CN108208177A - Composition and its application containing butyric acid compound - Google Patents
Composition and its application containing butyric acid compound Download PDFInfo
- Publication number
- CN108208177A CN108208177A CN201711218599.6A CN201711218599A CN108208177A CN 108208177 A CN108208177 A CN 108208177A CN 201711218599 A CN201711218599 A CN 201711218599A CN 108208177 A CN108208177 A CN 108208177A
- Authority
- CN
- China
- Prior art keywords
- butyric acid
- acid compound
- liver
- formula
- preparation
- 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.)
- Pending
Links
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 title claims abstract description 126
- -1 butyric acid compound Chemical class 0.000 title claims abstract description 65
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 208000019425 cirrhosis of liver Diseases 0.000 claims abstract description 54
- 230000001587 cholestatic effect Effects 0.000 claims abstract description 47
- 238000002360 preparation method Methods 0.000 claims abstract description 46
- 235000016709 nutrition Nutrition 0.000 claims abstract description 29
- 230000002265 prevention Effects 0.000 claims abstract description 10
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 8
- 239000000126 substance Substances 0.000 claims abstract description 8
- MFBOGIVSZKQAPD-UHFFFAOYSA-M sodium butyrate Chemical compound [Na+].CCCC([O-])=O MFBOGIVSZKQAPD-UHFFFAOYSA-M 0.000 claims description 45
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 42
- 235000013350 formula milk Nutrition 0.000 claims description 40
- 235000013305 food Nutrition 0.000 claims description 29
- 239000003814 drug Substances 0.000 claims description 25
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 23
- 201000010099 disease Diseases 0.000 claims description 22
- 230000035764 nutrition Effects 0.000 claims description 16
- 229940079593 drug Drugs 0.000 claims description 14
- 235000013336 milk Nutrition 0.000 claims description 11
- 210000004080 milk Anatomy 0.000 claims description 11
- 239000008267 milk Substances 0.000 claims description 11
- 239000000843 powder Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 7
- 235000015097 nutrients Nutrition 0.000 claims description 6
- 238000009472 formulation Methods 0.000 claims description 5
- 239000007924 injection Substances 0.000 claims description 5
- 238000002347 injection Methods 0.000 claims description 5
- 239000002960 lipid emulsion Substances 0.000 claims description 5
- 235000016236 parenteral nutrition Nutrition 0.000 claims description 5
- 108090000765 processed proteins & peptides Proteins 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- PQLMXFQTAMDXIZ-UHFFFAOYSA-N isoamyl butyrate Chemical compound CCCC(=O)OCCC(C)C PQLMXFQTAMDXIZ-UHFFFAOYSA-N 0.000 claims description 4
- JXPHLUCMHXXHEJ-UHFFFAOYSA-N 2-(aminomethyl)-4-bromoaniline Chemical compound NCC1=CC(Br)=CC=C1N JXPHLUCMHXXHEJ-UHFFFAOYSA-N 0.000 claims description 3
- FYPVXEILSNEKOO-UHFFFAOYSA-L calcium;butanoate Chemical compound [Ca+2].CCCC([O-])=O.CCCC([O-])=O FYPVXEILSNEKOO-UHFFFAOYSA-L 0.000 claims description 3
- 235000015872 dietary supplement Nutrition 0.000 claims description 3
- 235000020256 human milk Nutrition 0.000 claims description 3
- 210000004251 human milk Anatomy 0.000 claims description 3
- 208000019423 liver disease Diseases 0.000 claims description 3
- RWMKSKOZLCXHOK-UHFFFAOYSA-M potassium;butanoate Chemical compound [K+].CCCC([O-])=O RWMKSKOZLCXHOK-UHFFFAOYSA-M 0.000 claims description 3
- 206010061958 Food Intolerance Diseases 0.000 claims description 2
- 206010020751 Hypersensitivity Diseases 0.000 claims description 2
- 206010067508 Low birth weight baby Diseases 0.000 claims description 2
- 102000014171 Milk Proteins Human genes 0.000 claims description 2
- 108010011756 Milk Proteins Proteins 0.000 claims description 2
- 208000006399 Premature Obstetric Labor Diseases 0.000 claims description 2
- 206010036600 Premature labour Diseases 0.000 claims description 2
- 208000026935 allergic disease Diseases 0.000 claims description 2
- 230000007815 allergy Effects 0.000 claims description 2
- 235000020616 amino acid formula Nutrition 0.000 claims description 2
- 150000001413 amino acids Chemical class 0.000 claims description 2
- 230000004064 dysfunction Effects 0.000 claims description 2
- 230000007062 hydrolysis Effects 0.000 claims description 2
- 238000006460 hydrolysis reaction Methods 0.000 claims description 2
- 239000003978 infusion fluid Substances 0.000 claims description 2
- 229940094941 isoamyl butyrate Drugs 0.000 claims description 2
- 235000020214 lactose-free milk formula Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 235000021239 milk protein Nutrition 0.000 claims description 2
- 230000000474 nursing effect Effects 0.000 claims description 2
- 230000035935 pregnancy Effects 0.000 claims description 2
- 208000026440 premature labor Diseases 0.000 claims description 2
- 235000018102 proteins Nutrition 0.000 claims description 2
- 102000004169 proteins and genes Human genes 0.000 claims description 2
- 108090000623 proteins and genes Proteins 0.000 claims description 2
- 229940126062 Compound A Drugs 0.000 claims 1
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 16
- 230000004888 barrier function Effects 0.000 abstract description 2
- 210000004185 liver Anatomy 0.000 description 65
- 210000004027 cell Anatomy 0.000 description 26
- 241000700159 Rattus Species 0.000 description 19
- 230000000694 effects Effects 0.000 description 16
- WSFSSNUMVMOOMR-UHFFFAOYSA-N Formaldehyde Chemical compound O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 description 14
- 210000004369 blood Anatomy 0.000 description 14
- 239000008280 blood Substances 0.000 description 14
- 241000193171 Clostridium butyricum Species 0.000 description 12
- 235000011187 glycerol Nutrition 0.000 description 12
- 230000002440 hepatic effect Effects 0.000 description 12
- 238000011160 research Methods 0.000 description 12
- 206010016654 Fibrosis Diseases 0.000 description 11
- 210000000013 bile duct Anatomy 0.000 description 11
- 238000004043 dyeing Methods 0.000 description 11
- 230000004761 fibrosis Effects 0.000 description 11
- 206010019668 Hepatic fibrosis Diseases 0.000 description 10
- HSINOMROUCMIEA-FGVHQWLLSA-N (2s,4r)-4-[(3r,5s,6r,7r,8s,9s,10s,13r,14s,17r)-6-ethyl-3,7-dihydroxy-10,13-dimethyl-2,3,4,5,6,7,8,9,11,12,14,15,16,17-tetradecahydro-1h-cyclopenta[a]phenanthren-17-yl]-2-methylpentanoic acid Chemical compound C([C@@]12C)C[C@@H](O)C[C@H]1[C@@H](CC)[C@@H](O)[C@@H]1[C@@H]2CC[C@]2(C)[C@@H]([C@H](C)C[C@H](C)C(O)=O)CC[C@H]21 HSINOMROUCMIEA-FGVHQWLLSA-N 0.000 description 9
- 239000003613 bile acid Substances 0.000 description 9
- 230000003247 decreasing effect Effects 0.000 description 9
- 230000003908 liver function Effects 0.000 description 9
- 206010008635 Cholestasis Diseases 0.000 description 8
- 230000000968 intestinal effect Effects 0.000 description 7
- 239000002932 luster Substances 0.000 description 7
- 230000007935 neutral effect Effects 0.000 description 7
- 210000001519 tissue Anatomy 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- 238000010171 animal model Methods 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000000576 coating method Methods 0.000 description 6
- 230000009977 dual effect Effects 0.000 description 6
- 102000014736 Notch Human genes 0.000 description 5
- 108010070047 Notch Receptors Proteins 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 230000007870 cholestasis Effects 0.000 description 5
- 231100000359 cholestasis Toxicity 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- 238000003364 immunohistochemistry Methods 0.000 description 5
- 230000008569 process Effects 0.000 description 5
- 210000000130 stem cell Anatomy 0.000 description 5
- 241001465754 Metazoa Species 0.000 description 4
- 230000015572 biosynthetic process Effects 0.000 description 4
- 239000000835 fiber Substances 0.000 description 4
- 230000006870 function Effects 0.000 description 4
- 210000000936 intestine Anatomy 0.000 description 4
- 230000007774 longterm Effects 0.000 description 4
- 230000002980 postoperative effect Effects 0.000 description 4
- 230000001737 promoting effect Effects 0.000 description 4
- 150000004666 short chain fatty acids Chemical class 0.000 description 4
- 235000021391 short chain fatty acids Nutrition 0.000 description 4
- 206010010317 Congenital absence of bile ducts Diseases 0.000 description 3
- 125000001931 aliphatic group Chemical group 0.000 description 3
- 201000005271 biliary atresia Diseases 0.000 description 3
- 230000008859 change Effects 0.000 description 3
- 210000002919 epithelial cell Anatomy 0.000 description 3
- 238000002474 experimental method Methods 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 230000002503 metabolic effect Effects 0.000 description 3
- 230000001575 pathological effect Effects 0.000 description 3
- 230000000750 progressive effect Effects 0.000 description 3
- 238000010186 staining Methods 0.000 description 3
- 241000894006 Bacteria Species 0.000 description 2
- 241000186000 Bifidobacterium Species 0.000 description 2
- 208000008439 Biliary Liver Cirrhosis Diseases 0.000 description 2
- DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 241000186660 Lactobacillus Species 0.000 description 2
- 208000034189 Sclerosis Diseases 0.000 description 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 235000005911 diet Nutrition 0.000 description 2
- 230000037213 diet Effects 0.000 description 2
- 230000004069 differentiation Effects 0.000 description 2
- 239000002552 dosage form Substances 0.000 description 2
- 210000002603 extrahepatic bile duct Anatomy 0.000 description 2
- 208000009866 extrahepatic cholestasis Diseases 0.000 description 2
- 230000004129 fatty acid metabolism Effects 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 210000004969 inflammatory cell Anatomy 0.000 description 2
- 208000001024 intrahepatic cholestasis Diseases 0.000 description 2
- 230000007872 intrahepatic cholestasis Effects 0.000 description 2
- 229940039696 lactobacillus Drugs 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 230000006676 mitochondrial damage Effects 0.000 description 2
- 235000020601 preterm formula Nutrition 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 238000012453 sprague-dawley rat model Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- IAKHMKGGTNLKSZ-INIZCTEOSA-N (S)-colchicine Chemical compound C1([C@@H](NC(C)=O)CC2)=CC(=O)C(OC)=CC=C1C1=C2C=C(OC)C(OC)=C1OC IAKHMKGGTNLKSZ-INIZCTEOSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 206010004659 Biliary cirrhosis Diseases 0.000 description 1
- 208000033222 Biliary cirrhosis primary Diseases 0.000 description 1
- 241000193403 Clostridium Species 0.000 description 1
- 206010009900 Colitis ulcerative Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 108010037362 Extracellular Matrix Proteins Proteins 0.000 description 1
- 102000010834 Extracellular Matrix Proteins Human genes 0.000 description 1
- 208000004930 Fatty Liver Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 239000004471 Glycine Substances 0.000 description 1
- 206010019663 Hepatic failure Diseases 0.000 description 1
- 206010019708 Hepatic steatosis Diseases 0.000 description 1
- 206010019728 Hepatitis alcoholic Diseases 0.000 description 1
- 206010019799 Hepatitis viral Diseases 0.000 description 1
- 208000022559 Inflammatory bowel disease Diseases 0.000 description 1
- 102000014150 Interferons Human genes 0.000 description 1
- 108010050904 Interferons Proteins 0.000 description 1
- 102000003814 Interleukin-10 Human genes 0.000 description 1
- 108090000174 Interleukin-10 Proteins 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 208000031816 Pathologic Dilatation Diseases 0.000 description 1
- 208000012654 Primary biliary cholangitis Diseases 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 241000194017 Streptococcus Species 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 201000006704 Ulcerative Colitis Diseases 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 208000002353 alcoholic hepatitis Diseases 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 229940124599 anti-inflammatory drug Drugs 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 210000000941 bile Anatomy 0.000 description 1
- 238000013248 bile duct ligation model Methods 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000033228 biological regulation Effects 0.000 description 1
- 210000000481 breast Anatomy 0.000 description 1
- BJUFAVXYJRJBLQ-UHFFFAOYSA-N butanoic acid;propane-1,2,3-triol Chemical compound CCCC(O)=O.OCC(O)CO BJUFAVXYJRJBLQ-UHFFFAOYSA-N 0.000 description 1
- SWEYNHYBJHPVJL-UHFFFAOYSA-N butanoic acid;sodium Chemical compound [Na].CCCC(O)=O SWEYNHYBJHPVJL-UHFFFAOYSA-N 0.000 description 1
- 150000004652 butanoic acids Chemical class 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000007894 caplet Substances 0.000 description 1
- 208000003167 cholangitis Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000004140 cleaning Methods 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 230000008021 deposition Effects 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 230000029087 digestion Effects 0.000 description 1
- 239000007884 disintegrant Substances 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 210000002744 extracellular matrix Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 208000010706 fatty liver disease Diseases 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 208000006454 hepatitis Diseases 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 206010020718 hyperplasia Diseases 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229940079322 interferon Drugs 0.000 description 1
- 229940076144 interleukin-10 Drugs 0.000 description 1
- 230000006651 lactation Effects 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 231100000835 liver failure Toxicity 0.000 description 1
- 208000007903 liver failure Diseases 0.000 description 1
- 208000018191 liver inflammation Diseases 0.000 description 1
- 210000004698 lymphocyte Anatomy 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 230000007948 negative regulation of Notch signaling pathway Effects 0.000 description 1
- 235000021590 normal diet Nutrition 0.000 description 1
- 230000008520 organization Effects 0.000 description 1
- 239000003182 parenteral nutrition solution Substances 0.000 description 1
- 230000007170 pathology Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 230000035790 physiological processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 239000006041 probiotic Substances 0.000 description 1
- 235000018291 probiotics Nutrition 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- 230000002784 sclerotic effect Effects 0.000 description 1
- 230000009291 secondary effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 230000011664 signaling Effects 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 235000011083 sodium citrates Nutrition 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 231100000240 steatosis hepatitis Toxicity 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000009469 supplementation Effects 0.000 description 1
- 208000011580 syndromic disease Diseases 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/16—Agglomerating or granulating milk powder; Making instant milk powder; Products obtained thereby
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23C—DAIRY PRODUCTS, e.g. MILK, BUTTER OR CHEESE; MILK OR CHEESE SUBSTITUTES; MAKING THEREOF
- A23C9/00—Milk preparations; Milk powder or milk powder preparations
- A23C9/152—Milk preparations; Milk powder or milk powder preparations containing additives
- A23C9/1528—Fatty acids; Mono- or diglycerides; Petroleum jelly; Paraffine; Phospholipids; Derivatives thereof
-
- 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
-
- 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
- A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
- A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
- A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- 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
Abstract
The present invention provides a kind of application of butyric acid compound in cholestatic liver fibrosis is prevented, the butyric acid compound can be used for preventing cholestatic liver fibrosis.The composition containing butyric acid compound, including butyric acid compound and nutritional preparation or excipient substance；A concentration of 5~70mM of the butyric acid compound.The present invention solves the technical barrier of cholestatic liver fibrosis prevention, and the prevention for cholestatic liver fibrosis provides a kind of safe, economic and effective method.
Description
Technical field
The present invention relates to food and medicine technical field, specifically, being related to a kind of composition containing butyric acid compound
And its application in cholestatic liver fibrosis is prevented.
Background technology
Liver fibrosis refers to a large amount of depositions of extracellular matrix components in liver, is that various chronic liver diseases develop into hepatic sclerosis
Only stage which must be passed by, due to liver fibrosis be liver parenchyma venereal disease become, medical field generally believes more difficult reverse, in the treatment except liver
Transplanting is outer, lacks other effective control measures.Liver fibrosis is divided into number of different types, virus hepatitis, alcoholic hepatitis, non-wine
The a variety of causes such as essence fatty liver and cholestasis can all lead to liver fibrosis.Different types of liver fibrosis, the cause of disease and hair
Interpretation of the cause, onset and process of an illness system is different, and control measure is also entirely different.
Cholestatic liver fibrosis caused by cholestatic disease is clinically a big difficulty, there is no safety at present
Effectively preventing measure.With the progress of the state of an illness, cholestatic disease can gradually develop into chronic hepatic fibrosis, hepatic sclerosis and
Liver failure finally needs to carry out liver transfer operation.Cholestatic disease can be divided into extrahepatic cholestasis and intrahepatic cholestasis.
Extrahepatic cholestasis refers to the cholestasis caused by the obstruction of extrahepatic bile ducts system mechanics；Intrahepatic cholestasis refers to small courage in liver
A series of pathology and clinical manifestation caused by the obstruction of pipe diffusivity.Common cholestatic disease includes intestines failure correlation courage
Juice siltation, Biliary atresia, primary biliary cirrhosis, primary sclerotic cholangitis etc..
At present, some achievements are had been achieved for for the research for the treatment of liver fibrosis both at home and abroad.Clinically common treatment
The drug of liver fibrosis mainly has interferon, colchicin, interleukin-10 etc., but the therapeutic effect of these drugs is limited, secondary
Effect is big.However, for cholestatic liver fibrosis, safely and effectively control method there is no at present.
Butyric acid is one of metabolite of natural component and internal intestinal flora in mammal milk.Butyric acid is made
For one kind of short chain fatty acids, played an important role in terms of enteron aisle normal physiological function is maintained.At present, grinding about butyric acid
Study carefully and focus primarily upon intestines problem.Research confirms that butyric acid has some intestines problems such as ulcerative colitis, inflammatory bowel disease
Protective effect, however the effect of butyric acid is really not so in cholestatic disease.
Research finds that in the cholestatic disease animal model caused by bile duct ligation liver is to the metabolic energy of aliphatic acid
Power declines, and especially short chain fatty acids such as butyric acid etc. can not be decomposed metabolism, leads to the raising of short-chain fat acid concentration, may aggravate
Cholestatic liver disease (Reichen J, ect.Mechanisms of impaired hepatic fatty acid
metabolism in rats with long-term bile duct ligation.Hepatology.1994May；19
(5):1272-81)(S,ect.Reversibility of hepatic mitochondrial damage in
rats with long-term cholestasis.J Hepatol.1998Jun；28(6):1000-7).On the other hand,
Notch signal paths and bile duct cell hyperplasia play an important role in the cholestatic liver fibrosis of progressive.Zhang X
Researchs is waited to find that butyric acid is divided into bile duct epithelial cell by promoting Notch signal paths and hepatic progenitor cell, so as to play
Promote effect (Zhang X, the et a1.Inhibition of notch signaling of cholestatic liver fibrosis
pathway prevents cholestatic liver fibrosis by decreasing the differentiation
of hepatic progenitor cells in to cholangiocytes.Lab Invest.2016Mar；96(3):
350-60).Therefore, based on these results of study, short chain fatty acids such as butyric acid is considered as to promote cholestatic liver fibrosis
An important factor for.
Invention content
The technical problem to be solved by the present invention is in view of the shortcomings of the prior art, provide a kind of group containing butyric acid compound
Close object and its application in cholestatic liver fibrosis is prevented.
Innovative use butyric acid compound of the invention is intervened, very effective to have prevented cholestatic liver fibre
Dimensionization solves the problems, such as clinically.
The prevention of cholestatic liver fibrosis is extremely difficult, even if can to alleviate liver inflammation anti-for common anti-inflammatory drug
It answers, can not but alleviate the process of liver fibrosis.And it is directed to work of the drug of bile acid biosynthesis in cholestatic liver fibrosis
With also very limited.Because of cholestatic disease such as Biliary atresia, Biliary Cirrhosis etc., extrahepatic duct obstruction is held
It renews so that the degree of cholestasis is very serious in liver, and the concentration of bile acid is usually above more than ten times of normal value even
Tens times or more.Some inhibit the synthesis that the drug of bile acid biosynthesis is enabled reduction bile acid, cholestatic disease liver
In bile acid concentration be still higher than normal value decades of times.And research confirms the degree and bile acid of cholestatic liver fibrosis
Horizontal and non-correlation, thus inhibit effect of the bile acid biosynthesis in cholestatic liver fibrosis is prevented very limited.
Research finds that in cholestatic disease animal model liver declines the metabolic capability of aliphatic acid, causes short
The raising of chain fatty acid concentration may aggravate cholestatic liver disease (Reichen J, ect.Mechanisms of impaired
hepatic fatty acid metabolism in rats with long-term bile duct
ligation.Hepatology.1994May；19(5):1272-81)(S,ect.Reversibility of
hepatic mitochondrial damage in rats with long-term cholestasis.J
Hepatol.1998Jun；28(6):1000-7).But we carefully analyze discovery, and positive evidence confirmation is had no in these researchs
Effect of the butyric acid in progressive cholestatic liver fibrosis.On the other hand, the researchs such as Zhang X find that sodium butyrate passes through rush
Bile duct epithelial cell is divided into Notch signal paths and hepatic progenitor cell so as to play promotion cholestatic liver fibrosis
Effect (Zhang X, et a1.Inhibition of notch signaling pathway prevents
cholestatic liver fibrosis by decreasing the differentiation of hepatic
progenitor cells in to cholangiocytes.Lab Invest.2016Mar；96(3):350-60).However,
The research confirms the effect of sodium butyrate only with experiment in vitro, and function and effect in vivo are not necessarily so.
Of the invention innovative intervenes the animal model of cholestatic liver fibrosis using butyric acid compound
And treatment, it is very effective to have prevented cholestatic liver fibrosis, prior art prejudice is overcome, solves difficulty clinically
Topic.
Research confirms the degree of hepatic fibrosis of cholestatic disease and bile acid levels, inflammatory cell infiltration, ALT, AST
Etc. indexs and non-correlation.Present invention firstly discovers that in cholestatic liver fibrosis, liver Th1 types cell proportion and liver
Fibrosis is proportionate, and Th1 types cell plays an important role in liver fibrosis process is promoted, and uses butyric acid class chemical combination
After object is intervened or treated, Th1 type cell proportions are remarkably decreased.Butyric acid compound inhibits liver Th1 types by specificity
The ratio of cell plays an important role in cholestatic liver fibrosis is prevented.
The purpose of the present invention is what is be achieved through the following technical solutions：
The present invention provides a kind of butyric acid compound in the composition for preparing prevention cholestatic liver fibrosis
Purposes.
The present invention provides a kind of composition containing butyric acid compound, including butyric acid compound and nutritional preparation or
Excipient substance；A concentration of 5~70mM (mmol/L) of the butyric acid compound.
Preferably, a concentration of 15~45mM in the butyric acid compound.
Preferably, the butyric acid compound is 0.5-7mmol/kg/d as the effective dose of drug.
It is highly preferred that the butyric acid compound is 1.5-4.5mmol/kg/d as the effective dose of drug.
Preferably, the butyric acid compound is selected from sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, butyric acid glycerine
At least one of ester, isoamyl butyrate.
Preferably, the butyric acid compound is selected from least one of sodium butyrate, glycerol monobutyralte, butyric acid.
Preferably, the nutritional preparation is selected from conventional formulation food, special medicine purposes formula food, parenteral nutrition system
At least one of agent, enteral nutrition preparation.
Preferably, the conventional formulation food is included in babies ' formula milk powder, pregnancy period and nursing period formula milk at least
It is a kind of；The special medicine purposes formula food includes premature labor/low birth weight baby formula milk, lactose-free formula or low breast
Sugared formula milk, milk protein part hydrolyzed formulas milk powder, lactoprotein depth hydrolysis formula or amino acid formula milk, breast milk and baby
The hardening agent or nutritional supplement of youngster's formula food, suitable for food intolerance, allergy, hepatopathy special formulation food,
At least one of formula food of disease or dysfunction；The parenteral nutrition preparation includes fat emulsion injection, All-In-One
At least one of nutrient solution, intravenous fluid；The enteral nutrition preparation includes amino acid pattern enteral nutrition preparation, short peptide type
At least one of enteral nutrition preparation, whole protein type enteral nutrition preparation, assembly type enteral nutrition preparation.
The present invention also provides a kind of preparation methods of the composition containing butyric acid compound, which is characterized in that the system
Preparation Method includes：Butyric acid compound is proportionally added into the nutritional preparation or excipient substance, is uniformly mixed, you can.
Special medicine purposes formula food (Food for Special Medical Purpose, FSMP) is in order to full
Foot feed is limited, the special requirement of Disorder of Digestion and A orption, metabolic disorder or particular disease states crowd to nutrient or diet, specially
The formula food that door processing is formulated.Such product must under doctor or clinical nutrition's teacher guidance, it is individually edible or and its
His food is matched.Special medicine purposes formula food belongs to food for special foods.When target group can not feed commonly
Diet or when can not meet its nutritional need with ordinary meal, special medicine purposes formula food can be used as a kind of nutritional supplementation
Approach, maintained to treatment, rehabilitation and body function etc. play important nutritional support and act on.
Preferably, the excipient substance includes pharmaceutically acceptable carrier or excipient, such as lactose hydrous, crystallite
Cellulose, mannitol, sodium citrate, calcium phosphate, glycine, starch；Disintegrant such as crospovidone, copolyvidone, hydroxyl
Amylcose acetate sodium, croscarmellose sodium and specific composition silicate；Binder such as polyvinylpyrrolidone, hydroxypropyl
Ylmethyl cellulose (HPMC), hydroxypropyl cellulose (HPC), sucrose, gelatin and Arabic gum etc..
Preferably, the butyric acid compound be butyric acid when, butyric acid compound by coating or it is coated in the form of add.
It should be noted that the administration form of butyric acid compound is inessential in the present invention, butyric acid compound is added
Into formula milk, special medicine purposes formula food, other enterals, parenteral nutrition preparation or excipient substance, as long as applying
The effect of prevention cholestatic liver fibrosis can be achieved with effective quantity.
As an alternative solution of formula food application, butyric acid compound of the invention can be used as replenishers to apply
Rather than it is integrated into formula food.For example, butyric acid compound can be with pill, tablet, capsule, caplet, powder, liquid or solidifying
Glue form is absorbed.For example, butyric acid compound can be absorbed with other nutritional supplements as breast milk replenishers combine.
Compared with prior art, the present invention has following advantageous effect：
1st, research is thought at present, and in cholestatic disease animal model, liver declines the metabolic capability of aliphatic acid,
Cause the raising of short-chain fat acid concentration that may aggravate cholestatic liver disease；And sodium butyrate is by promoting Notch signals to lead to
Road and hepatic progenitor cell are divided into bile duct epithelial cell, so as to play the effect for promoting cholestatic liver fibrosis.This hair
It is bright to overcome prior art prejudice, using butyric acid compound intervention and treatment cholestatic liver fibrosis model, as a result show
Representation model group shows as severe liver fibrosis, 3 grades of fibrosis, and intervention group and treatment group have no apparent liver fibrosis.Cause
This, the present invention solves the technical barrier of cholestatic liver fibrosis prevention, provides a kind of safe, economical and effectively prevents
Control method.
2nd, research confirm cholestatic disease degree of hepatic fibrosis and bile acid levels, inflammatory cell infiltration, ALT,
The indexs such as AST and non-correlation.Present invention firstly discovers that in bile duct ligation model liver, Th1 types cell proportion and liver fiber
Change degree is proportionate, and Th1 types cell plays an important role in progressive liver fibrosis process.Using butyric acid compound
After being intervened or being treated, Th1 type cell proportions are remarkably decreased.Butyric acid compound inhibits liver Th1 types thin by specificity
The ratio of born of the same parents plays an important role in cholestatic liver fibrosis is prevented.
3rd, the speed being metabolized in vivo due to butyric acid is very fast, and in order to preferably play the function and effect of butyric acid, we will
Butyric acid compound is added to suitable for the nutritional preparation of specific crowd so that butyric acid is as nutritional preparation slowly enters body
It digests and assimilates, more efficient plays a role.
Therefore, add the nutritional preparation of butyric acid compound and drug be it is a kind of safely, effectively, feasible prevention bile becomes silted up
The method of product property liver fibrosis.
Description of the drawings
Upon reading the detailed description of non-limiting embodiments with reference to the following drawings, other feature of the invention,
Objects and advantages will become more apparent upon：
Fig. 1:Bile duct ligation (BDL) model liver HE and Masson are dyed；Wherein Fig. 1 a are contaminated for BDL model group livers HE
Color；Fig. 1 b are dyed for BDL model group livers Masson；Fig. 1 c are dyed for BDL+ sodium butyrates intervention (30mM) liver HE；Fig. 1 d are
BDL+ sodium butyrates intervention (30mM) liver Masson is dyed；Fig. 1 e treat (45mM) liver HE dyeing for BDL+ sodium butyrates；Fig. 1 f
(45mM) liver Masson dyeing is treated for BDL+ sodium butyrates；Fig. 1 g treat (70mM) liver HE dyeing for BDL+ sodium butyrates；Figure
1h treats (70mM) liver Masson dyeing for BDL+ sodium butyrates.
Fig. 2:Bile duct ligation (BDL) model liver lymphocyte FCM analysis Th1 type cell proportions；Wherein Fig. 2 a are
BDL model group liver Th1 types cell proportions (black circle)；Fig. 2 b are the intervention of BDL+ sodium butyrates (30mM) liver Th1 types cell ratio
Example (black circle)；Fig. 2 c treat (45mM) liver Th1 types cell proportion (black circle) for BDL+ sodium butyrates；Fig. 2 d are BDL+ butyric acid
Sodium treatment (70mM) liver Th1 types cell proportion (black circle)；Fig. 2 e are the liver of BDL model groups and each sodium butyrate intervention group
Th1 types cell proportion counts；Fig. 2 f are that BDL model groups and the liver Th1 types cell proportion of each sodium butyrate treatment group count.
Specific embodiment
With reference to specific embodiment, the present invention is described in detail.Following embodiment will be helpful to the technology of this field
Personnel further understand the present invention, but the invention is not limited in any way.It should be pointed out that the ordinary skill to this field
For personnel, without departing from the inventive concept of the premise, several changes and improvements can also be made.These belong to the present invention
Protection domain.
Embodiment 1
Babies ' formula milk powder of a kind of butyric acid containing coating and preparation method thereof is present embodiments provided, the method is：It will
Food-grade coating butyric acid add in babies ' formula milk powder in, be uniformly mixed to get.Coating butyric acid in the formula milk of the preparation
A concentration of 5mmol/L.
Embodiment 2
A kind of pregnant and lying-in women's formula milk containing sodium butyrate and preparation method thereof is present embodiments provided, the method is：It will
Food-grade sodium butyrate add in pregnant and lying-in women's formula milk in, be uniformly mixed to get.Sodium butyrate is dense in the formula milk of the preparation
It spends for 15mmol/L.
Embodiment 3
Present embodiments provide a kind of preterm formula milk powder containing glycerol monobutyralte and preparation method thereof, the method
For：Will food-grade glycerol monobutyralte add in preterm formula milk powder in, be uniformly mixed to get.In the formula milk of the preparation
A concentration of 20mmol/L of glycerol monobutyralte.
Embodiment 4
A kind of fat emulsion injection containing sodium butyrate and preparation method thereof is present embodiments provided, the method is：It will note
Grade sodium butyrate is penetrated to add in fat emulsion injection, be uniformly mixed to get.Sodium butyrate is dense in the fat emulsion injection of the preparation
It spends for 30mmol/L.
Embodiment 5
A kind of All-In-One nutrient solution containing sodium butyrate and preparation method thereof is present embodiments provided, the method is：It will note
Grade sodium butyrate is penetrated to add in All-In-One nutrient solution, be uniformly mixed to get.Sodium butyrate is dense in the All-In-One nutrient solution of the preparation
It spends for 45mmol/L.
Embodiment 6
Present embodiments provide a kind of short peptide type enteral nutrition preparation containing glycerol monobutyralte and preparation method thereof, the side
Method is：Will food-grade glycerol monobutyralte add in short peptide type enteral nutrition preparation in, be uniformly mixed to get.The small peptide of the preparation
A concentration of 55mmol/L of glycerol monobutyralte in type enteral nutrition preparation.
Embodiment 7
A kind of special disease formula food containing sodium butyrate and preparation method thereof is present embodiments provided, the method is：
Will food-grade sodium butyrate add in special disease formula food in, be uniformly mixed to get.The special disease formula food of the preparation
A concentration of 70mmol/L of middle sodium butyrate.
Embodiment 8
Present embodiments provide a kind of pharmaceutical composition containing butyric acid compound and excipient substance.
The butyric acid compound is selected from sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, glycerol monobutyralte, butyric acid
At least one of isopentyl ester.
The effective dose of the butyric acid compound is 0.5~7mmol/kg/d.
The drug further includes other compatible medicine classes and pharmaceutically acceptable load with the butyric acid compound
Body and/or auxiliary material.
The drug is pharmaceutically acceptable arbitrary dosage form.
The dosage form is pulvis, parenteral solution, capsule, tablet or oral liquid.
The butyric acid compound be butyric acid when, butyric acid compound by coating or it is coated in the form of be added into drug.
Composition containing butyric acid compound made from above example can effectively prevent cholestatic liver fibrosis.Its
The optimum effective dose of prevention is 15-30mmol/L or 1.5~3mmol/kg/d；The optimum effective dose for the treatment of is 30-
45mmol/L or 3~4.5mmol/kg/d；.
Animal experiment compliance test result：
1st, the effect in Biliary atresia liver fibrosis is verified using extrahepatic bile ducts ligation model
1.1 experimental animal
Cleaning grade three week old Sprague-Dawley (SD) rat, male and female are unlimited, weight about 50g, purchased from the western Poole in Shanghai-
Bi Kai experimental animals Co., Ltd.In Xinhua Hospital Attached to Medical School, Shanghai Jiaotong Univ.'s animal experimental center raising.
1.2 processing method
Bile duct ligation (BDL) model group：Rat is fed using water and normal diet, rat ductus choledochus is carried out after 7 days double
It ligatures and is cut from centre again；Without administration, the 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, is used
In subsequent experimental.It is fixed with neutral formalin and carries out histotomy, do H-E dyeing, Masson and immunohistochemistry detection respectively.
BDL+ sodium butyrate intervention groups：Sodium butyrate is added to the water and feeds rat, butyric acid na concn is respectively 5mM, 15mM,
30mM, 45mM, dosage are respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d.Feed 7
After it, dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.It takes
Liver and intestinal tissue, for subsequent experimental.Fixed with neutral formalin and carry out histotomy, be respectively H-E dyeing,
Masson and immunohistochemistry detection.
BDL+ butyric acid intervention groups：Butyric acid is added to the water and feeds rat, butyric acid density is respectively 5mM, 15mM, 30mM,
45mM, dosage are respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d.After feeding 7 days,
Dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Take liver and
Intestinal tissue, for subsequent experimental.It is fixed with neutral formalin and carries out histotomy, be H-E dyeing, Masson respectively and exempted from
Epidemic disease groupization detects.
BDL+ glycerol monobutyralte intervention groups：Glycerol monobutyralte is added to the water and feeds rat, glycerol monobutyralte concentration difference
For 5mM, 15mM, 30mM, 45mM, dosage is respectively 0.5mmol/kg/d, 1.5mmol/kg/d, 3mmol/kg/d,
4.5mmol/kg/d.After feeding 7 days, dual ligation is carried out to rat ductus choledochus and is cut from centre.Postoperative fasting in 14th day
Night takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, for subsequent experimental.It is fixed with neutral formalin and carries out histotomy,
H-E dyeing, Masson and immunohistochemistry detection are done respectively.
BDL+ sodium butyrates treatment group：Dual ligation is carried out to rat ductus choledochus and is cut from centre.It opens within the 7th day after modeling
Beginning, sodium butyrate is added to the water and feeds rat, for successive administration to the 14th day, butyric acid na concn was respectively 15mM, 30mM, 45mM,
70mM, dosage are respectively 1.5mmol/kg/d, 3mmol/kg/d, 4.5mmol/kg/d, 7mmol/kg/d.Fasting in 14th day
Night takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, for subsequent experimental.It is fixed with neutral formalin and carries out histotomy,
H-E dyeing, Masson and immunohistochemistry detection are done respectively.
BDL+ clostridium butyricum intervention groups：Clostridium butyricum is added to the water and feeds rat, the viable count of clostridium butyricum for 1 ×
107-4×107CFU/mL, dosage are 1 × 109-4×109CFU/kg/d.After feeding 7 days, rat ductus choledochus is carried out dual
It ligatures and is cut from centre.Postoperative 14th day overnight fasting takes blood to survey blood biochemistry.Liver and intestinal tissue are taken, for follow-up real
It tests.It is fixed with neutral formalin and carries out histotomy, do H-E dyeing, Masson and immunohistochemistry detection respectively.
BDL+ clostridium butyricums treatment group：Dual ligation is carried out to rat ductus choledochus and is cut from centre.The 7th day after modeling
Start, clostridium butyricum is added to the water and feeds rat, for successive administration to the 14th day, the viable count of clostridium butyricum was 5 × 107-9×
107CFU/mL, dosage are 5 × 109-9×109CFU/kg/d.14th day overnight fasting takes blood to survey blood biochemistry.Take liver and intestines
Road tissue, for subsequent experimental.It is fixed with neutral formalin and carries out histotomy, be H-E dyeing, Masson respectively and be immunized
Groupization detects.
1.3 result
Bile duct ligation (BDL) model group：Animal blood serum liver function index ALT, AST, GGT, TBA, TBIL are significantly increased, liver
Dirty color is significantly turned to be yellow, rough, and quality is harder；There is severe liver fibrosis in liver organization, and fibrosis reaches 3 grades
(Fig. 1 a, Fig. 1 b)；The Th1 type cell proportions for promoting progression of fibrosis in BDL model group livers significantly increase, and mean value reaches 21.3%
(Fig. 2 a, Fig. 2 e).
BDL+ sodium butyrate intervention groups:
Sodium butyrate intervention group (5mM)：Liver function index slightly reduces, and liver color is slightly turned to be yellow, and pathological staining result is shown
Liver moderate liver fibrosis, 2 grades of degree of hepatic fibrosis, compared with BDL groups, liver Th1 types cell proportion declines, and mean value is
12.7% (Fig. 2 e)；
Sodium butyrate intervention group (15mM)：Liver function index is substantially reduced, and liver color and luster is red, any surface finish, soft texture, disease
The reason coloration result display slight liver fibrosis of liver, 1 grade of degree of hepatic fibrosis, compared with BDL groups, liver Th1 type cell proportions
It is decreased obviously, mean value is 6.9% (Fig. 2 e)；
Sodium butyrate intervention group (30mM)：Liver function index significantly reduces, and liver color and luster is scarlet, any surface finish, soft texture,
Pathological staining result shows that liver has no obvious fibrosis (Fig. 1 c, Fig. 1 d)；And FCM analysis is the results show that promote fiber
The liver Th1 type cell proportions of change process are remarkably decreased and close to normal values, and mean value is 1.8% (Fig. 2 b, Fig. 2 e)；
Sodium butyrate intervention group (45mM)：Liver function index significantly reduces, and liver color and luster is scarlet, any surface finish, soft texture,
Pathological staining result shows liver mild fibrosis, 1 grade of degree of hepatic fibrosis, and liver Th1 type cell proportions mean value is 2.4%
(Fig. 2 e).
The result of coating butyric acid intervention group and glycerol monobutyralte intervention group and the result of sodium butyrate intervention group are basically identical.
BDL+ sodium butyrates treatment group:
Sodium butyrate treatment group (15mM)：Every liver function index reduces, and liver color and luster is slightly yellow, 2 grades of hepatic fibrosis-renal tubular ectasia syndrome degree,
Compared with BDL groups, liver Th1 types cell proportion declines, and mean value is 15.7% (Fig. 2 f)；
Sodium butyrate treatment group (30mM)：Every liver function index is substantially reduced, and liver color and luster is redder, and quality is softer, liver
Slight liver fibrosis, 1 grade of fibrosis, compared with BDL groups, liver Th1 type cell proportions are decreased obviously, mean value 7.6%
(Fig. 2 f)；
Sodium butyrate treatment group (45mM)：Every liver function index significantly reduces, and liver color and luster is scarlet, and surface is smooth, quality
Softness, liver have no obvious fibrosis (Fig. 1 e, Fig. 1 f)；Compared with BDL groups, liver Th1 type cell proportions are remarkably decreased, mean value
It is down to 4.8% (Fig. 2 c, Fig. 2 f)；
Sodium butyrate treatment group (70mM)：Every liver function index significantly reduces, and liver color and luster is scarlet, and surface is smooth, quality
Softness, liver mild fibrosis, 1 grade of degree of hepatic fibrosis (Fig. 1 g, Fig. 1 h), liver Th1 type cell proportions are down to 5.5% (figure
2d, Fig. 2 f).
BDL+ clostridium butyricum groups：
The result of clostridium butyricum intervention group is shown：Give 1 × 107-4×107After CFU/mL clostridium butyricum active bacterias are intervened
Degree of hepatic fibrosis and the reduction of Th1 types cell proportion are not obvious, and fibrosis is 2-3 grades；
The result of clostridium butyricum treatment group is shown：Give 5 × 107-9×107CFU/mL clostridium butyricum active bacterias are treated,
Degree of hepatic fibrosis and Th1 type cell proportions have no and are decreased obviously that fibrosis is still 3 grades.
Therefore, give butyric acid compound to be intervened, have for prevention cholestatic liver fibrosis extraordinary
Effect；Especially after butyric acid na concn reaches 30mM-45mM, control effect is especially pronounced.BDL modeling groups show as severe hepatic fibre
Dimensionization, fibrosis are 3 grades, and BDL intervention groups and treatment group have no apparent liver fibrosis.And the function and effect of clostridium butyricum are simultaneously
Unobvious, and hygiene department's regulation only has these three probiotics of lactobacillus, Bifidobacterium and streptococcus that can add safely at present
It adds in food, only Bifidobacterium and lactobacillus can be with security applications in baby formula milk powder.Therefore, Clostridium butylicum is made
For a kind of active microorganism can generate in vivo what kind of influence it is unclear, may there are security risks.
In conclusion butyric acid compound can effectively prevent cholestatic liver fibrosis.Butyric acid is to exist to move with lactation
A kind of short chain fatty acids in object milk, and from the point of view of the result of animal experiment, butyric acid compound is given in the concentration range
Medicine does not cause experimental animal any damage and side effect, illustrates that its drug safety is higher.Butyric acid compound is used to prevent
Cholestatic liver fibrosis will have very big application prospect.
Specific embodiments of the present invention are described above.It is to be appreciated that the invention is not limited in above-mentioned
Particular implementation, those skilled in the art can make a variety of changes or change within the scope of the claims, this not shadow
Ring the substantive content of the present invention.In the absence of conflict, the feature in embodiments herein and embodiment can arbitrary phase
Mutually combination.
Claims (10)
1. a kind of purposes of butyric acid compound in the composition for preparing prevention cholestatic liver fibrosis.
2. a kind of composition containing butyric acid compound, which is characterized in that including butyric acid compound and nutritional preparation or medicine
Object auxiliary material；A concentration of 5~70mM of the butyric acid compound.
3. the composition according to claim 2 containing butyric acid compound, which is characterized in that the butyric acid compound
A concentration of 15~45mM.
4. the composition according to claim 2 containing butyric acid compound, which is characterized in that the butyric acid compound is made
Effective dose for drug is 0.5-7mmol/kg/d.
5. the composition according to claim 4 containing butyric acid compound, which is characterized in that the butyric acid compound is made
Effective dose for drug is 1.5-4.5mmol/kg/d.
6. according to composition of the claim 1-5 any one of them containing butyric acid compound, which is characterized in that the butyric acid class
Compound is selected from least one of sodium butyrate, potassium butyrate, calcium butyrate, magnesium butyrate, butyric acid, glycerol monobutyralte, isoamyl butyrate.
7. the composition according to claim 6 containing butyric acid compound, which is characterized in that the butyric acid compound choosing
From at least one of sodium butyrate, glycerol monobutyralte, butyric acid.
8. the composition according to claim 2 containing butyric acid compound, which is characterized in that the nutritional preparation is selected from normal
Advise at least one of formula food, special medicine purposes formula food, parenteral nutrition preparation, enteral nutrition preparation.
9. the composition according to claim 8 containing butyric acid compound, which is characterized in that the conventional formulation food packet
Include at least one of babies ' formula milk powder, pregnancy period and nursing period formula milk；The special medicine purposes formula food includes
Premature labor/low birth weight baby formula milk, lactose-free formula or Low lactose milk formula milk, milk protein part hydrolyzed formula
Powder, lactoprotein depth hydrolysis formula or amino acid formula milk, the hardening agent of breast milk and infant formula or nutritional supplement,
Suitable for the formula food of food intolerance, allergy, hepatopathy special formulation food, disease or dysfunction at least
It is a kind of；The parenteral nutrition preparation includes at least one of fat emulsion injection, All-In-One nutrient solution, intravenous fluid；Institute
It states enteral nutrition preparation and includes amino acid pattern enteral nutrition preparation, short peptide type enteral nutrition preparation, whole protein type enteral nutrition system
At least one of agent, assembly type enteral nutrition preparation.
A kind of 10. preparation method of the composition according to claim 2 containing butyric acid compound, which is characterized in that institute
Preparation method is stated to include：Butyric acid compound is proportionally added into the nutritional preparation or excipient substance, is uniformly mixed, i.e.,
It can.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711218599.6A CN108208177A (en) | 2017-11-28 | 2017-11-28 | Composition and its application containing butyric acid compound |
| PCT/CN2018/084676 WO2019104936A1 (en) | 2017-11-28 | 2018-04-26 | Composition containing butyric acid compound and use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201711218599.6A CN108208177A (en) | 2017-11-28 | 2017-11-28 | Composition and its application containing butyric acid compound |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN108208177A true CN108208177A (en) | 2018-06-29 |
Family
ID=62653012
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201711218599.6A Pending CN108208177A (en) | 2017-11-28 | 2017-11-28 | Composition and its application containing butyric acid compound |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN108208177A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019169712A1 (en) * | 2018-03-09 | 2019-09-12 | 上海交通大学医学院附属新华医院 | Application of butyric acid compound in promoting tissue endogenous stem cell activation, proliferation and differentiation |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1477950A (en) * | 2000-11-17 | 2004-02-25 | ������Ŧ˹���ȵ¹�����˾ | Supplement to be enterally administered for parenteral nutrition or partial enteral/oral nutrition of critically ill, chronically ill and people with malnutrition |
| CN101292969A (en) * | 2007-04-27 | 2008-10-29 | 青岛东海药业有限公司 | Application of butyric acid (butanoic acid) in preparing medicaments for treating anorectal diseases |
| CN101896176A (en) * | 2007-10-14 | 2010-11-24 | 佛罗里达大学研究基金公司 | Improve the preparation of gastrointestinal function |
| CN107074848A (en) * | 2014-09-26 | 2017-08-18 | 葛兰素史密斯克莱知识产权发展有限公司 | Noval chemical compound |
| CN107074849A (en) * | 2014-09-26 | 2017-08-18 | 葛兰素史密斯克莱知识产权发展有限公司 | New compound |
| CN108283632A (en) * | 2017-11-28 | 2018-07-17 | 上海交通大学医学院附属新华医院 | Composition containing butyric acid compound and its application |
-
2017
- 2017-11-28 CN CN201711218599.6A patent/CN108208177A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1477950A (en) * | 2000-11-17 | 2004-02-25 | ������Ŧ˹���ȵ¹�����˾ | Supplement to be enterally administered for parenteral nutrition or partial enteral/oral nutrition of critically ill, chronically ill and people with malnutrition |
| CN101292969A (en) * | 2007-04-27 | 2008-10-29 | 青岛东海药业有限公司 | Application of butyric acid (butanoic acid) in preparing medicaments for treating anorectal diseases |
| CN101896176A (en) * | 2007-10-14 | 2010-11-24 | 佛罗里达大学研究基金公司 | Improve the preparation of gastrointestinal function |
| CN107074848A (en) * | 2014-09-26 | 2017-08-18 | 葛兰素史密斯克莱知识产权发展有限公司 | Noval chemical compound |
| CN107074849A (en) * | 2014-09-26 | 2017-08-18 | 葛兰素史密斯克莱知识产权发展有限公司 | New compound |
| CN108283632A (en) * | 2017-11-28 | 2018-07-17 | 上海交通大学医学院附属新华医院 | Composition containing butyric acid compound and its application |
Non-Patent Citations (1)
| Title |
|---|
| JIN CHENGJUN等: "supplementation of sodium butyrate protects mice from the development of non-alcoholic steatohepatitis", 《BRITISH JOURNAL OF NUTRITION》 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2019169712A1 (en) * | 2018-03-09 | 2019-09-12 | 上海交通大学医学院附属新华医院 | Application of butyric acid compound in promoting tissue endogenous stem cell activation, proliferation and differentiation |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Rosenberg et al. | Impairment of intestinal deconjugation of dietary folate: a possible explanation of megaloblastic anaemia associated with phenytoin therapy | |
| CN101069745B (en) | Medicine composition for treating 2-type diabetes | |
| BR112018014809B1 (en) | KIT AND USE OF A PHARMACEUTICAL COMPOSITION COMPRISING A THERAPEUTICLY EFFECTIVE AMOUNT OF 3?-ARACHIDYLAMIDO-7?, 12?-DIHYDROXY-5?-CHOLAN-24-OIC ACID (ARAMCHOL) OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF | |
| JP6389889B2 (en) | Application of andrographolide in pharmaceutical preparations for the treatment of inflammatory bowel disease, andrographolide enteric target micropellets and method for producing the same | |
| WO2011091019A1 (en) | Methods and compositions for treating and preventing parenteral nutrition associated liver disease | |
| Mayer et al. | Management of short bowel syndrome in postoperative very low birth weight infants | |
| CN109419814B (en) | Application of paradisella gordonii to inhibition of fatty liver disease | |
| CN107736614A (en) | Nutritional preparation containing butyric acid | |
| CA3008195A1 (en) | Treatment of intrahepatic cholestasis and related liver diseases | |
| CN108283632B (en) | Composition and its application containing butyric acid compound | |
| BR112020019979A2 (en) | COMPOSITIONS AND METHODS FOR TREATING INTESTINAL INFLAMMATORY DISEASES | |
| ES2200145T3 (en) | BACTERIA BODIES WITH ALTERED METABOLISM OF BILIAR ACIDS AND ITS USE. | |
| US11554131B2 (en) | Mixture of HMOs for treating autoimmune diseases | |
| CN108402371A (en) | A kind of prebiotic compositions that suitable person in middle and old age's constipation crowd takes | |
| TW200812594A (en) | Medicine for prevention of and/or recovery from fatigue | |
| CN108208177A (en) | Composition and its application containing butyric acid compound | |
| CN109125315A (en) | Composition and purposes with hypoglycemic, reducing blood lipid and hypotensive activity | |
| CA3158132A1 (en) | Compositions and methods for delivering a bacterial metabolite to a subject | |
| CN107684554A (en) | Butyric acid compound is preparing the application in preventing and treating NEC medicines | |
| CN108904519A (en) | Hericium erinaceus Polysaccharides are in the purposes prepared in the drug for treating colitis and include its pharmaceutical composition | |
| JP2023546794A (en) | Direct delivery of vitamins to restore balance in the gut microbiome after exposure to antibiotics | |
| WO2019104936A1 (en) | Composition containing butyric acid compound and use thereof | |
| CN101700231B (en) | Solid preparation comprising pantoprazole sodium submicron emulsion particles | |
| CN105194658A (en) | Traditional Chinese medicinal preparation for treating obesity and enhancing physique and preparation method of traditional Chinese medicinal preparation | |
| CN114585380A (en) | Gastrointestinal health composition |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| AD01 | Patent right deemed abandoned |
Effective date of abandoning: 20210528 |
|
| AD01 | Patent right deemed abandoned |