5
- 239000007858 starting material Substances 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- -1 PGÆ3 Chemical class 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 235000012716 cod liver oil Nutrition 0.000 description 4
- 239000003026 cod liver oil Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- IZFHEQBZOYJLPK-UHFFFAOYSA-N dihydrolipoic acid Chemical compound OC(=O)CCCCC(S)CCS IZFHEQBZOYJLPK-UHFFFAOYSA-N 0.000 description 4
- 238000009472 formulation Methods 0.000 description 4
- 229960004488 linolenic acid Drugs 0.000 description 4
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 150000007513 acids Chemical class 0.000 description 3
- 235000005911 diet Nutrition 0.000 description 3
- 230000037213 diet Effects 0.000 description 3
- XEYBRNLFEZDVAW-ARSRFYASSA-N dinoprostone Chemical compound CCCCC[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O XEYBRNLFEZDVAW-ARSRFYASSA-N 0.000 description 3
- 229960002986 dinoprostone Drugs 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 239000003925 fat Substances 0.000 description 3
- 239000002243 precursor Substances 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- XEYBRNLFEZDVAW-UHFFFAOYSA-N prostaglandin E2 Natural products CCCCCC(O)C=CC1C(O)CC(=O)C1CC=CCCCC(O)=O XEYBRNLFEZDVAW-UHFFFAOYSA-N 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
- 206010003210 Arteriosclerosis Diseases 0.000 description 2
- BHELIUBJHYAEDK-OAIUPTLZSA-N Aspoxicillin Chemical compound C1([C@H](C(=O)N[C@@H]2C(N3[C@H](C(C)(C)S[C@@H]32)C(O)=O)=O)NC(=O)[C@H](N)CC(=O)NC)=CC=C(O)C=C1 BHELIUBJHYAEDK-OAIUPTLZSA-N 0.000 description 2
- 201000001320 Atherosclerosis Diseases 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 2
- 108090000790 Enzymes Proteins 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- QFWWSZLGTLNVMS-UHFFFAOYSA-N acetic acid;ethoxyethane;hexane Chemical compound CC(O)=O.CCOCC.CCCCCC QFWWSZLGTLNVMS-UHFFFAOYSA-N 0.000 description 2
- 230000003110 anti-inflammatory effect Effects 0.000 description 2
- 229940114079 arachidonic acid Drugs 0.000 description 2
- 235000021342 arachidonic acid Nutrition 0.000 description 2
- 235000014121 butter Nutrition 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 150000001735 carboxylic acids Chemical class 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 210000001072 colon Anatomy 0.000 description 2
- 229940013317 fish oils Drugs 0.000 description 2
- 238000000703 high-speed centrifugation Methods 0.000 description 2
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 2
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 229910052740 iodine Inorganic materials 0.000 description 2
- 239000011630 iodine Substances 0.000 description 2
- 239000006210 lotion Substances 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 238000007254 oxidation reaction Methods 0.000 description 2
- 230000003119 painkilling effect Effects 0.000 description 2
- 239000000741 silica gel Substances 0.000 description 2
- 229910002027 silica gel Inorganic materials 0.000 description 2
- 229960001866 silicon dioxide Drugs 0.000 description 2
- SQGYOTSLMSWVJD-UHFFFAOYSA-N silver(1+) nitrate Chemical compound [Ag+].[O-]N(=O)=O SQGYOTSLMSWVJD-UHFFFAOYSA-N 0.000 description 2
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 235000009434 Actinidia chinensis Nutrition 0.000 description 1
- 244000298697 Actinidia deliciosa Species 0.000 description 1
- 235000009436 Actinidia deliciosa Nutrition 0.000 description 1
- 241000024188 Andala Species 0.000 description 1
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 description 1
- 208000023275 Autoimmune disease Diseases 0.000 description 1
- 241000273930 Brevoortia tyrannus Species 0.000 description 1
- 102000008186 Collagen Human genes 0.000 description 1
- 108010035532 Collagen Proteins 0.000 description 1
- 208000027932 Collagen disease Diseases 0.000 description 1
- 206010051055 Deep vein thrombosis Diseases 0.000 description 1
- 241001414890 Delia Species 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 206010065390 Inflammatory pain Diseases 0.000 description 1
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 244000028344 Primula vulgaris Species 0.000 description 1
- 235000016311 Primula vulgaris Nutrition 0.000 description 1
- 241000220317 Rosa Species 0.000 description 1
- 235000019485 Safflower oil Nutrition 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 206010047249 Venous thrombosis Diseases 0.000 description 1
- VAYROLOSUUAGTR-UHFFFAOYSA-N [Ag].[I] Chemical compound [Ag].[I] VAYROLOSUUAGTR-UHFFFAOYSA-N 0.000 description 1
- 229960001138 acetylsalicylic acid Drugs 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000003466 anti-cipated effect Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003139 biocide Substances 0.000 description 1
- 230000004071 biological effect Effects 0.000 description 1
- 201000011510 cancer Diseases 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 239000004927 clay Substances 0.000 description 1
- 229920001436 collagen Polymers 0.000 description 1
- 230000036570 collagen biosynthesis Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 239000003246 corticosteroid Substances 0.000 description 1
- 229960001334 corticosteroids Drugs 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 125000002433 cyclopentenyl group Chemical group C1(=CCCC1)* 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000005831 deiodination reaction Methods 0.000 description 1
- 230000002939 deleterious effect Effects 0.000 description 1
- 238000004821 distillation Methods 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 229940096118 ella Drugs 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 210000002889 endothelial cell Anatomy 0.000 description 1
- 230000002255 enzymatic effect Effects 0.000 description 1
- 125000004494 ethyl ester group Chemical group 0.000 description 1
- 239000010685 fatty oil Substances 0.000 description 1
- 235000021588 free fatty acids Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 238000004452 microanalysis Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 235000014593 oils and fats Nutrition 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 159000000001 potassium salts Chemical class 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- CBOMORHDRONZRN-QLOYDKTKSA-N prostaglandin E3 Chemical compound CC\C=C/C[C@H](O)\C=C\[C@H]1[C@H](O)CC(=O)[C@@H]1C\C=C/CCCC(O)=O CBOMORHDRONZRN-QLOYDKTKSA-N 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 235000005713 safflower oil Nutrition 0.000 description 1
- 239000003813 safflower oil Substances 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 229910001961 silver nitrate Inorganic materials 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
- 238000011200 topical administration Methods 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 125000005457 triglyceride group Chemical group 0.000 description 1
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 235000019155 vitamin A Nutrition 0.000 description 1
- 239000011719 vitamin A Substances 0.000 description 1
- 235000019166 vitamin D Nutrition 0.000 description 1
- 239000011710 vitamin D Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
- C11C1/00—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids
- C11C1/02—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils
- C11C1/025—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids from fats or fatty oils by saponification and release of fatty acids
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D7/00—Edible oil or fat compositions containing an aqueous phase, e.g. margarines
- A23D7/005—Edible oil or fat compositions containing an aqueous phase, e.g. margarines characterised by ingredients other than fatty acid triglycerides
- A23D7/0056—Spread compositions
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23D—EDIBLE OILS OR FATS, e.g. MARGARINES, SHORTENINGS, COOKING OILS
- A23D9/00—Other edible oils or fats, e.g. shortenings, cooking oils
- A23D9/007—Other edible oils or fats, e.g. shortenings, cooking oils characterised by ingredients other than fatty acid triglycerides
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/115—Fatty acids or derivatives thereof; Fats or oils
- A23L33/12—Fatty acids or derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
- C07C51/42—Separation; Purification; Stabilisation; Use of additives
- C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
- C07C57/02—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms with only carbon-to-carbon double bonds as unsaturation
- C07C57/03—Monocarboxylic acids
-
- C—CHEMISTRY; METALLURGY
- C11—ANIMAL OR VEGETABLE OILS, FATS, FATTY SUBSTANCES OR WAXES; FATTY ACIDS THEREFROM; DETERGENTS; CANDLES
- C11C—FATTY ACIDS FROM FATS, OILS OR WAXES; CANDLES; FATS, OILS OR FATTY ACIDS BY CHEMICAL MODIFICATION OF FATS, OILS, OR FATTY ACIDS OBTAINED THEREFROM
- C11C1/00—Preparation of fatty acids from fats, fatty oils, or waxes; Refining the fatty acids
- C11C1/005—Splitting up mixtures of fatty acids into their constituents
-
- 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
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Engineering & Computer Science (AREA)
- Health & Medical Sciences (AREA)
- Food Science & Technology (AREA)
- Polymers & Plastics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Wood Science & Technology (AREA)
- Microbiology (AREA)
- Nutrition Science (AREA)
- Mycology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Edible Oils And Fats (AREA)
Abstract
ABSTRACT OF THE DISCLOSURE A pharmaceutical composition includes a combination of eicosapentaenoic acid and/or docosahexaenoic acid together with one or more of dihomo-.gamma.-linolenic acid, cis-linoleic acid and .gamma.-linolenic acid. This particular combination of fatty acids may also be administered in the form of a food product such as mar-garine or cooking oil. The composition causes lowering of blood cholesterol and triglyceride levels. The fatty acids used in this composition may be separated from mixtures thereof or from natural sources thereof by iodinating the double bonds in the starting fat or oil, saponifying, extracting the iodinated fatty acids, methyl-ating and separating by column chromatography, and then deiodin-ating.
Description
~239'~37 cor1BINED FATTY ACID COMPOSITION FOR LOWERING BLOOD
CHOLESTEROL AND TRIGLYCERIDE LEVELS
weld of the Invention The present invention relates to pharmaceutical combo-sessions and food products, and more particularly, to such combo-sessions or food products containing a specific combination of fatty acids which can be used for the treatment of a human being or other mammal in order to lower the blood cholesterol and in-glyceride levels of the subject.
Background of the Invention It is known that Greenland Eskimos rarely suffer from atherosclerotic cardiovascular diseases. This fact has been at-tribute to the consumption of high amounts of fish oil. The active ingredients in fish oil are (all-7)-5,~,11,]4,17-eicosa-pentaenoic acid, sometimes designated 20:5~3 fatty acid (herein-after referred to as "EPA") and (all-Z)-4,7,10,13,16,19-docosa-hexaenoic acid, sometimes designated 22:6~3 fatty acid (herein-after referred to as Ala EPA and HA are known to he pro-cursors in the biosynthesis of the prostaglandin PGE3.
The above alternate designations, such as 20:5~3, refer to the total number of carbon atoms in the chain, before the colon: the number of unsaturated bonds, after the colon and the number of carbon atoms from the end opposite the carboxylic acid at which the first unsaturation appears, following the omega.
Members of a given omega series of fatty acids, e.g. I can usually be converted to acids of differing lengths and total numb bier of unsaturations by normal bodily enzymes, but it is generally impossible to change a compound from one omega series to another, e.g. I to I This is because bodily enzymes generally cause changes of length and unsaturation to occur starting from the carboxylic acid end of the chain.
It is disclosed in British patents 1,604,554 and
CHOLESTEROL AND TRIGLYCERIDE LEVELS
weld of the Invention The present invention relates to pharmaceutical combo-sessions and food products, and more particularly, to such combo-sessions or food products containing a specific combination of fatty acids which can be used for the treatment of a human being or other mammal in order to lower the blood cholesterol and in-glyceride levels of the subject.
Background of the Invention It is known that Greenland Eskimos rarely suffer from atherosclerotic cardiovascular diseases. This fact has been at-tribute to the consumption of high amounts of fish oil. The active ingredients in fish oil are (all-7)-5,~,11,]4,17-eicosa-pentaenoic acid, sometimes designated 20:5~3 fatty acid (herein-after referred to as "EPA") and (all-Z)-4,7,10,13,16,19-docosa-hexaenoic acid, sometimes designated 22:6~3 fatty acid (herein-after referred to as Ala EPA and HA are known to he pro-cursors in the biosynthesis of the prostaglandin PGE3.
The above alternate designations, such as 20:5~3, refer to the total number of carbon atoms in the chain, before the colon: the number of unsaturated bonds, after the colon and the number of carbon atoms from the end opposite the carboxylic acid at which the first unsaturation appears, following the omega.
Members of a given omega series of fatty acids, e.g. I can usually be converted to acids of differing lengths and total numb bier of unsaturations by normal bodily enzymes, but it is generally impossible to change a compound from one omega series to another, e.g. I to I This is because bodily enzymes generally cause changes of length and unsaturation to occur starting from the carboxylic acid end of the chain.
It is disclosed in British patents 1,604,554 and
2,033,745 that EPA can be used to treat effectively, or provide effective prophylaxis against, thromboembolic conditions such as myocardial infarctions, strokes, or deep vein thrombosis during surgical operations. They disclose the extraction of EPA from ~L239~8'7 fish oil, such as cod liver oil or menhaden oil. The EPA may be administered by replacing butter or ordinary margarine by a special margarine formulated so that in normal usage the recipient would receive the required amount of the EPA.
This process has not achieved widespread attention, ales-pile the fact that it uses a natural substance which can readily be incorporated into the daily diet. One reason may be due to the difficulty of efficiently separating EPA from natural fish oils to obtain a pure product at reasonable cost. Another reason may be that the effects of administration of EPA are not as dramatic as had been anticipated.
summary of the Invention It is an object of the present invention to eliminate the above-discussed deficiencies in the prior art.
It is another object of the present invention to pro-vise improvements in compositions of the type of British patents 1,604,554 and 2,033,7~5.
It is a further object of the present invention to pro-vise a composition which has superior therapeutic effects compared to those of the prior art.
It is yet another object of the present invention to provide a therapeutic composition containing naturally obtainable fatty acids which will serve to reduce blood cholesterol and triglyceride levels.
It is still another object of the present invention to provide a therapeutic composition which will increase the Peel :
PGE2 ratio in the patient and increase the absolute amount of PIE
in the system.
These and other objects are obtained through the Somali-Tunis administratiorl of one or more of EPA and HA, together with one or more of clihomo-y-linolenic acid (ekes-trunk acid), i.e., 20:3~6 fatty acid, (hereinafter referred to as "DHLA"), cis-lino]eic acid ((Z,Z)-9,12-octadecadienoic acid), ire, 13:2~6 fatty acid, and y-]inolenic acid, ((Z,Z,Z-6,9,12-octa-c]ecatrienoic acid), i.e., 18:3~6 fatty acid, either in the form of a pharmaceutical dosage or in the form of a food product such as margarine or cooking oil, or in the form of skin ointments or 395~7 lotions for topical administration.
Detailed Description of Preferred Embodiments The prostaqlandins are a family of substances showing a wide diversity of biological effects. Prostag]andins of the 1-, 2- and 3-series, respectively, incorporate one, two or three double bonds in their basic 20-carbon carboxylic fatty acid starlike-lure which includes a 5-member cyclopentene ring.
The l-series of prostaglandins are strong vasodilators and inhibit cholesterol and kilojoule biosynthesis, as well as platelet aggregation. On the other hand the 2-series priest-gland ins are known to enhance platelet aggregation, cholesterol and collagen biosynthesis, and also to enhance endothelial cell proliferation. The main effect of the 3-series prostaglandins, particularly PGÆ3, is the suppression of the 2-series priest-gland ins.
The precursor of the 2-series prostaqlandins is Karachi-tonic acid ((all Z)-5,8,11,14-eicosatetraenoic acid), i.e., 20:4~6 fatty acid. DHLA is the precursor for the l-series prostaglan-dins, and, as indicated hereinabove, EPA and DOW are the precut-sons for the 3-series prostaglandins.
It is believed that the effectiveness of EPA and DOW in preventing atherosclerotic cardiovascular diseases lies both in their effect as a precursor for prostaqlandin PGF3, which sup-presses the 2-series prostaglandins, as well as the fact that the SPA and/or Diva itself competes with arachidonic acid on the same enzymatic system and thus inhibits the biosynthesis of 2-series prostalandins. This inhibition of the 2-series prostaglandins results in an increase of the ratio of Peel : PGE2.
In order to improve the effects of the administration of SPA and/or DIVA alone, by further increasing the Peel : PGÆ2 ratio, as well as effecting an increase in the absolute amount of Peel in the system, Della should be administered simultaneously with the pure SPA and/or Ella. Since cis-linoleic acid and y-linolenic acid hot form Della metabolically within the body, either or both of these fatty acids may be substituted, in whole or in part, for Della.
It has been found that the combination of EPA (and/or DOW) and DHLA (and/or cis-linoleic acid and/or -linolenic acid) causes a substantial reduction in hood cholesterol and trimly-derides. Recent research has definitely linked blood cholesterol levels with incidence of coronary heart disease (JAM, 251, 351-36~ (198~) and JAM 251, 365 -374 (198~)). Additionally, it is expected that such a combination will have other beneficial there-peptic properties. For example, it is known that in Chihuahuas-frown, rheumatoid arthritis and outlawry collagen and auto-immune diseases, as well as in some forms of cancer, there are evidences of extremely low levels of Peel and high levels of PIE Thus, it its expected that the combination of the present invention may be able to serve as an effective treatment for such conditions.
Furthermore, the anti-inflammatory effect of cortico-steroids and the pain killing effect of aspirin are believed to be due to their suppressing effect of PGE2 formation. Thus, the use of the combination of the present invention can be expected to be a natural and most effective anti-inflammatory pain killing agent.
The dose of the composition of the present invention, comprising a combination of SPA (and/or DOW) and DOYLE (and/or is-linoleic acid and/or y-linolenic acid), needed for therapeutic or prophylactic effect will vary with the route of administration and the nature of the condition being treated, but will generally be at least 1 gram, preferably from 1.5 to 3 grams, per clay. This is the dose for an average 70 kg man, and the dose for other men or animals will vary pro fate according to their weight, i.e. about 20-40 mg/kg.
The relative amounts of EPA Andre Ala and ALA
(and/or cis-linoleic acid and/or ~-linolenic acid) in the come position of the present invention is preferably 1:1, although the ratio may vary from 3:1 to 1:3.
The EPA (and/or DOW) and DOYLE (and/or cis-linoleic acid and/or ~-linolenic acid) need not be administered as the acids themselves but may he used as their pharmaceutically acceptable salts, esters or asides. Esters or asides which can be converted in viva to the acid and other pharmaceutically acceptable pro-ducts may be used, the preferred ester being the ethyl ester. The preferred salts are the sodium or potassium salts, or any other pharmaceutically acceptable solid salt, as these are suitable for 3L~3~
making into tablets.
While it is preferred to administer the composition of the present invention orally, as this is a convenient route for routine administration, the active compounds may be administered by any route by which it may be successfully absorbed, e.g., parenterally (i.e. subcutaneously, intramuscularly or intro-venously), rectally or vaginal, or topically, for example as a skin ointment or lotion.
While it is possible for the active compounds to be administered as such, as a simple mixture of components, it is preferable to present them as a pharmaceutical formulation. The formulations, both for veterinary and for human medical use, of the present invention comprise the active compounds as defined, together with one or rrlore pharmaceutically acceptable carriers therefore and, optionally, other therapelltic ingredients, although other unsaturated fatty acids should be avoided, particularly arachidonic acid. The carrier(s) must be "pharmaceutically accept table" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
Formulations include those suitable for oral, rectal, vaginal, intrapulmonary or parenteral (including subcutaneous, intro-muscular and intravenous) administration. Formulations for oral administration, such as tablets or capsules are preferred.
The EPA (and/or HA) - DHLA (and or cis-linoleic acid and/or y-linolenic acid) combination may also be administered by replacing butter and/or ordinary margarine by a special margarine, e.g. of the emulsion type, formulated so that in normal usage the recipient would receive the required amount of the combination.
Cooking oils and fats may also be similarly formulated to contain the composition of the present invention.
The EPA (and/or HA) and DHLA (and/or cis-linoleic acid and/or y-linolenic acid) used in the compositions of the present invention should be as pure as possible. EPA and/or ha cannot be used in the form of fish oil Directly, as the use of the amount of fish oil necessary in order to provide the desired amount of EPA
and/or HA would provide excessive calories and potential toxic amounts of vitamins A and D. Thus, pure EPA and/or HA should be extracted from the fish oil. The presence of unsaturated fatty ~3~5~7 acids other than EPA, HA, THEA, cis-linoleic acid and y-linolenic acid should be avoided.
Substantially pure EPA and/or HA may be extracted from fish oil, such as cod liver oil, by means of the process set forth, for example, in U.S. Patent ~,377,526. Alternatively, the separation may be accomplished by a novel process of the present applicant involving iodination of the double bonds of the unset-unrated fatty acids in the starting fat or oil. Such iodination permits protection of the fatty acids from oxidation during further processing, and increases the resolution of the fatty acids upon eventual column chromatography. After iodination, the fat or oil is saponified and the iodinated fatty acid extracted from the saponification mixture. The iodinated fatty acids are then methylated and separated by column chromatography, after which the desired fractions are cleiodinated. This process can be used not only for the separation of EPA and Delia from fish oils, but also for the separation and extraction of other unsaturated fatty acids, such as c~-linolenic acid and y-linolenic acid from the triglyceride forms in which they naturally occur in, for example, soybean oil, cottonseed oil, safflower oil, oil of eve-nine primrose, etc. The separation of any unsaturated fatty acid can be facilitated by means of the present iodination process.
The starting material in the present process can be a natural fat or fatty oil in which the first step is iodination followed by saponification. Ivory, the starting material may also be any mixture of unsaturated fatty acids which are difficult to separate, in which the first step will be iodination but no saponification will be required as the starting material is not a triglyceride.
Iodination takes place by adding iodine, in an organic solvent, preferably 20% ethanolic solution, slowly to the starting material until the color fails to disappear in the starting material. This reaction takes place at room temperature under continuous stirring.
The saponification step can take place in any convent tonal manner such as, for example, with a 20% ethanolic solution of KOCH for two hours.
The iodinated fatty acid is extracted from the supine-5~37 ligation mixture by means of any conventional procedure, for example, extraction with ether.
The next step is the methylation of the iodinated fatty acids to prepare them for column chromatography. Again, this is a conventional step and may be done, for example, with 56 hydrogen chloride in methanol.
Finally, the fatty acids are separated by means of column chromatography. The column chromatography is carried out in a known manner with a conventional elusion mixture. While resolution among the various fatty acids it very poor in the con-ventional processes, the resolution is greatly improved when the fatty acids are iodinated at the time of column chromatography.
The column may be packed with silica gel as is conventional and the elusion solution may be any conventional solution, such as hexane-ether-acetic acid (85-10-5).
After the fractions are obtained from the column, the fatty acids are deiodinated using, for example, silver nitrate.
While specific reagents and process conditions are set forth for the various steps of the present process, it should be understood that those skilled in the art will readily be aware of other reagents and conditions in order to carry out the steps once the desirability of each step is known. The critical factor is the concept of iodination prior to chromatography in order to increase the resolution and to protect the fatty acids from ox-ration.
Furthermore, although the separation is accomplished ho column chromatography in the above description, it should be understood that other means of separation may be used as, for example, high speed centrifugation. The resolution will also be improved by iodination in such other separation means.
The following is an example of a method for the spear-anion of EPA and HA from cod liver oil in accordance with this process.
Preparative Example:
A 2nQ6 ethanolic solution of iodine is added slowly to 300g of cod liver oil. The iodine is added as long as its color disappears in the oil. The reaction takes place at room temper-~2~5~
azure under continuous stirring. When iodination is completed, the iodinated oily solution is saponified with 20% ethanolic soul-lion of KIWI for two hours. The iodinated fatty acid, 260 g, is extracted with ease from the saponification mixture.
The iodinated fatty acids are then methylated with 5%
hydrogen chloride in methanol. The EPA and the HA are separated by column chromatography (silica-gel 1,500 g, Kieselgel* 70-230 mesh, Merck). The elusion is done with 5 liters hexane-ether-acetic acid (35-10-5). The first fraction to be extracted is the iodinated HA. The second fraction is iodinated EPA.
Once the suh~tantially pure methylated and iodinated fatty acid mixture is obtained, it may also be separated by other conventional techniques, such as high speed centrifugation or distillation. Deiodination takes place by shaking the iodinated Mud and Me-EPA, separately, with 10% aqueous solutions of sit-Yen nitrate. Precipitates of silver-iodine appears and the organ nix phases are separated. The same procedure is repeated until no more precipitation occurs. Microanalysis, HPLC and NOR proved that the desired products are obtained. The yield is above 90%, the purity 96-100%. There is no need to carry out the procedure under nitrogen since the fatty acids are saturated with iodine, thus preventing oxidation from taking place.
The following clinical tests illustrate the synergistic effects which are obtained when using the combination of the pros-en invention as compared to the effects of each of the components administered alone.
Therapeutic Example:
Thirty-six outpatients, ages 35-75, males and females, were divided into three groups of twelve. Each group added to their normal diet 5 cc/day of free fatty acids for 45 days. Group I added S cc/day of substantially pure EPA. Group II added to their diet 5 cc/day of substantially pure cis-linoleic acid, and group III added to their diet 3 cc/day of substantially pure EPA
and 2 cc/ day of substantially pure cis-linoleic acid. sty the term "substantially pure" is meant a purity of about 96-100%.
Blood cholesterol and triglycerides were tested one day before the treatment began and after 45 days of treatment. The * Trade mark ~3g58~
results of these treatments are set forth in Tables I, II and III
hereinbelow:
Table I: 5 cc/day Pure SPA
Patient age sex Total Total Triglycerides Triglycerides No. cholesterol cholesterol day after 45 1 day after buffer days before days treatment treatment my% my% my% my%
This process has not achieved widespread attention, ales-pile the fact that it uses a natural substance which can readily be incorporated into the daily diet. One reason may be due to the difficulty of efficiently separating EPA from natural fish oils to obtain a pure product at reasonable cost. Another reason may be that the effects of administration of EPA are not as dramatic as had been anticipated.
summary of the Invention It is an object of the present invention to eliminate the above-discussed deficiencies in the prior art.
It is another object of the present invention to pro-vise improvements in compositions of the type of British patents 1,604,554 and 2,033,7~5.
It is a further object of the present invention to pro-vise a composition which has superior therapeutic effects compared to those of the prior art.
It is yet another object of the present invention to provide a therapeutic composition containing naturally obtainable fatty acids which will serve to reduce blood cholesterol and triglyceride levels.
It is still another object of the present invention to provide a therapeutic composition which will increase the Peel :
PGE2 ratio in the patient and increase the absolute amount of PIE
in the system.
These and other objects are obtained through the Somali-Tunis administratiorl of one or more of EPA and HA, together with one or more of clihomo-y-linolenic acid (ekes-trunk acid), i.e., 20:3~6 fatty acid, (hereinafter referred to as "DHLA"), cis-lino]eic acid ((Z,Z)-9,12-octadecadienoic acid), ire, 13:2~6 fatty acid, and y-]inolenic acid, ((Z,Z,Z-6,9,12-octa-c]ecatrienoic acid), i.e., 18:3~6 fatty acid, either in the form of a pharmaceutical dosage or in the form of a food product such as margarine or cooking oil, or in the form of skin ointments or 395~7 lotions for topical administration.
Detailed Description of Preferred Embodiments The prostaqlandins are a family of substances showing a wide diversity of biological effects. Prostag]andins of the 1-, 2- and 3-series, respectively, incorporate one, two or three double bonds in their basic 20-carbon carboxylic fatty acid starlike-lure which includes a 5-member cyclopentene ring.
The l-series of prostaglandins are strong vasodilators and inhibit cholesterol and kilojoule biosynthesis, as well as platelet aggregation. On the other hand the 2-series priest-gland ins are known to enhance platelet aggregation, cholesterol and collagen biosynthesis, and also to enhance endothelial cell proliferation. The main effect of the 3-series prostaglandins, particularly PGÆ3, is the suppression of the 2-series priest-gland ins.
The precursor of the 2-series prostaqlandins is Karachi-tonic acid ((all Z)-5,8,11,14-eicosatetraenoic acid), i.e., 20:4~6 fatty acid. DHLA is the precursor for the l-series prostaglan-dins, and, as indicated hereinabove, EPA and DOW are the precut-sons for the 3-series prostaglandins.
It is believed that the effectiveness of EPA and DOW in preventing atherosclerotic cardiovascular diseases lies both in their effect as a precursor for prostaqlandin PGF3, which sup-presses the 2-series prostaglandins, as well as the fact that the SPA and/or Diva itself competes with arachidonic acid on the same enzymatic system and thus inhibits the biosynthesis of 2-series prostalandins. This inhibition of the 2-series prostaglandins results in an increase of the ratio of Peel : PGE2.
In order to improve the effects of the administration of SPA and/or DIVA alone, by further increasing the Peel : PGÆ2 ratio, as well as effecting an increase in the absolute amount of Peel in the system, Della should be administered simultaneously with the pure SPA and/or Ella. Since cis-linoleic acid and y-linolenic acid hot form Della metabolically within the body, either or both of these fatty acids may be substituted, in whole or in part, for Della.
It has been found that the combination of EPA (and/or DOW) and DHLA (and/or cis-linoleic acid and/or -linolenic acid) causes a substantial reduction in hood cholesterol and trimly-derides. Recent research has definitely linked blood cholesterol levels with incidence of coronary heart disease (JAM, 251, 351-36~ (198~) and JAM 251, 365 -374 (198~)). Additionally, it is expected that such a combination will have other beneficial there-peptic properties. For example, it is known that in Chihuahuas-frown, rheumatoid arthritis and outlawry collagen and auto-immune diseases, as well as in some forms of cancer, there are evidences of extremely low levels of Peel and high levels of PIE Thus, it its expected that the combination of the present invention may be able to serve as an effective treatment for such conditions.
Furthermore, the anti-inflammatory effect of cortico-steroids and the pain killing effect of aspirin are believed to be due to their suppressing effect of PGE2 formation. Thus, the use of the combination of the present invention can be expected to be a natural and most effective anti-inflammatory pain killing agent.
The dose of the composition of the present invention, comprising a combination of SPA (and/or DOW) and DOYLE (and/or is-linoleic acid and/or y-linolenic acid), needed for therapeutic or prophylactic effect will vary with the route of administration and the nature of the condition being treated, but will generally be at least 1 gram, preferably from 1.5 to 3 grams, per clay. This is the dose for an average 70 kg man, and the dose for other men or animals will vary pro fate according to their weight, i.e. about 20-40 mg/kg.
The relative amounts of EPA Andre Ala and ALA
(and/or cis-linoleic acid and/or ~-linolenic acid) in the come position of the present invention is preferably 1:1, although the ratio may vary from 3:1 to 1:3.
The EPA (and/or DOW) and DOYLE (and/or cis-linoleic acid and/or ~-linolenic acid) need not be administered as the acids themselves but may he used as their pharmaceutically acceptable salts, esters or asides. Esters or asides which can be converted in viva to the acid and other pharmaceutically acceptable pro-ducts may be used, the preferred ester being the ethyl ester. The preferred salts are the sodium or potassium salts, or any other pharmaceutically acceptable solid salt, as these are suitable for 3L~3~
making into tablets.
While it is preferred to administer the composition of the present invention orally, as this is a convenient route for routine administration, the active compounds may be administered by any route by which it may be successfully absorbed, e.g., parenterally (i.e. subcutaneously, intramuscularly or intro-venously), rectally or vaginal, or topically, for example as a skin ointment or lotion.
While it is possible for the active compounds to be administered as such, as a simple mixture of components, it is preferable to present them as a pharmaceutical formulation. The formulations, both for veterinary and for human medical use, of the present invention comprise the active compounds as defined, together with one or rrlore pharmaceutically acceptable carriers therefore and, optionally, other therapelltic ingredients, although other unsaturated fatty acids should be avoided, particularly arachidonic acid. The carrier(s) must be "pharmaceutically accept table" in the sense of being compatible with the other ingredients of the formulations and not deleterious to the recipient thereof.
Formulations include those suitable for oral, rectal, vaginal, intrapulmonary or parenteral (including subcutaneous, intro-muscular and intravenous) administration. Formulations for oral administration, such as tablets or capsules are preferred.
The EPA (and/or HA) - DHLA (and or cis-linoleic acid and/or y-linolenic acid) combination may also be administered by replacing butter and/or ordinary margarine by a special margarine, e.g. of the emulsion type, formulated so that in normal usage the recipient would receive the required amount of the combination.
Cooking oils and fats may also be similarly formulated to contain the composition of the present invention.
The EPA (and/or HA) and DHLA (and/or cis-linoleic acid and/or y-linolenic acid) used in the compositions of the present invention should be as pure as possible. EPA and/or ha cannot be used in the form of fish oil Directly, as the use of the amount of fish oil necessary in order to provide the desired amount of EPA
and/or HA would provide excessive calories and potential toxic amounts of vitamins A and D. Thus, pure EPA and/or HA should be extracted from the fish oil. The presence of unsaturated fatty ~3~5~7 acids other than EPA, HA, THEA, cis-linoleic acid and y-linolenic acid should be avoided.
Substantially pure EPA and/or HA may be extracted from fish oil, such as cod liver oil, by means of the process set forth, for example, in U.S. Patent ~,377,526. Alternatively, the separation may be accomplished by a novel process of the present applicant involving iodination of the double bonds of the unset-unrated fatty acids in the starting fat or oil. Such iodination permits protection of the fatty acids from oxidation during further processing, and increases the resolution of the fatty acids upon eventual column chromatography. After iodination, the fat or oil is saponified and the iodinated fatty acid extracted from the saponification mixture. The iodinated fatty acids are then methylated and separated by column chromatography, after which the desired fractions are cleiodinated. This process can be used not only for the separation of EPA and Delia from fish oils, but also for the separation and extraction of other unsaturated fatty acids, such as c~-linolenic acid and y-linolenic acid from the triglyceride forms in which they naturally occur in, for example, soybean oil, cottonseed oil, safflower oil, oil of eve-nine primrose, etc. The separation of any unsaturated fatty acid can be facilitated by means of the present iodination process.
The starting material in the present process can be a natural fat or fatty oil in which the first step is iodination followed by saponification. Ivory, the starting material may also be any mixture of unsaturated fatty acids which are difficult to separate, in which the first step will be iodination but no saponification will be required as the starting material is not a triglyceride.
Iodination takes place by adding iodine, in an organic solvent, preferably 20% ethanolic solution, slowly to the starting material until the color fails to disappear in the starting material. This reaction takes place at room temperature under continuous stirring.
The saponification step can take place in any convent tonal manner such as, for example, with a 20% ethanolic solution of KOCH for two hours.
The iodinated fatty acid is extracted from the supine-5~37 ligation mixture by means of any conventional procedure, for example, extraction with ether.
The next step is the methylation of the iodinated fatty acids to prepare them for column chromatography. Again, this is a conventional step and may be done, for example, with 56 hydrogen chloride in methanol.
Finally, the fatty acids are separated by means of column chromatography. The column chromatography is carried out in a known manner with a conventional elusion mixture. While resolution among the various fatty acids it very poor in the con-ventional processes, the resolution is greatly improved when the fatty acids are iodinated at the time of column chromatography.
The column may be packed with silica gel as is conventional and the elusion solution may be any conventional solution, such as hexane-ether-acetic acid (85-10-5).
After the fractions are obtained from the column, the fatty acids are deiodinated using, for example, silver nitrate.
While specific reagents and process conditions are set forth for the various steps of the present process, it should be understood that those skilled in the art will readily be aware of other reagents and conditions in order to carry out the steps once the desirability of each step is known. The critical factor is the concept of iodination prior to chromatography in order to increase the resolution and to protect the fatty acids from ox-ration.
Furthermore, although the separation is accomplished ho column chromatography in the above description, it should be understood that other means of separation may be used as, for example, high speed centrifugation. The resolution will also be improved by iodination in such other separation means.
The following is an example of a method for the spear-anion of EPA and HA from cod liver oil in accordance with this process.
Preparative Example:
A 2nQ6 ethanolic solution of iodine is added slowly to 300g of cod liver oil. The iodine is added as long as its color disappears in the oil. The reaction takes place at room temper-~2~5~
azure under continuous stirring. When iodination is completed, the iodinated oily solution is saponified with 20% ethanolic soul-lion of KIWI for two hours. The iodinated fatty acid, 260 g, is extracted with ease from the saponification mixture.
The iodinated fatty acids are then methylated with 5%
hydrogen chloride in methanol. The EPA and the HA are separated by column chromatography (silica-gel 1,500 g, Kieselgel* 70-230 mesh, Merck). The elusion is done with 5 liters hexane-ether-acetic acid (35-10-5). The first fraction to be extracted is the iodinated HA. The second fraction is iodinated EPA.
Once the suh~tantially pure methylated and iodinated fatty acid mixture is obtained, it may also be separated by other conventional techniques, such as high speed centrifugation or distillation. Deiodination takes place by shaking the iodinated Mud and Me-EPA, separately, with 10% aqueous solutions of sit-Yen nitrate. Precipitates of silver-iodine appears and the organ nix phases are separated. The same procedure is repeated until no more precipitation occurs. Microanalysis, HPLC and NOR proved that the desired products are obtained. The yield is above 90%, the purity 96-100%. There is no need to carry out the procedure under nitrogen since the fatty acids are saturated with iodine, thus preventing oxidation from taking place.
The following clinical tests illustrate the synergistic effects which are obtained when using the combination of the pros-en invention as compared to the effects of each of the components administered alone.
Therapeutic Example:
Thirty-six outpatients, ages 35-75, males and females, were divided into three groups of twelve. Each group added to their normal diet 5 cc/day of free fatty acids for 45 days. Group I added S cc/day of substantially pure EPA. Group II added to their diet 5 cc/day of substantially pure cis-linoleic acid, and group III added to their diet 3 cc/day of substantially pure EPA
and 2 cc/ day of substantially pure cis-linoleic acid. sty the term "substantially pure" is meant a purity of about 96-100%.
Blood cholesterol and triglycerides were tested one day before the treatment began and after 45 days of treatment. The * Trade mark ~3g58~
results of these treatments are set forth in Tables I, II and III
hereinbelow:
Table I: 5 cc/day Pure SPA
Patient age sex Total Total Triglycerides Triglycerides No. cholesterol cholesterol day after 45 1 day after buffer days before days treatment treatment my% my% my% my%
3 47 M 230 210 102 90
4 73 M 270 240 95 90 a 52 F aye 250 115 100 12 35 M 200 190 90 90+7 Average: 256.9+43.2227.9+24.4111.8+18.6 94.95+
% reduction: 11.2% 15~, Table II: 5 cc/day Pure cis-Linoleic Acid Patient age sex Total Total Triglycerides Triglycerides No. cholesterol cholesterol day after 45 1 day after buffer days before days treatment treatment my% my% my% my%
9 62 F 310 300 lay 140 Average: 265.3+61.75250+50112+22.8 109.16+19.4 % reduction: 5% 2%
~23~S~7 Table III: 3 cc/day Pure EPA and 2 cc/day Pure cis-Linoleic Acid Patient age sex Total Total Triglycerides Triglycerides Jo. cholesterol cholesterol day after 45 1 day after 45 before days before days treatment treatment McKee my% my% my%
Average: 270.1~67.5217.9+24.499.5 59.16+16 % reduction: 19.3% 40.5 While the administration of 5 cc/day of SPA alone pro-voided a reduction in serum cholesterol and triglyceride levels during the 45 days of treatment, i.e. an average reduction of 11.2% for total cholesterol and 15~ for triglycerides, the effect of the administration of pure cis-linoleic acid alone for 45 days is almost insignificant. In fact, in many patients the chores-twirl level actually rose.
A definite synergism, however, is observed by ad minis-traction of the combination of 3 cc EPA plus 2 cc cis-linoleic acid per day. By use of the combination, a very significant reduction of serum cholesterol (an average of 19.3% decrease) and serum triglycerides (an average of 40.5~ decrease) is observed.
It will be obvious to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is described in the specification.
% reduction: 11.2% 15~, Table II: 5 cc/day Pure cis-Linoleic Acid Patient age sex Total Total Triglycerides Triglycerides No. cholesterol cholesterol day after 45 1 day after buffer days before days treatment treatment my% my% my% my%
9 62 F 310 300 lay 140 Average: 265.3+61.75250+50112+22.8 109.16+19.4 % reduction: 5% 2%
~23~S~7 Table III: 3 cc/day Pure EPA and 2 cc/day Pure cis-Linoleic Acid Patient age sex Total Total Triglycerides Triglycerides Jo. cholesterol cholesterol day after 45 1 day after 45 before days before days treatment treatment McKee my% my% my%
Average: 270.1~67.5217.9+24.499.5 59.16+16 % reduction: 19.3% 40.5 While the administration of 5 cc/day of SPA alone pro-voided a reduction in serum cholesterol and triglyceride levels during the 45 days of treatment, i.e. an average reduction of 11.2% for total cholesterol and 15~ for triglycerides, the effect of the administration of pure cis-linoleic acid alone for 45 days is almost insignificant. In fact, in many patients the chores-twirl level actually rose.
A definite synergism, however, is observed by ad minis-traction of the combination of 3 cc EPA plus 2 cc cis-linoleic acid per day. By use of the combination, a very significant reduction of serum cholesterol (an average of 19.3% decrease) and serum triglycerides (an average of 40.5~ decrease) is observed.
It will be obvious to those skilled in the art that various changes may be made without departing from the scope of the invention and the invention is not to be considered limited to what is described in the specification.
Claims (11)
1. A pharmaceutical composition for causing a reduction of blood cholesterol and triglyceride levels, consisting essen-tially of an effective amount of a combination of a first com-ponent selected from the group consisting of 5,8,11,14,17-eicosa-pentaenoic acid, 4,7,10,13,16,19-docosahexaenoic acid and a com-bination thereof, and a second component selected from the group consisting of dihomo-.gamma.-linolenic acid, cis-linoleic acid, .gamma.-lino-lenic acid and combinations thereof, said first and second com-ponents being present in relative amounts of 3:1 to 1:3.
2. A composition in accordance with claim 1, further including a pharameceutically acceptable excipient.
3. A composition in accordance with claim 1, wherein said composition is substantially free of other unsaturated fatty acids.
4. A composition in accordance with claim 1, wherein said first component is 5,8,11,14,17-eicosapentaenoic acid.
5. A composition in accordance with claim 1, wherein said second component is cis-linoleic acid.
6. A composition in accordance with claim 4, wherein said second component is cis-linoleic acid.
7. A food product containing a substantial amount of at least one fatty acid, characterized in that said at least one fatty acid present in said food product consists essentially of a combination of a first component selected from the group consis-ting of 5,8,11,14,17-eicosapentaenoic acid, 4,7,10,13,16,19-do-cosahexaenoic acid and a combination thereof, and a second com-ponent selected from the group consisting of dihomo-.gamma.-linolenic acid, cis-linoleic acid, .gamma.-linolenic acid and combinations there-of, said first and second components being present in relative amounts of 3:1 to 1:3.
8. A food product in accordance with claim 7 which is substantially free of other unsaturated fatty acids.
9. A food product in accordance with claim 7, wherein said first component is 5,8,11,14,17-eicosapentaenoic acid.
10. A food product in accordance with claim 7 wherein said second component is cis-linoleic acid.
11. A food product in accordance with claim 9, wherein said second component is cis-linoleic acid.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US54535083A | 1983-10-24 | 1983-10-24 | |
US06/545,349 US4526902A (en) | 1983-10-24 | 1983-10-24 | Combined fatty acid composition for treatment or prophylaxis of thrombo-embolic conditions |
US545,350 | 1983-10-24 | ||
US545,349 | 1995-10-19 |
Publications (1)
Publication Number | Publication Date |
---|---|
CA1239587A true CA1239587A (en) | 1988-07-26 |
Family
ID=27067902
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CA000465531A Expired CA1239587A (en) | 1983-10-24 | 1984-10-16 | Combined fatty acid composition for lowering blood cholestrol and triglyceride levels |
Country Status (7)
Country | Link |
---|---|
CA (1) | CA1239587A (en) |
CH (1) | CH661209A5 (en) |
DE (1) | DE3438630A1 (en) |
FR (1) | FR2553662B1 (en) |
GB (1) | GB2148713B (en) |
IT (1) | IT1178170B (en) |
SE (1) | SE462701B (en) |
Cited By (1)
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WO2007063158A2 (en) | 2005-11-30 | 2007-06-07 | La Morella Nuts, S.A. | Functional food having positive effects in the prevention of cardiovascular diseases |
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GB8601915D0 (en) * | 1986-01-27 | 1986-03-05 | Efamol Ltd | Pharmaceutical compositions |
DE3603000A1 (en) * | 1986-01-31 | 1987-08-06 | Milupa Ag | NEW FATTY MIXTURE OF POLYENIC ACID AND THEIR USE IN THE PRODUCTION OF INFANT FOODS |
DE3615710A1 (en) * | 1986-05-09 | 1987-11-26 | Hoechst Ag | PREPARATIONS FOR THE SYNTHESIS OF PROSTAGLANDINES AND HYDROXY FATTY ACIDS IN BIOLOGICAL SYSTEMS |
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FR2623692B1 (en) * | 1987-11-30 | 1991-05-03 | Vernin Jean Gilles | NEW DIETETIC OIL |
HU210122B (en) * | 1988-03-23 | 1995-02-28 | Biorex Kutato Fejlesztoe Kft | Process for production of composition against thromboembolytic conditions of circulating system and heart |
GB8813766D0 (en) * | 1988-06-10 | 1988-07-13 | Efamol Holdings | Essential fatty acid compositions |
GB8819110D0 (en) * | 1988-08-11 | 1988-09-14 | Norsk Hydro As | Antihypertensive drug & method for production |
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DE19503993A1 (en) * | 1995-02-08 | 1996-08-14 | Johann Friedrich Dr Med Desaga | Enteral product contg n-3-fatty acid or deriv and medium chain length tri:glyceride |
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SE0202188D0 (en) | 2002-07-11 | 2002-07-11 | Pronova Biocare As | A process for decreasing environmental pollutants in an oil or a fat, a volatile fat or oil environmental pollutants decreasing working fluid, a health supplement, and an animal feed product |
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GB8319073D0 (en) * | 1983-07-14 | 1983-08-17 | Efamol Ltd | Fatty acid compositions |
-
1984
- 1984-10-16 CA CA000465531A patent/CA1239587A/en not_active Expired
- 1984-10-22 DE DE19843438630 patent/DE3438630A1/en not_active Ceased
- 1984-10-23 GB GB08426765A patent/GB2148713B/en not_active Expired
- 1984-10-23 CH CH5070/84A patent/CH661209A5/en not_active IP Right Cessation
- 1984-10-23 FR FR8416171A patent/FR2553662B1/en not_active Expired
- 1984-10-24 IT IT49063/84A patent/IT1178170B/en active
- 1984-10-24 SE SE8405308A patent/SE462701B/en not_active IP Right Cessation
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2007063158A2 (en) | 2005-11-30 | 2007-06-07 | La Morella Nuts, S.A. | Functional food having positive effects in the prevention of cardiovascular diseases |
Also Published As
Publication number | Publication date |
---|---|
GB8426765D0 (en) | 1984-11-28 |
SE8405308L (en) | 1985-04-25 |
GB2148713B (en) | 1987-04-23 |
DE3438630A1 (en) | 1985-05-02 |
FR2553662A1 (en) | 1985-04-26 |
IT1178170B (en) | 1987-09-09 |
GB2148713A (en) | 1985-06-05 |
SE462701B (en) | 1990-08-20 |
SE8405308D0 (en) | 1984-10-24 |
IT8449063A0 (en) | 1984-10-24 |
CH661209A5 (en) | 1987-07-15 |
IT8449063A1 (en) | 1986-04-24 |
FR2553662B1 (en) | 1989-06-09 |
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