JPH04300828A - Preventive or therapeutic agent for fatty liver - Google Patents
Preventive or therapeutic agent for fatty liverInfo
- Publication number
- JPH04300828A JPH04300828A JP6483991A JP6483991A JPH04300828A JP H04300828 A JPH04300828 A JP H04300828A JP 6483991 A JP6483991 A JP 6483991A JP 6483991 A JP6483991 A JP 6483991A JP H04300828 A JPH04300828 A JP H04300828A
- Authority
- JP
- Japan
- Prior art keywords
- diglyceride
- fatty acid
- preventive
- therapeutic agent
- liver
- 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.)
- Granted
Links
- 208000010706 fatty liver disease Diseases 0.000 title claims abstract description 17
- 208000004930 Fatty Liver Diseases 0.000 title claims abstract description 16
- 206010019708 Hepatic steatosis Diseases 0.000 title claims abstract description 16
- 231100000240 steatosis hepatitis Toxicity 0.000 title claims abstract description 16
- 230000003449 preventive effect Effects 0.000 title claims abstract description 12
- 239000003814 drug Substances 0.000 title claims abstract description 10
- 229940124597 therapeutic agent Drugs 0.000 title claims abstract description 10
- 235000021122 unsaturated fatty acids Nutrition 0.000 claims abstract description 6
- 125000002252 acyl group Chemical group 0.000 claims abstract description 5
- 150000004670 unsaturated fatty acids Chemical class 0.000 claims abstract description 5
- 239000004480 active ingredient Substances 0.000 claims abstract description 4
- 150000004671 saturated fatty acids Chemical class 0.000 claims abstract description 4
- 150000001875 compounds Chemical class 0.000 claims abstract 3
- 125000004432 carbon atom Chemical group C* 0.000 claims description 5
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 2
- 235000003441 saturated fatty acids Nutrition 0.000 claims description 2
- 239000003795 chemical substances by application Substances 0.000 claims 1
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 abstract description 20
- 108090001060 Lipase Proteins 0.000 abstract description 16
- 239000004367 Lipase Substances 0.000 abstract description 16
- 102000004882 Lipase Human genes 0.000 abstract description 16
- 235000014113 dietary fatty acids Nutrition 0.000 abstract description 16
- 239000000194 fatty acid Substances 0.000 abstract description 16
- 229930195729 fatty acid Natural products 0.000 abstract description 16
- 235000019421 lipase Nutrition 0.000 abstract description 16
- 150000002632 lipids Chemical class 0.000 abstract description 13
- 239000000203 mixture Substances 0.000 abstract description 11
- 150000004665 fatty acids Chemical class 0.000 abstract description 10
- 210000004185 liver Anatomy 0.000 abstract description 6
- 235000019484 Rapeseed oil Nutrition 0.000 abstract description 5
- 239000003921 oil Substances 0.000 abstract description 4
- 235000019198 oils Nutrition 0.000 abstract description 4
- 238000005809 transesterification reaction Methods 0.000 abstract description 4
- 150000002148 esters Chemical class 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 239000003513 alkali Substances 0.000 abstract 1
- 238000006243 chemical reaction Methods 0.000 abstract 1
- 239000003925 fat Substances 0.000 abstract 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 abstract 1
- -1 fatty acid ester Chemical class 0.000 description 9
- 235000011187 glycerol Nutrition 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000000047 product Substances 0.000 description 5
- 239000007795 chemical reaction product Substances 0.000 description 4
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 description 4
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- 241000235395 Mucor Species 0.000 description 3
- DTOSIQBPPRVQHS-PDBXOOCHSA-N alpha-linolenic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCC(O)=O DTOSIQBPPRVQHS-PDBXOOCHSA-N 0.000 description 3
- 235000020661 alpha-linolenic acid Nutrition 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000005886 esterification reaction Methods 0.000 description 3
- 229960004488 linolenic acid Drugs 0.000 description 3
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000000199 molecular distillation Methods 0.000 description 3
- 239000007901 soft capsule Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- NWUYHJFMYQTDRP-UHFFFAOYSA-N 1,2-bis(ethenyl)benzene;1-ethenyl-2-ethylbenzene;styrene Chemical compound C=CC1=CC=CC=C1.CCC1=CC=CC=C1C=C.C=CC1=CC=CC=C1C=C NWUYHJFMYQTDRP-UHFFFAOYSA-N 0.000 description 2
- 241000228212 Aspergillus Species 0.000 description 2
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- OYHQOLUKZRVURQ-HZJYTTRNSA-N Linoleic acid Chemical compound CCCCC\C=C/C\C=C/CCCCCCCC(O)=O OYHQOLUKZRVURQ-HZJYTTRNSA-N 0.000 description 2
- 201000002451 Overnutrition Diseases 0.000 description 2
- 241000235527 Rhizopus Species 0.000 description 2
- 235000019485 Safflower oil Nutrition 0.000 description 2
- 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 description 2
- 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 2
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-N 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 238000001816 cooling Methods 0.000 description 2
- 235000005687 corn oil Nutrition 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 238000004821 distillation Methods 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 230000003834 intracellular effect Effects 0.000 description 2
- 239000003456 ion exchange resin Substances 0.000 description 2
- 229920003303 ion-exchange polymer Polymers 0.000 description 2
- 235000020778 linoleic acid Nutrition 0.000 description 2
- OYHQOLUKZRVURQ-IXWMQOLASA-N linoleic acid Natural products CCCCC\C=C/C\C=C\CCCCCCCC(O)=O OYHQOLUKZRVURQ-IXWMQOLASA-N 0.000 description 2
- 239000000944 linseed oil Substances 0.000 description 2
- 235000021388 linseed oil Nutrition 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 235000020823 overnutrition Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 239000003813 safflower oil Substances 0.000 description 2
- 235000005713 safflower oil Nutrition 0.000 description 2
- 229920006395 saturated elastomer Polymers 0.000 description 2
- 239000010409 thin film Substances 0.000 description 2
- HOBAELRKJCKHQD-UHFFFAOYSA-N (8Z,11Z,14Z)-8,11,14-eicosatrienoic acid Natural products CCCCCC=CCC=CCC=CCCCCCCC(O)=O HOBAELRKJCKHQD-UHFFFAOYSA-N 0.000 description 1
- OYHQOLUKZRVURQ-NTGFUMLPSA-N (9Z,12Z)-9,10,12,13-tetratritiooctadeca-9,12-dienoic acid Chemical compound C(CCCCCCC\C(=C(/C\C(=C(/CCCCC)\[3H])\[3H])\[3H])\[3H])(=O)O OYHQOLUKZRVURQ-NTGFUMLPSA-N 0.000 description 1
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- 241000228245 Aspergillus niger Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010008909 Chronic Hepatitis Diseases 0.000 description 1
- 235000021298 Dihomo-γ-linolenic acid Nutrition 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 108010093096 Immobilized Enzymes Proteins 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 108010048733 Lipozyme Proteins 0.000 description 1
- 208000002720 Malnutrition Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 241000498617 Mucor javanicus Species 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- 102000019280 Pancreatic lipases Human genes 0.000 description 1
- 108050006759 Pancreatic lipases Proteins 0.000 description 1
- 235000004347 Perilla Nutrition 0.000 description 1
- 244000124853 Perilla frutescens Species 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 241000700157 Rattus norvegicus Species 0.000 description 1
- 241000303962 Rhizopus delemar Species 0.000 description 1
- 240000005384 Rhizopus oryzae Species 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 231100000460 acute oral toxicity Toxicity 0.000 description 1
- 150000001298 alcohols Chemical class 0.000 description 1
- 229910000272 alkali metal oxide Inorganic materials 0.000 description 1
- 150000001340 alkali metals Chemical class 0.000 description 1
- 229910001860 alkaline earth metal hydroxide Inorganic materials 0.000 description 1
- 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 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000021342 arachidonic acid Nutrition 0.000 description 1
- 229940114079 arachidonic acid Drugs 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011942 biocatalyst Substances 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- AXCZMVOFGPJBDE-UHFFFAOYSA-L calcium dihydroxide Chemical compound [OH-].[OH-].[Ca+2] AXCZMVOFGPJBDE-UHFFFAOYSA-L 0.000 description 1
- 239000000920 calcium hydroxide Substances 0.000 description 1
- 229910001861 calcium hydroxide Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 235000014633 carbohydrates Nutrition 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 208000019425 cirrhosis of liver Diseases 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000015872 dietary supplement Nutrition 0.000 description 1
- 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 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 235000020669 docosahexaenoic acid Nutrition 0.000 description 1
- 229940090949 docosahexaenoic acid Drugs 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000020673 eicosapentaenoic acid Nutrition 0.000 description 1
- 229960005135 eicosapentaenoic acid Drugs 0.000 description 1
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 description 1
- 235000019197 fats Nutrition 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000012041 food component Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 230000003100 immobilizing effect Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 229910052740 iodine Inorganic materials 0.000 description 1
- 239000011630 iodine Substances 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- FCCDDURTIIUXBY-UHFFFAOYSA-N lipoamide Chemical compound NC(=O)CCCCC1CCSS1 FCCDDURTIIUXBY-UHFFFAOYSA-N 0.000 description 1
- 210000005229 liver cell Anatomy 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 230000001071 malnutrition Effects 0.000 description 1
- 235000000824 malnutrition Nutrition 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 230000000813 microbial effect Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 235000016709 nutrition Nutrition 0.000 description 1
- 230000035764 nutrition Effects 0.000 description 1
- 208000015380 nutritional deficiency disease Diseases 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 235000021313 oleic acid Nutrition 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Description
【0001】0001
【産業上の利用分野】本発明は脂肪肝の予防又は治療剤
に関し、更に詳細に肝臓の脂質濃度の上昇を防止する作
用を有し、安全性の高い脂肪肝の予防又は治療剤に関す
る。BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a preventive or therapeutic agent for fatty liver, and more particularly to a highly safe preventive or therapeutic agent for fatty liver that has the effect of preventing an increase in hepatic lipid concentration.
【0002】0002
【従来の技術及び発明が解決しようとする課題】脂肪肝
は、肝細胞内に脂質が多量に蓄積した状態をいい、慢性
肝炎、肝硬変等の原因の一つであることから、その予防
及び治療は極めて重要である。かかる脂肪肝の原因とし
ては、アルコールの過剰摂取、過栄養、薬剤の副作用、
糖尿病等の他、低栄養も挙げられる。原因が過栄養の場
合、その治療法として糖質、脂質等の摂取を減らすこと
が考えられるが、逆にあまり脂質摂取を低下させると肝
臓での内因性脂質の合成が増加し、脂肪肝が生ずるとい
われている。このように、脂肪肝の治療は、栄養のコン
トロールが難しく、簡便な予防又は治療手段の開発が熱
望されていた。[Prior Art and Problems to be Solved by the Invention] Fatty liver refers to a state in which a large amount of lipid accumulates within liver cells, and since it is one of the causes of chronic hepatitis, liver cirrhosis, etc., its prevention and treatment are is extremely important. Causes of fatty liver include excessive intake of alcohol, overnutrition, side effects of drugs,
In addition to diabetes, malnutrition can also be cited. If the cause is overnutrition, one possible treatment would be to reduce the intake of carbohydrates, lipids, etc. However, on the other hand, if the intake of lipids is reduced too much, the synthesis of endogenous lipids in the liver will increase, leading to fatty liver disease. It is said that it occurs. As described above, it is difficult to control nutrition in the treatment of fatty liver, and the development of simple preventive or therapeutic means has been eagerly awaited.
【0003】0003
【課題を解決するための手段】かかる実状において本発
明者らは、上記課題を解決すべく鋭意検討した結果、ジ
グリセリドが、投与量が多くとも少なくとも肝臓の脂質
濃度の上昇を防止し、かつ安全性の高いものであること
を見出し、本発明を完成した。[Means for Solving the Problems] Under these circumstances, the present inventors have made extensive studies to solve the above problems, and have found that diglyceride, even at a large dose, at least prevents an increase in liver lipid concentration and is safe. The present invention was completed based on the discovery that it has high properties.
【0004】すなわち、本発明はジグリセリドを有効成
分とする脂肪肝予防又は治療剤を提供するものである。That is, the present invention provides a preventive or therapeutic agent for fatty liver containing diglyceride as an active ingredient.
【0005】本発明の脂肪肝予防又は治療剤に用いられ
るジグリセリドとしては、例えば次の一般式(1)[0005] As the diglyceride used in the fatty liver preventive or therapeutic agent of the present invention, for example, the following general formula (1) is used.
【0
006】0
006]
【化2】[Chemical 2]
【0007】〔式中、R1 、R2 及びR3 のうち
2個は炭素数12〜22の飽和脂肪酸又は不飽和脂肪酸
由来のアシル基を示し、残余は水素原子を示す〕で表わ
されるジグリセリドから選ばれる1種又は2種以上が挙
げられる。かかる飽和脂肪酸又は不飽和脂肪酸としては
、ステアリン酸、オレイン酸、リノール酸、リノレン酸
、ジホモγ−リノレン酸、アラキドン酸、エイコサペン
タエン酸、ドコサヘキサエン酸等が挙げられる。より好
ましくは、炭素数16〜20の不飽和脂肪酸由来のアシ
ル基を有するジグリセリドである。[0007] [In the formula, two of R1, R2 and R3 represent an acyl group derived from a saturated or unsaturated fatty acid having 12 to 22 carbon atoms, and the remainder represents a hydrogen atom.] One or more types may be mentioned. Examples of such saturated or unsaturated fatty acids include stearic acid, oleic acid, linoleic acid, linolenic acid, dihomo-γ-linolenic acid, arachidonic acid, eicosapentaenoic acid, docosahexaenoic acid, and the like. More preferably, it is a diglyceride having an acyl group derived from an unsaturated fatty acid having 16 to 20 carbon atoms.
【0008】かかるジグリセリドの製造法は、特に制限
されないが、例えば油脂とグリセリンの混合物をアルカ
リ金属及び/又はアルカリ土類金属の水酸化物の存在下
でエステル交換反応させるか、あるいは脂肪酸又は脂肪
酸エステルとグリセリンとの混合物にリパーゼを作用さ
せてエステル化反応を行なうことにより製造される。エ
ステル交換反応の具体例を挙げれば、リノール酸高含有
トリグリセリド 100部とリノレン酸高含有トリグリ
セリド 100部との混合物に精製グリセリン30〜1
00部(好ましくは約50部)を配合し、触媒としてC
a(OH)2 を0.2 部添加し、窒素気流減圧下で
230℃、30分間攪拌を続けてランダムエステル交
換反応を行う。冷却後脱グリセリンし、薄膜式分子蒸留
にてモノグリセリドを除去する。蒸留残渣物として濃度
85%のジグリセリドを得る。本製造で用いるリノール
酸高含有トリグリセリドとしてサフラワー油、大豆油、
トウモロコシ油等が挙げられるが、特にサフラワー油が
好ましい。またリノレン酸高含有トリグリセリドとして
アマニ油、シソ油、トウハゼ油、エノ油等が挙げられる
が、特にアマニ油が好ましい。[0008] The method for producing such diglycerides is not particularly limited, but for example, a mixture of oil and fat and glycerin is transesterified in the presence of an alkali metal and/or alkaline earth metal hydroxide, or a fatty acid or a fatty acid ester is transesterified. It is produced by applying lipase to a mixture of glycerin and glycerin to perform an esterification reaction. To give a specific example of the transesterification reaction, 30 to 1 part of purified glycerin is added to a mixture of 100 parts of linoleic acid-rich triglyceride and 100 parts of linolenic acid-rich triglyceride.
00 parts (preferably about 50 parts) and C as a catalyst.
0.2 part of a(OH)2 is added, and stirring is continued at 230° C. for 30 minutes under reduced pressure in a nitrogen stream to carry out a random transesterification reaction. After cooling, deglycerol is removed, and monoglycerides are removed by thin film molecular distillation. Diglyceride with a concentration of 85% is obtained as a distillation residue. The linoleic acid-rich triglycerides used in this production include safflower oil, soybean oil,
Examples include corn oil, but safflower oil is particularly preferred. Examples of triglycerides with high linolenic acid content include linseed oil, perilla oil, corn goby oil, and eno oil, with linseed oil being particularly preferred.
【0009】また、リパーゼによるエステル化反応の具
体例を挙げれば、グリセリン1モルに対し脂肪酸又は脂
肪酸エステル 1.5モル以上を添加した混合物に、リ
パーゼを脂肪酸又は脂肪酸エステル1gに対し 200
〜1000units 添加し、40℃で21時間攪拌
を続けてエステル化反応を行なう。反応終了物よりリパ
ーゼをろ別後、未反応脂肪酸又は脂肪酸エステル及びモ
ノグリセリドを分子蒸留にて除去することにより、ジグ
リセリドを得る。使用する脂肪酸は、目的とするジグリ
セリドに応じて選択すればよい。また、脂肪酸エステル
としては、炭素数1〜3の低級アルコール類とのエステ
ルが好ましい。ここで炭素数1〜3の低級アルコールと
しては、例えばメタノール、エタノール、プロパノール
、イソプロパノールなどが挙げられる。これらの脂肪酸
又は脂肪酸エステルは単独又は2種以上混合して用いる
ことができる。また、リパーゼとしては、固定化又は菌
体内1,3−位選択的リパーゼが挙げられる。固定化1
,3−位選択的リパーゼは1,3−位選択的リパーゼを
公知の方法で固定化することにより得られる。固定化の
ための公知の方法は、例えば「固定化酵素」千畑一郎編
集、講談社刊、9〜85頁及び「固定化生体触媒」千畑
一郎編、講談社刊、12〜101 頁に記載されている
が、イオン交換樹脂により固定する方法が好ましいもの
として例示される。固定化に用いられる1,3−位選択
的リパーゼとしては、リゾプス(Rhizopus)属
、アスペルギルス(Aspergtllus )属、ム
コール(Mucor )属等の微生物由来のリパーゼ、
膵臓リパーゼ等がある。例えばリゾプス・デレマー(R
hizopus delemar)、リゾプス・ジャポ
ニカス(Rhizopus japonicus)、ア
スペルギルス・ニガー(Aspergillus nt
ger)、ムコール・ジャパニカス(Mucorjav
anicus )、ムコール・ミーハイ(Mucor
miehei)などを起源とするリパーゼを使用するこ
とができる。市販の固定化1,3−位選択的リパーゼと
しては、ノボ・インダストリーA.S.社製の商品名「
Lipozyme 3A 」がある。菌体内1,3−位
選択的リパーゼは、微生物菌体に1,3−位選択的リパ
ーゼが吸着又は結合したもので、市販品としては、大阪
細菌研究所製の商品名「オリパーゼ」がある。
これらのうちイオン交換樹脂で固定化したリパーゼを用
いるのが特に好ましい。得られたジグリセリド粗生成物
中のジグリセリド含量は、蒸留法又はケイ酸カラムクロ
マトグラフ法により増加させることができる。[0009] To give a specific example of an esterification reaction using lipase, in a mixture in which 1.5 moles or more of fatty acid or fatty acid ester is added to 1 mole of glycerin, lipase is added to 1 g of fatty acid or fatty acid ester at 200%
~1000 units were added, and stirring was continued at 40°C for 21 hours to carry out the esterification reaction. After filtering off the lipase from the reaction product, unreacted fatty acids or fatty acid esters and monoglycerides are removed by molecular distillation to obtain diglycerides. The fatty acid to be used may be selected depending on the desired diglyceride. Furthermore, as the fatty acid ester, esters with lower alcohols having 1 to 3 carbon atoms are preferable. Examples of the lower alcohol having 1 to 3 carbon atoms include methanol, ethanol, propanol, and isopropanol. These fatty acids or fatty acid esters can be used alone or in combination of two or more. Furthermore, examples of the lipase include immobilized or intracellular 1,3-position selective lipase. Immobilization 1
, 3-position selective lipase can be obtained by immobilizing 1,3-position selective lipase by a known method. Known methods for immobilization are described, for example, in "Immobilized Enzymes" edited by Ichiro Chibata, published by Kodansha, pages 9-85 and "Immobilized Biocatalysts" edited by Ichiro Chibata, published by Kodansha, pages 12-101. However, a method of fixing with an ion exchange resin is exemplified as a preferred method. The 1,3-position selective lipase used for immobilization includes lipases derived from microorganisms such as Rhizopus, Aspergillus, and Mucor;
There are pancreatic lipases, etc. For example, Rhizopus delemer (R
Rhizopus delemar), Rhizopus japonicus, Aspergillus niger (Aspergillus nt.
ger), Mucorjav
anicus), Mucor Mihai (Mucor
Lipases originating from A. miehei) can be used. Commercially available immobilized 1,3-position selective lipases include Novo Industries A. S. Company product name “
Lipozyme 3A" is available. Intracellular 1,3-position selective lipase is a 1,3-position selective lipase adsorbed or bound to microbial cells, and a commercially available product is the product name "Olipase" manufactured by Osaka Bacteria Research Institute. . Among these, it is particularly preferable to use lipase immobilized with an ion exchange resin. The diglyceride content in the obtained crude diglyceride product can be increased by distillation or silicic acid column chromatography.
【0010】これらのジグリセリドのラットにおける経
口急性毒性は10g/kg体重以上であり、安全性の高
いものである。[0010] The acute oral toxicity of these diglycerides in rats is 10 g/kg body weight or more, and they are highly safe.
【0011】本発明の脂肪肝予防又は治療剤は、経口、
非経口の何れの方法によっても投与することができ、経
口投与用の剤型としては、例えば錠剤、カプセル剤、散
剤、顆粒剤及びシロップ剤等が挙げられ、非経口投与用
の剤型としては注射剤、経腸用製剤等が挙げられる。こ
れらの調製には通常の賦形剤、崩壊剤、結合剤、滑沢剤
、色素、希釈剤などが用いられる。[0011] The fatty liver preventive or therapeutic agent of the present invention can be administered orally;
It can be administered by any parenteral method, and dosage forms for oral administration include, for example, tablets, capsules, powders, granules, and syrups. Examples include injections and enteral preparations. Conventional excipients, disintegrants, binders, lubricants, dyes, diluents, etc. are used in their preparation.
【0012】賦形剤としてはブドウ糖、乳糖などが、崩
壊剤としてデンプン、アルギン酸ナトリウムなどが、滑
沢剤としてはステアリン酸マグネシウム、硫酸パラフィ
ン、タルクなどが、結合剤としてはジメチルセルロース
、ゼラチン、ポリビニルピロリドンなどが用いられる。
投与量は通常成人においてジグリセリドとして1日1g
〜70gであるが、年齢、症状等により増減することが
できる。また、食事成分、栄養剤中にジグリセリドを配
合して投与することもでき、この場合、通常のトリグリ
セリドの50重量%以上をジグリセリドに置き換えるこ
とにより配合するのが好ましい。Excipients include glucose, lactose, etc., disintegrants include starch, sodium alginate, etc., lubricants include magnesium stearate, paraffin sulfate, talc, etc., and binders include dimethyl cellulose, gelatin, polyvinyl, etc. Pyrrolidone and the like are used. The usual dosage for adults is 1 g of diglyceride per day.
~70g, but can be increased or decreased depending on age, symptoms, etc. Furthermore, diglyceride can be administered by blending it into dietary ingredients and nutritional supplements. In this case, it is preferable to replace 50% by weight or more of normal triglyceride with diglyceride.
【0013】[0013]
【実施例】次に実施例を挙げて本発明を更に説明するが
、本発明はこれに限定されるものではない。EXAMPLES Next, the present invention will be further explained with reference to Examples, but the present invention is not limited thereto.
【0014】参考例1 ジグリセリドの製造:なたね
油(ヨウ素価168 )375gにグリセリン125g
を配合し、全系に対して 0.1重量%の水酸化カルシ
ウムを添加して、窒素雰囲気下、 230℃で30分間
攪拌を続けてラングムエステル交換反応を行なった。冷
却後、反応物を分液ロートに移して分層後、下層を除去
した。更に10%クエン酸水溶液 500ml加えて攪
拌し、放置分離後、上層部を脱水ろ過し、粗なたね油脂
肪酸組成ジグリセリドを得た。更に粗なたね油脂肪酸組
成ジグリセリドを 190℃、0.01mmHgの条件
下で薄膜式分子蒸留器に通して、本発明に適するジグリ
セリドを含有する反応生成物を165g得た。得られた
反応生成物の脂肪酸組成及び含有分子種を表1及び表2
にそれぞれ示す。なお、これらの表中にはトリグリセリ
ドとしてなたね油についての分析結果を併せて示す。Reference Example 1 Production of diglyceride: 125 g of glycerin in 375 g of rapeseed oil (iodine value 168)
0.1% by weight of calcium hydroxide was added to the total system, and stirring was continued at 230° C. for 30 minutes in a nitrogen atmosphere to carry out Langueum transesterification reaction. After cooling, the reaction product was transferred to a separatory funnel, separated into layers, and the lower layer was removed. Furthermore, 500 ml of 10% citric acid aqueous solution was added and stirred, and after standing to separate, the upper layer was dehydrated and filtered to obtain a crude diglyceride having a fatty acid composition of rapeseed oil. Furthermore, the crude rapeseed oil fatty acid composition diglyceride was passed through a thin film molecular distillation vessel under conditions of 190° C. and 0.01 mmHg to obtain 165 g of a reaction product containing diglyceride suitable for the present invention. The fatty acid composition and molecular species contained in the obtained reaction product are shown in Tables 1 and 2.
are shown respectively. In addition, these tables also show the analysis results for rapeseed oil as triglyceride.
【0015】[0015]
【表1】[Table 1]
【0016】[0016]
【表2】[Table 2]
【0017】実施例1
表3に示す組成の食餌でWistar系雄性ラットを3
週間飼育し、肝臓の脂質濃度を測定した。その結果を表
4に示す。Example 1 Three male Wistar rats were fed with a diet having the composition shown in Table 3.
The animals were kept for a week, and the lipid concentration in the liver was measured. The results are shown in Table 4.
【0018】[0018]
【表3】[Table 3]
【0019】[0019]
【表4】[Table 4]
【0020】その結果、通常の脂質(トリグリセリド)
を投与した場合には、その投与量が少なくとも、多くと
も肝臓の脂質濃度は上昇した。これに対し、ジグリセリ
ドを投与すると、その投与量が少ない場合も、多い場合
も通常の脂質を投与した場合に比べ肝臓中の脂質濃度は
低下し、ジグリセリドに脂肪肝の予防作用が認められた
。As a result, normal lipids (triglycerides)
When administered, hepatic lipid concentrations increased at least and at most doses. On the other hand, when diglyceride was administered, the lipid concentration in the liver was lower than when normal lipids were administered, regardless of whether the dose was small or high, indicating that diglyceride had a preventive effect on fatty liver.
【0021】実施例2 錠剤:
軟カプセル剤組成
ゼラチン
70.0% グリセリン
22.
9% パラオキシ安息香酸メチル
0.15% パラオキシ安息香酸プロピル
0.15% 水
適量 計
100%上記成
分を成る、軟カプセル剤皮の中に参考例1の製造物 5
00mg(ジグリセリドとして 395mg含有)を常
法により充填し、軟カプセル剤を製造した。Example 2 Tablet: Soft capsule composition Gelatin
70.0% glycerin
22.
9% Methyl paraoxybenzoate
0.15% Propyl paraoxybenzoate
0.15% water
Appropriate amount total
The product of Reference Example 1 in a soft capsule shell consisting of 100% of the above ingredients 5
00 mg (containing 395 mg as diglyceride) was filled in a conventional manner to produce soft capsules.
【0022】[0022]
【発明の効果】本発明の脂肪肝予防又は治療剤によれば
、安全で、かつ容易に肝臓中の脂質濃度を低下させるこ
とができ、脂肪肝を有効に予防又は治療することができ
る。Effects of the Invention According to the preventive or therapeutic agent for fatty liver of the present invention, the lipid concentration in the liver can be safely and easily lowered, and fatty liver can be effectively prevented or treated.
Claims (2)
予防又は治療剤。1. A preventive or therapeutic agent for fatty liver containing diglyceride as an active ingredient.
化1】 〔式中、R1 、R2 及びR3 のうち2個の炭素数
12〜22の飽和脂肪酸又は不飽和脂肪酸由来のアシル
基を示し、残余は水素原子を示す〕で表わされる化合物
である請求項1記載の脂肪肝予防又は治療剤。[Claim 2] The diglyceride has the following general formula (1) [
A claim is a compound represented by the formula [wherein, two of R1, R2 and R3 represent acyl groups derived from saturated fatty acids or unsaturated fatty acids having 12 to 22 carbon atoms, and the remainder represent hydrogen atoms] Item 1. The agent for preventing or treating fatty liver according to item 1.
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03064839A JP3098559B2 (en) | 1991-03-28 | 1991-03-28 | Agent for preventing or treating fatty liver |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP03064839A JP3098559B2 (en) | 1991-03-28 | 1991-03-28 | Agent for preventing or treating fatty liver |
Publications (2)
Publication Number | Publication Date |
---|---|
JPH04300828A true JPH04300828A (en) | 1992-10-23 |
JP3098559B2 JP3098559B2 (en) | 2000-10-16 |
Family
ID=13269808
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP03064839A Expired - Lifetime JP3098559B2 (en) | 1991-03-28 | 1991-03-28 | Agent for preventing or treating fatty liver |
Country Status (1)
Country | Link |
---|---|
JP (1) | JP3098559B2 (en) |
Cited By (16)
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JP2002104965A (en) * | 2000-09-27 | 2002-04-10 | Kanegafuchi Chem Ind Co Ltd | Composition having function of prophylaxis and amelioration of fatty liver |
US6448292B2 (en) | 2000-03-21 | 2002-09-10 | Kao Corporation | Oil composition |
US6630189B2 (en) | 2000-07-13 | 2003-10-07 | Kao Corporation | Solid-liquid fractionation process of oil composition |
US6743459B2 (en) | 2000-12-15 | 2004-06-01 | Kao Corporation | Acidic oil-in-water type emulsion composition |
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JP2007262079A (en) * | 2007-05-18 | 2007-10-11 | Kao Corp | Fat and oil composition |
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1991
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US6468556B1 (en) | 1997-09-05 | 2002-10-22 | Otsuka Pharmaceutical Co., Ltd. | Liver fat accumulation inhibitory composition, food additive for liver fat accumulation, inhibition, and method of inhibiting liver fat accumulation |
WO1999012538A1 (en) * | 1997-09-05 | 1999-03-18 | Otsuka Pharmaceutical Co., Ltd. | Liver fat accumulation inhibitory composition, food additive for liver fat accumulation inhibition, and method of inhibiting liver fat accumulation |
US6762203B2 (en) | 1999-08-03 | 2004-07-13 | Kao Corporation | Oil composition |
US6852758B2 (en) | 1999-08-03 | 2005-02-08 | Kao Corporation | Oil composition |
US6448292B2 (en) | 2000-03-21 | 2002-09-10 | Kao Corporation | Oil composition |
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JP2002104965A (en) * | 2000-09-27 | 2002-04-10 | Kanegafuchi Chem Ind Co Ltd | Composition having function of prophylaxis and amelioration of fatty liver |
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US6956058B2 (en) | 2001-04-26 | 2005-10-18 | Kao Corporation | Method for improving insulin resistance |
US7160569B2 (en) | 2002-07-01 | 2007-01-09 | Kao Corporation | Acidic oil-in-water type emulsified compositions |
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