JP2022017496A - 組成物、ならびにその適用および薬学的調製の方法 - Google Patents
組成物、ならびにその適用および薬学的調製の方法 Download PDFInfo
- Publication number
- JP2022017496A JP2022017496A JP2021180724A JP2021180724A JP2022017496A JP 2022017496 A JP2022017496 A JP 2022017496A JP 2021180724 A JP2021180724 A JP 2021180724A JP 2021180724 A JP2021180724 A JP 2021180724A JP 2022017496 A JP2022017496 A JP 2022017496A
- Authority
- JP
- Japan
- Prior art keywords
- acid
- acceptable ester
- disorders
- composition according
- pharmaceutical
- 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
- 239000000203 mixture Substances 0.000 title claims abstract description 73
- 239000000825 pharmaceutical preparation Substances 0.000 title claims description 10
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 125
- 150000002148 esters Chemical class 0.000 claims abstract description 114
- 208000035475 disorder Diseases 0.000 claims abstract description 72
- QISXPYZVZJBNDM-UHFFFAOYSA-N berberine Natural products COc1ccc2C=C3N(Cc2c1OC)C=Cc4cc5OCOc5cc34 QISXPYZVZJBNDM-UHFFFAOYSA-N 0.000 claims abstract description 63
- 229940093265 berberine Drugs 0.000 claims abstract description 63
- YBHILYKTIRIUTE-UHFFFAOYSA-N berberine Chemical compound C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 YBHILYKTIRIUTE-UHFFFAOYSA-N 0.000 claims abstract description 61
- 201000010099 disease Diseases 0.000 claims abstract description 50
- 238000011282 treatment Methods 0.000 claims abstract description 32
- 208000008338 non-alcoholic fatty liver disease Diseases 0.000 claims abstract description 30
- 206010012601 diabetes mellitus Diseases 0.000 claims abstract description 29
- 150000003839 salts Chemical class 0.000 claims abstract description 29
- 208000032928 Dyslipidaemia Diseases 0.000 claims abstract description 27
- 208000017170 Lipid metabolism disease Diseases 0.000 claims abstract description 27
- 208000015122 neurodegenerative disease Diseases 0.000 claims abstract description 23
- 206010053219 non-alcoholic steatohepatitis Diseases 0.000 claims abstract description 19
- 208000019622 heart disease Diseases 0.000 claims abstract description 16
- 230000004054 inflammatory process Effects 0.000 claims abstract description 13
- 235000020660 omega-3 fatty acid Nutrition 0.000 claims abstract description 9
- 201000000585 muscular atrophy Diseases 0.000 claims abstract description 8
- 229940012843 omega-3 fatty acid Drugs 0.000 claims abstract description 8
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 claims abstract description 3
- MBMBGCFOFBJSGT-KUBAVDMBSA-N all-cis-docosa-4,7,10,13,16,19-hexaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCC(O)=O MBMBGCFOFBJSGT-KUBAVDMBSA-N 0.000 claims description 120
- 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 claims description 70
- 235000020673 eicosapentaenoic acid Nutrition 0.000 claims description 70
- 229960005135 eicosapentaenoic acid Drugs 0.000 claims description 70
- JAZBEHYOTPTENJ-UHFFFAOYSA-N eicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O JAZBEHYOTPTENJ-UHFFFAOYSA-N 0.000 claims description 70
- 235000020669 docosahexaenoic acid Nutrition 0.000 claims description 62
- 229940090949 docosahexaenoic acid Drugs 0.000 claims description 60
- 238000004519 manufacturing process Methods 0.000 claims description 33
- 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 claims description 27
- 239000008103 glucose Substances 0.000 claims description 27
- 208000019423 liver disease Diseases 0.000 claims description 25
- 208000031226 Hyperlipidaemia Diseases 0.000 claims description 23
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 20
- 210000004185 liver Anatomy 0.000 claims description 20
- 230000002265 prevention Effects 0.000 claims description 19
- 206010028980 Neoplasm Diseases 0.000 claims description 17
- 201000011510 cancer Diseases 0.000 claims description 17
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims description 16
- 210000004369 blood Anatomy 0.000 claims description 15
- 239000008280 blood Substances 0.000 claims description 15
- 125000004494 ethyl ester group Chemical group 0.000 claims description 15
- 150000002632 lipids Chemical class 0.000 claims description 15
- 208000030159 metabolic disease Diseases 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- 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 claims description 14
- 239000003085 diluting agent Substances 0.000 claims description 14
- UFTFJSFQGQCHQW-UHFFFAOYSA-N triformin Chemical compound O=COCC(OC=O)COC=O UFTFJSFQGQCHQW-UHFFFAOYSA-N 0.000 claims description 14
- GVJHHUAWPYXKBD-UHFFFAOYSA-N (±)-α-Tocopherol Chemical compound OC1=C(C)C(C)=C2OC(CCCC(C)CCCC(C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-UHFFFAOYSA-N 0.000 claims description 12
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 12
- 108010028554 LDL Cholesterol Proteins 0.000 claims description 12
- 108010023302 HDL Cholesterol Proteins 0.000 claims description 11
- 206010061218 Inflammation Diseases 0.000 claims description 11
- 239000002775 capsule Substances 0.000 claims description 11
- 239000003937 drug carrier Substances 0.000 claims description 11
- 208000010706 fatty liver disease Diseases 0.000 claims description 11
- 208000001072 type 2 diabetes mellitus Diseases 0.000 claims description 11
- 208000004930 Fatty Liver Diseases 0.000 claims description 10
- 206010019708 Hepatic steatosis Diseases 0.000 claims description 10
- 239000002253 acid Substances 0.000 claims description 10
- 235000012000 cholesterol Nutrition 0.000 claims description 10
- 231100000240 steatosis hepatitis Toxicity 0.000 claims description 10
- 201000001320 Atherosclerosis Diseases 0.000 claims description 9
- 206010070901 Diabetic dyslipidaemia Diseases 0.000 claims description 9
- 235000020661 alpha-linolenic acid Nutrition 0.000 claims description 9
- 230000002829 reductive effect Effects 0.000 claims description 9
- YUFFSWGQGVEMMI-JLNKQSITSA-N (7Z,10Z,13Z,16Z,19Z)-docosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCCC(O)=O YUFFSWGQGVEMMI-JLNKQSITSA-N 0.000 claims description 8
- 235000021294 Docosapentaenoic acid Nutrition 0.000 claims description 8
- 208000006575 hypertriglyceridemia Diseases 0.000 claims description 8
- 229960004488 linolenic acid Drugs 0.000 claims description 8
- 206010012689 Diabetic retinopathy Diseases 0.000 claims description 7
- 206010022489 Insulin Resistance Diseases 0.000 claims description 7
- KXVFBCSUGDNXQF-DZDBOGACSA-N (2z,4z,6z,8z,10z)-tetracosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCCCCCC\C=C/C=C\C=C/C=C\C=C/C(O)=O KXVFBCSUGDNXQF-DZDBOGACSA-N 0.000 claims description 6
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 claims description 6
- ZZZCUOFIHGPKAK-UHFFFAOYSA-N D-erythro-ascorbic acid Natural products OCC1OC(=O)C(O)=C1O ZZZCUOFIHGPKAK-UHFFFAOYSA-N 0.000 claims description 6
- 208000007342 Diabetic Nephropathies Diseases 0.000 claims description 6
- 208000032131 Diabetic Neuropathies Diseases 0.000 claims description 6
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 6
- OPGOLNDOMSBSCW-CLNHMMGSSA-N Fursultiamine hydrochloride Chemical compound Cl.C1CCOC1CSSC(\CCO)=C(/C)N(C=O)CC1=CN=C(C)N=C1N OPGOLNDOMSBSCW-CLNHMMGSSA-N 0.000 claims description 6
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 claims description 6
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 claims description 6
- 229930003779 Vitamin B12 Natural products 0.000 claims description 6
- 229930003268 Vitamin C Natural products 0.000 claims description 6
- 229930003316 Vitamin D Natural products 0.000 claims description 6
- QYSXJUFSXHHAJI-XFEUOLMDSA-N Vitamin D3 Natural products C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C/C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-XFEUOLMDSA-N 0.000 claims description 6
- 229930003427 Vitamin E Natural products 0.000 claims description 6
- 238000010521 absorption reaction Methods 0.000 claims description 6
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 claims description 6
- -1 berberine organic acid salts Chemical class 0.000 claims description 6
- 229940046374 chromium picolinate Drugs 0.000 claims description 6
- GJYSUGXFENSLOO-UHFFFAOYSA-N chromium;pyridine-2-carboxylic acid Chemical compound [Cr].OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1.OC(=O)C1=CC=CC=N1 GJYSUGXFENSLOO-UHFFFAOYSA-N 0.000 claims description 6
- AGVAZMGAQJOSFJ-WZHZPDAFSA-M cobalt(2+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+2].N#[C-].[N-]([C@@H]1[C@H](CC(N)=O)[C@@]2(C)CCC(=O)NC[C@@H](C)OP(O)(=O)O[C@H]3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)\C2=C(C)/C([C@H](C\2(C)C)CCC(N)=O)=N/C/2=C\C([C@H]([C@@]/2(CC(N)=O)C)CCC(N)=O)=N\C\2=C(C)/C2=N[C@]1(C)[C@@](C)(CC(N)=O)[C@@H]2CCC(N)=O AGVAZMGAQJOSFJ-WZHZPDAFSA-M 0.000 claims description 6
- 208000033679 diabetic kidney disease Diseases 0.000 claims description 6
- IQLUYYHUNSSHIY-HZUMYPAESA-N eicosatetraenoic acid Chemical compound CCCCCCCCCCC\C=C\C=C\C=C\C=C\C(O)=O IQLUYYHUNSSHIY-HZUMYPAESA-N 0.000 claims description 6
- WIGCFUFOHFEKBI-UHFFFAOYSA-N gamma-tocopherol Natural products CC(C)CCCC(C)CCCC(C)CCCC1CCC2C(C)C(O)C(C)C(C)C2O1 WIGCFUFOHFEKBI-UHFFFAOYSA-N 0.000 claims description 6
- 208000010125 myocardial infarction Diseases 0.000 claims description 6
- 230000001105 regulatory effect Effects 0.000 claims description 6
- 208000001076 sarcopenia Diseases 0.000 claims description 6
- JIWBIWFOSCKQMA-UHFFFAOYSA-N stearidonic acid Natural products CCC=CCC=CCC=CCC=CCCCCC(O)=O JIWBIWFOSCKQMA-UHFFFAOYSA-N 0.000 claims description 6
- 229910052720 vanadium Inorganic materials 0.000 claims description 6
- 235000019155 vitamin A Nutrition 0.000 claims description 6
- 239000011719 vitamin A Substances 0.000 claims description 6
- 235000019163 vitamin B12 Nutrition 0.000 claims description 6
- 239000011715 vitamin B12 Substances 0.000 claims description 6
- 235000019154 vitamin C Nutrition 0.000 claims description 6
- 239000011718 vitamin C Substances 0.000 claims description 6
- 235000019166 vitamin D Nutrition 0.000 claims description 6
- 239000011710 vitamin D Substances 0.000 claims description 6
- 150000003710 vitamin D derivatives Chemical class 0.000 claims description 6
- 235000019165 vitamin E Nutrition 0.000 claims description 6
- 239000011709 vitamin E Substances 0.000 claims description 6
- 229940046009 vitamin E Drugs 0.000 claims description 6
- 229940045997 vitamin a Drugs 0.000 claims description 6
- 229940046008 vitamin d Drugs 0.000 claims description 6
- SZQQHKQCCBDXCG-BAHYSTIISA-N (2e,4e,6e)-hexadeca-2,4,6-trienoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C(O)=O SZQQHKQCCBDXCG-BAHYSTIISA-N 0.000 claims description 5
- OQOCQFSPEWCSDO-JLNKQSITSA-N 6Z,9Z,12Z,15Z,18Z-Heneicosapentaenoic acid Chemical compound CC\C=C/C\C=C/C\C=C/C\C=C/C\C=C/CCCCC(O)=O OQOCQFSPEWCSDO-JLNKQSITSA-N 0.000 claims description 5
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 5
- 230000017531 blood circulation Effects 0.000 claims description 5
- 230000004110 gluconeogenesis Effects 0.000 claims description 5
- OQOCQFSPEWCSDO-UHFFFAOYSA-N heneicosapentaenoic acid Natural products CCC=CCC=CCC=CCC=CCC=CCCCCC(O)=O OQOCQFSPEWCSDO-UHFFFAOYSA-N 0.000 claims description 5
- 230000003914 insulin secretion Effects 0.000 claims description 5
- 230000004155 insulin signaling pathway Effects 0.000 claims description 5
- AHANXAKGNAKFSK-PDBXOOCHSA-N all-cis-icosa-11,14,17-trienoic acid Chemical compound CC\C=C/C\C=C/C\C=C/CCCCCCCCCC(O)=O AHANXAKGNAKFSK-PDBXOOCHSA-N 0.000 claims description 4
- 229960002873 benfotiamine Drugs 0.000 claims description 4
- BTNNPSLJPBRMLZ-LGMDPLHJSA-N benfotiamine Chemical compound C=1C=CC=CC=1C(=O)SC(/CCOP(O)(O)=O)=C(/C)N(C=O)CC1=CN=C(C)N=C1N BTNNPSLJPBRMLZ-LGMDPLHJSA-N 0.000 claims description 4
- 229940045605 vanadium Drugs 0.000 claims description 4
- VKJGBAJNNALVAV-UHFFFAOYSA-M Berberine chloride (TN) Chemical compound [Cl-].C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 VKJGBAJNNALVAV-UHFFFAOYSA-M 0.000 claims description 3
- PRHHYVQTPBEDFE-UHFFFAOYSA-N eicosatrienoic acid Natural products CCCCCC=CCC=CCCCCC=CCCCC(O)=O PRHHYVQTPBEDFE-UHFFFAOYSA-N 0.000 claims description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 2
- OJVABJMSSDUECT-UHFFFAOYSA-L berberin sulfate Chemical compound [O-]S([O-])(=O)=O.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2.C1=C2CC[N+]3=CC4=C(OC)C(OC)=CC=C4C=C3C2=CC2=C1OCO2 OJVABJMSSDUECT-UHFFFAOYSA-L 0.000 claims description 2
- KQQKGWQCNNTQJW-UHFFFAOYSA-N linolenic acid Natural products CC=CCCC=CCC=CCCCCCCCC(O)=O KQQKGWQCNNTQJW-UHFFFAOYSA-N 0.000 claims description 2
- 235000001727 glucose Nutrition 0.000 claims 2
- 150000002304 glucoses Chemical class 0.000 claims 1
- 239000008177 pharmaceutical agent Substances 0.000 claims 1
- LEONUFNNVUYDNQ-UHFFFAOYSA-N vanadium atom Chemical compound [V] LEONUFNNVUYDNQ-UHFFFAOYSA-N 0.000 claims 1
- 239000003814 drug Substances 0.000 abstract description 31
- 238000000034 method Methods 0.000 abstract description 24
- 230000004770 neurodegeneration Effects 0.000 abstract description 16
- 208000001145 Metabolic Syndrome Diseases 0.000 abstract description 9
- 208000008589 Obesity Diseases 0.000 abstract description 9
- 235000020824 obesity Nutrition 0.000 abstract description 9
- 208000002249 Diabetes Complications Diseases 0.000 abstract description 6
- 206010012655 Diabetic complications Diseases 0.000 abstract description 5
- 206010018429 Glucose tolerance impaired Diseases 0.000 abstract description 4
- 208000002231 Muscle Neoplasms Diseases 0.000 abstract description 2
- 206010028289 Muscle atrophy Diseases 0.000 abstract description 2
- 201000002481 Myositis Diseases 0.000 abstract description 2
- 230000020763 muscle atrophy Effects 0.000 abstract description 2
- 208000001280 Prediabetic State Diseases 0.000 abstract 1
- 201000009104 prediabetes syndrome Diseases 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 description 31
- 150000001875 compounds Chemical class 0.000 description 30
- 229940079593 drug Drugs 0.000 description 17
- 241000282472 Canis lupus familiaris Species 0.000 description 11
- 201000001421 hyperglycemia Diseases 0.000 description 10
- 239000000463 material Substances 0.000 description 10
- 208000024172 Cardiovascular disease Diseases 0.000 description 9
- 241000700159 Rattus Species 0.000 description 9
- 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 9
- 230000036470 plasma concentration Effects 0.000 description 8
- 125000006239 protecting group Chemical group 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 201000000690 abdominal obesity-metabolic syndrome Diseases 0.000 description 7
- 238000012360 testing method Methods 0.000 description 7
- 241000124008 Mammalia Species 0.000 description 6
- 239000000556 agonist Substances 0.000 description 6
- 230000008901 benefit Effects 0.000 description 6
- 230000000694 effects Effects 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 238000002360 preparation method Methods 0.000 description 6
- 230000001225 therapeutic effect Effects 0.000 description 6
- 241000282412 Homo Species 0.000 description 5
- 239000003795 chemical substances by application Substances 0.000 description 5
- 230000034994 death Effects 0.000 description 5
- 231100000517 death Toxicity 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- DNIAPMSPPWPWGF-UHFFFAOYSA-N monopropylene glycol Natural products CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 5
- 239000006014 omega-3 oil Substances 0.000 description 5
- GPPXJZIENCGNKB-UHFFFAOYSA-N vanadium Chemical compound [V]#[V] GPPXJZIENCGNKB-UHFFFAOYSA-N 0.000 description 5
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 4
- 206010020772 Hypertension Diseases 0.000 description 4
- 102000004895 Lipoproteins Human genes 0.000 description 4
- 108090001030 Lipoproteins Proteins 0.000 description 4
- 238000006243 chemical reaction Methods 0.000 description 4
- 150000003841 chloride salts Chemical class 0.000 description 4
- 230000001684 chronic effect Effects 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 235000019197 fats Nutrition 0.000 description 4
- 125000000524 functional group Chemical group 0.000 description 4
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 description 4
- 238000001727 in vivo Methods 0.000 description 4
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 4
- 210000002569 neuron Anatomy 0.000 description 4
- 238000012453 sprague-dawley rat model Methods 0.000 description 4
- 229940124597 therapeutic agent Drugs 0.000 description 4
- 206010016654 Fibrosis Diseases 0.000 description 3
- 206010019280 Heart failures Diseases 0.000 description 3
- 208000035150 Hypercholesterolemia Diseases 0.000 description 3
- 241001465754 Metazoa Species 0.000 description 3
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 3
- 230000001476 alcoholic effect Effects 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 239000000969 carrier Substances 0.000 description 3
- 230000004064 dysfunction Effects 0.000 description 3
- 239000007902 hard capsule Substances 0.000 description 3
- ZFGMDIBRIDKWMY-PASTXAENSA-N heparin Chemical compound CC(O)=N[C@@H]1[C@@H](O)[C@H](O)[C@@H](COS(O)(=O)=O)O[C@@H]1O[C@@H]1[C@@H](C(O)=O)O[C@@H](O[C@H]2[C@@H]([C@@H](OS(O)(=O)=O)[C@@H](O[C@@H]3[C@@H](OC(O)[C@H](OS(O)(=O)=O)[C@H]3O)C(O)=O)O[C@@H]2O)CS(O)(=O)=O)[C@H](O)[C@H]1O ZFGMDIBRIDKWMY-PASTXAENSA-N 0.000 description 3
- 229920000669 heparin Polymers 0.000 description 3
- 230000003908 liver function Effects 0.000 description 3
- 230000010534 mechanism of action Effects 0.000 description 3
- 230000004048 modification Effects 0.000 description 3
- 238000012986 modification Methods 0.000 description 3
- 239000003921 oil Substances 0.000 description 3
- 235000019198 oils Nutrition 0.000 description 3
- 229910052760 oxygen Inorganic materials 0.000 description 3
- 230000000144 pharmacologic effect Effects 0.000 description 3
- 125000001424 substituent group Chemical group 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- DVSZKTAMJJTWFG-SKCDLICFSA-N (2e,4e,6e,8e,10e,12e)-docosa-2,4,6,8,10,12-hexaenoic acid Chemical compound CCCCCCCCC\C=C\C=C\C=C\C=C\C=C\C=C\C(O)=O DVSZKTAMJJTWFG-SKCDLICFSA-N 0.000 description 2
- UUUHXMGGBIUAPW-UHFFFAOYSA-N 1-[1-[2-[[5-amino-2-[[1-[5-(diaminomethylideneamino)-2-[[1-[3-(1h-indol-3-yl)-2-[(5-oxopyrrolidine-2-carbonyl)amino]propanoyl]pyrrolidine-2-carbonyl]amino]pentanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-methylpentanoyl]pyrrolidine-2-carbon Chemical compound C1CCC(C(=O)N2C(CCC2)C(O)=O)N1C(=O)C(C(C)CC)NC(=O)C(CCC(N)=O)NC(=O)C1CCCN1C(=O)C(CCCN=C(N)N)NC(=O)C1CCCN1C(=O)C(CC=1C2=CC=CC=C2NC=1)NC(=O)C1CCC(=O)N1 UUUHXMGGBIUAPW-UHFFFAOYSA-N 0.000 description 2
- GZJLLYHBALOKEX-UHFFFAOYSA-N 6-Ketone, O18-Me-Ussuriedine Natural products CC=CCC=CCC=CCC=CCC=CCC=CCCCC(O)=O GZJLLYHBALOKEX-UHFFFAOYSA-N 0.000 description 2
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 2
- 201000004569 Blindness Diseases 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical group [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 2
- 206010008635 Cholestasis Diseases 0.000 description 2
- 206010009944 Colon cancer Diseases 0.000 description 2
- 241000037740 Coptis chinensis Species 0.000 description 2
- YZCKVEUIGOORGS-OUBTZVSYSA-N Deuterium Chemical compound [2H] YZCKVEUIGOORGS-OUBTZVSYSA-N 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000735432 Hydrastis canadensis Species 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- 206010058467 Lung neoplasm malignant Diseases 0.000 description 2
- 229910019142 PO4 Inorganic materials 0.000 description 2
- 102000004270 Peptidyl-Dipeptidase A Human genes 0.000 description 2
- 108090000882 Peptidyl-Dipeptidase A Proteins 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 241000700605 Viruses Species 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 230000002411 adverse Effects 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000036772 blood pressure Effects 0.000 description 2
- 210000004556 brain Anatomy 0.000 description 2
- 239000000460 chlorine Substances 0.000 description 2
- 230000007882 cirrhosis Effects 0.000 description 2
- 208000019425 cirrhosis of liver Diseases 0.000 description 2
- 208000029742 colonic neoplasm Diseases 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 230000003247 decreasing effect Effects 0.000 description 2
- 230000007850 degeneration Effects 0.000 description 2
- 229910052805 deuterium Inorganic materials 0.000 description 2
- 238000011161 development Methods 0.000 description 2
- KAUVQQXNCKESLC-UHFFFAOYSA-N docosahexaenoic acid (DHA) Natural products COC(=O)C(C)NOCC1=CC=CC=C1 KAUVQQXNCKESLC-UHFFFAOYSA-N 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 239000003995 emulsifying agent Substances 0.000 description 2
- MMXKVMNBHPAILY-UHFFFAOYSA-N ethyl laurate Chemical compound CCCCCCCCCCCC(=O)OCC MMXKVMNBHPAILY-UHFFFAOYSA-N 0.000 description 2
- 238000009472 formulation Methods 0.000 description 2
- 235000005679 goldenseal Nutrition 0.000 description 2
- 230000036541 health Effects 0.000 description 2
- 230000002440 hepatic effect Effects 0.000 description 2
- 208000006454 hepatitis Diseases 0.000 description 2
- 231100000283 hepatitis Toxicity 0.000 description 2
- 229910052739 hydrogen Inorganic materials 0.000 description 2
- 150000002431 hydrogen Chemical class 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 210000003734 kidney Anatomy 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 201000005202 lung cancer Diseases 0.000 description 2
- 208000020816 lung neoplasm Diseases 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
- 238000002483 medication Methods 0.000 description 2
- 230000037353 metabolic pathway Effects 0.000 description 2
- 230000000116 mitigating effect Effects 0.000 description 2
- 210000005036 nerve Anatomy 0.000 description 2
- 229910052757 nitrogen Inorganic materials 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 210000000056 organ Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 2
- 239000010452 phosphate Substances 0.000 description 2
- 239000000651 prodrug Substances 0.000 description 2
- 229940002612 prodrug Drugs 0.000 description 2
- 230000000750 progressive effect Effects 0.000 description 2
- 230000009467 reduction Effects 0.000 description 2
- 210000002966 serum Anatomy 0.000 description 2
- 239000012453 solvate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000000758 substrate Substances 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 229910052717 sulfur Inorganic materials 0.000 description 2
- 230000032258 transport Effects 0.000 description 2
- 150000003626 triacylglycerols Chemical class 0.000 description 2
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 208000007082 Alcoholic Fatty Liver Diseases 0.000 description 1
- 208000022309 Alcoholic Liver disease Diseases 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
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 208000000044 Amnesia Diseases 0.000 description 1
- 241001083847 Berberis Species 0.000 description 1
- 240000000724 Berberis vulgaris Species 0.000 description 1
- 235000016068 Berberis vulgaris Nutrition 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-NJFSPNSNSA-N Carbon-14 Chemical compound [14C] OKTJSMMVPCPJKN-NJFSPNSNSA-N 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 206010008342 Cervix carcinoma Diseases 0.000 description 1
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 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
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- RGHNJXZEOKUKBD-SQOUGZDYSA-M D-gluconate Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C([O-])=O RGHNJXZEOKUKBD-SQOUGZDYSA-M 0.000 description 1
- 240000001879 Digitalis lutea Species 0.000 description 1
- LVGKNOAMLMIIKO-UHFFFAOYSA-N Elaidinsaeure-aethylester Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC LVGKNOAMLMIIKO-UHFFFAOYSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 244000001381 Eschscholzia californica Species 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical compound FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 208000018522 Gastrointestinal disease Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 208000023105 Huntington disease Diseases 0.000 description 1
- 206010052341 Impaired insulin secretion Diseases 0.000 description 1
- 206010023379 Ketoacidosis Diseases 0.000 description 1
- 208000007976 Ketosis Diseases 0.000 description 1
- 108010007622 LDL Lipoproteins Proteins 0.000 description 1
- 102000007330 LDL Lipoproteins Human genes 0.000 description 1
- JVTAAEKCZFNVCJ-UHFFFAOYSA-M Lactate Chemical compound CC(O)C([O-])=O JVTAAEKCZFNVCJ-UHFFFAOYSA-M 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
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000026139 Memory disease Diseases 0.000 description 1
- 208000002693 Multiple Abnormalities Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 229940122392 PCSK9 inhibitor Drugs 0.000 description 1
- 208000018737 Parkinson disease Diseases 0.000 description 1
- 235000019483 Peanut oil Nutrition 0.000 description 1
- 241000972673 Phellodendron amurense Species 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- QOSMNYMQXIVWKY-UHFFFAOYSA-N Propyl levulinate Chemical compound CCCOC(=O)CCC(C)=O QOSMNYMQXIVWKY-UHFFFAOYSA-N 0.000 description 1
- 206010060862 Prostate cancer Diseases 0.000 description 1
- 208000000236 Prostatic Neoplasms Diseases 0.000 description 1
- 241000283984 Rodentia Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 208000005718 Stomach Neoplasms Diseases 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
- 229930006000 Sucrose Natural products 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 229920002253 Tannate Polymers 0.000 description 1
- 240000003428 Tinospora crispa Species 0.000 description 1
- YZCKVEUIGOORGS-NJFSPNSNSA-N Tritium Chemical compound [3H] YZCKVEUIGOORGS-NJFSPNSNSA-N 0.000 description 1
- 208000006105 Uterine Cervical Neoplasms Diseases 0.000 description 1
- 241000736819 Xanthorhiza simplicissima Species 0.000 description 1
- 230000003187 abdominal effect Effects 0.000 description 1
- 230000002159 abnormal effect Effects 0.000 description 1
- 230000005856 abnormality Effects 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
- 150000007513 acids Chemical class 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 208000026594 alcoholic fatty liver disease Diseases 0.000 description 1
- 239000000783 alginic acid Substances 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229960001126 alginic acid Drugs 0.000 description 1
- 150000004781 alginic acids Chemical class 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 150000001450 anions Chemical class 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229940124575 antispasmodic agent Drugs 0.000 description 1
- 206010003119 arrhythmia Diseases 0.000 description 1
- 230000006793 arrhythmia Effects 0.000 description 1
- 150000003836 berberines Chemical class 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 150000003842 bromide salts Chemical class 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 125000004432 carbon atom Chemical group C* 0.000 description 1
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000010261 cell growth Effects 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 201000010881 cervical cancer Diseases 0.000 description 1
- 238000009614 chemical analysis method Methods 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 238000002512 chemotherapy Methods 0.000 description 1
- 229910052801 chlorine Inorganic materials 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 208000037976 chronic inflammation Diseases 0.000 description 1
- 230000006020 chronic inflammation Effects 0.000 description 1
- 230000004087 circulation Effects 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 229940110456 cocoa butter Drugs 0.000 description 1
- 235000019868 cocoa butter Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000295 complement effect Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 235000005687 corn oil Nutrition 0.000 description 1
- 239000002285 corn oil Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 235000012343 cottonseed oil Nutrition 0.000 description 1
- 239000002385 cottonseed oil Substances 0.000 description 1
- 230000005574 cross-species transmission Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 238000001212 derivatisation Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000021045 dietary change Nutrition 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000037765 diseases and disorders Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 231100000673 dose–response relationship Toxicity 0.000 description 1
- 238000005538 encapsulation Methods 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- LVGKNOAMLMIIKO-QXMHVHEDSA-N ethyl oleate Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OCC LVGKNOAMLMIIKO-QXMHVHEDSA-N 0.000 description 1
- 229940093471 ethyl oleate Drugs 0.000 description 1
- 230000029142 excretion Effects 0.000 description 1
- 210000001508 eye Anatomy 0.000 description 1
- 150000002191 fatty alcohols Chemical class 0.000 description 1
- 230000004761 fibrosis Effects 0.000 description 1
- 239000000945 filler Substances 0.000 description 1
- 229910052731 fluorine Inorganic materials 0.000 description 1
- 239000011737 fluorine Substances 0.000 description 1
- 235000003599 food sweetener Nutrition 0.000 description 1
- 238000001640 fractional crystallisation Methods 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 206010017758 gastric cancer Diseases 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
- 230000002068 genetic effect Effects 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 229940050410 gluconate Drugs 0.000 description 1
- 230000009229 glucose formation Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 239000008187 granular material Substances 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 210000003494 hepatocyte Anatomy 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000001794 hormone therapy Methods 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 208000020346 hyperlipoproteinemia Diseases 0.000 description 1
- SBHCLVQMTBWHCD-UHFFFAOYSA-N icosa-2,4,6,8,10-pentaenoic acid Chemical compound CCCCCCCCCC=CC=CC=CC=CC=CC(O)=O SBHCLVQMTBWHCD-UHFFFAOYSA-N 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 150000004694 iodide salts Chemical class 0.000 description 1
- TWBYWOBDOCUKOW-UHFFFAOYSA-M isonicotinate Chemical compound [O-]C(=O)C1=CC=NC=C1 TWBYWOBDOCUKOW-UHFFFAOYSA-M 0.000 description 1
- 229930013397 isoquinoline alkaloid Natural products 0.000 description 1
- 238000001948 isotopic labelling Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 230000008604 lipoprotein metabolism Effects 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 230000005976 liver dysfunction Effects 0.000 description 1
- 210000005228 liver tissue Anatomy 0.000 description 1
- 108010030696 low density lipoprotein triglyceride Proteins 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 230000006984 memory degeneration Effects 0.000 description 1
- 208000023060 memory loss Diseases 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000010172 mouse model Methods 0.000 description 1
- 201000002077 muscle cancer Diseases 0.000 description 1
- 230000035772 mutation Effects 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 230000004112 neuroprotection Effects 0.000 description 1
- 239000004006 olive oil Substances 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 230000003287 optical effect Effects 0.000 description 1
- 238000011369 optimal treatment Methods 0.000 description 1
- 238000012261 overproduction Methods 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 230000036542 oxidative stress Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 239000000312 peanut oil Substances 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229910052698 phosphorus Inorganic materials 0.000 description 1
- 239000011574 phosphorus Substances 0.000 description 1
- 230000037081 physical activity Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000000106 platelet aggregation inhibitor Substances 0.000 description 1
- 238000002264 polyacrylamide gel electrophoresis Methods 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001451 polypropylene glycol Polymers 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000001959 radiotherapy Methods 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 102000005962 receptors Human genes 0.000 description 1
- 108020003175 receptors Proteins 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 230000008085 renal dysfunction Effects 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 230000002441 reversible effect Effects 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 230000037390 scarring Effects 0.000 description 1
- 239000008159 sesame oil Substances 0.000 description 1
- 235000011803 sesame oil Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000003549 soybean oil Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 210000000278 spinal cord Anatomy 0.000 description 1
- 238000010561 standard procedure Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 201000011549 stomach cancer Diseases 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 230000002459 sustained effect Effects 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 238000004885 tandem mass spectrometry Methods 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 238000003354 tissue distribution assay Methods 0.000 description 1
- 229910052722 tritium Inorganic materials 0.000 description 1
- JFJZZMVDLULRGK-URLMMPGGSA-O tubocurarine Chemical compound C([C@H]1[N+](C)(C)CCC=2C=C(C(=C(OC3=CC=C(C=C3)C[C@H]3C=4C=C(C(=CC=4CCN3C)OC)O3)C=21)O)OC)C1=CC=C(O)C3=C1 JFJZZMVDLULRGK-URLMMPGGSA-O 0.000 description 1
- 210000003934 vacuole Anatomy 0.000 description 1
- 230000004393 visual impairment Effects 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004580 weight loss Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/20—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
- A61K31/202—Carboxylic acids, e.g. valproic acid having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids having three or more double bonds, e.g. linolenic
-
- 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
- A61K31/23—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms
- A61K31/232—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin of acids having a carboxyl group bound to a chain of seven or more carbon atoms having three or more double bonds, e.g. etretinate
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4375—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
- A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
-
- 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
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/12—Drugs for disorders of the urinary system of the kidneys
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P21/00—Drugs for disorders of the muscular or neuromuscular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Epidemiology (AREA)
- Diabetes (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Emergency Medicine (AREA)
- Neurology (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Biomedical Technology (AREA)
- Heart & Thoracic Surgery (AREA)
- Urology & Nephrology (AREA)
- Vascular Medicine (AREA)
- Hospice & Palliative Care (AREA)
- Endocrinology (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Psychiatry (AREA)
- Gastroenterology & Hepatology (AREA)
- Orthopedic Medicine & Surgery (AREA)
- Physical Education & Sports Medicine (AREA)
- Ophthalmology & Optometry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
本発明は、概して、新規組成物、ならびにその調製法および治療的使用法に関する。特に、本発明は、ベルベリン(BBR)をオメガ-3脂肪酸、例えば、エイコサペンタエン酸(EPA)および/もしくはドコサヘキサエン酸(DHA)、またはそのエステルと組み合わせた新規薬学的組成物、およびその使用法に関する。本発明の薬学的組成物は、脂質異常症、高血糖症、高トリグリセリド血症、高脂血症、糖尿病性脂質異常症、糖尿病性高脂血症、スタチン不耐性患者における脂質異常症、糖尿病、糖尿病合併症、高コレステロール血症、または肥満などの代謝疾患または障害を含む、様々な疾患または障害を処置および/または予防する際に有用である。加えて、本発明の薬学的組成物は、アテローム性動脈硬化症、心疾患、神経変性疾患、炎症、がん、および、脂肪肝、非アルコール性脂肪性肝疾患、非アルコール性脂肪性肝炎、胆汁うっ滞性肝疾患、または肝臓の移植片対宿主病などの様々な肝疾患または障害を処置および/または予防する際に有用である。さらに、本発明の薬学的組成物は、慢性ウイルス関連肝疾患およびアルコール関連肝疾患における肝機能を改善する際に有用である。
脂質異常症は、リポタンパク質の過剰産生(高脂血症)または欠乏を含む、リポタンパク質代謝の障害である。脂質異常症は、血中の総コレステロール、「悪玉」低密度リポタンパク質コレステロール、およびトリグリセリド濃度の上昇、ならびに「善玉」高密度リポタンパク質コレステロール濃度の低下によって顕在化され得る。脂質異常症は、脂質異常症の一般的原因である糖尿病を含む多くの状況で想定されている。
[本発明1001]
(a)ベルベリンまたはその薬学的に許容される塩;および
(b)オメガ-3脂肪酸またはその許容されるエステル
を含む、組成物。
[本発明1002]
構成要素(b)が、ドコサヘキサエン酸またはその許容されるエステル、エイコサペンタエン酸またはその許容されるエステル、ドコサペンタエン酸またはその許容されるエステル、α-リノレン酸またはその許容されるエステル、エイコサトリエン酸またはその許容されるエステル、ヘキサデカトリエン酸またはその許容されるエステル、ステアリドン酸またはその許容されるエステル、エイコサテトラエン酸またはその許容されるエステル、ヘンエイコサペンタエン酸またはその許容されるエステル、テトラコサペンタエン酸またはその許容されるエステル、およびニシン酸またはその許容されるエステルからなる群の1つまたは複数より選択される、本発明1001の組成物。
[本発明1003]
構成要素(b)が、エイコサペンタエン酸もしくはその許容されるエステル、およびドコサヘキサエン酸もしくはその許容されるエステルの両方を含むか;または、構成要素(b)が、エイコサペンタエン酸もしくはその許容されるエステル、およびドコサヘキサエン酸もしくはその許容されるエステルのうちの1つを含む、本発明1001の組成物。
[本発明1004]
エイコサペンタエン酸の許容されるエステルが、エイコサペンタエン酸のエチルエステルであり、ドコサヘキサエン酸の許容されるエステルが、ドコサヘキサエン酸のエチルエステルである、本発明1003の組成物。
[本発明1005]
構成要素(b)が、ドコサペンタエン酸またはその許容されるエステル、α-リノレン酸またはその許容されるエステル、エイコサトリエン酸またはその許容されるエステル、ヘキサデカトリエン酸またはその許容されるエステル、ステアリドン酸またはその許容されるエステル、エイコサテトラエン酸またはその許容されるエステル、ヘンエイコサペンタエン酸またはその許容されるエステル、テトラコサペンタエン酸またはその許容されるエステル、およびニシン酸またはその許容されるエステルの1つまたは複数をさらに含む、本発明1003または1004の組成物。
[本発明1006]
組成物における構成要素(a)対構成要素(b)の重量比が、3:1~1:8の範囲にわたる、本発明1001~1004のいずれかの組成物。
[本発明1007]
ビタミンD、ビタミンC、ビタミンE、ビタミンB12、ビタミンA、ベンフォチアミン、ピコリン酸クロム、およびバナジウムの1つまたは複数をさらに含む、本発明1001~1004および1006のいずれかの組成物。
[本発明1008]
ベルベリンの薬学的に許容される塩が、塩酸ベルベリン、硫酸ベルベリン、クエン酸ベルベリン、または他のベルベリン有機酸塩の1つまたは複数である、本発明1001~1004のいずれかの組成物。
[本発明1009]
代謝疾患もしくは障害、心疾患もしくは障害、アテローム性動脈硬化症、神経変性疾患もしくは障害、サルコペニア、筋萎縮症、炎症、がん、および/または肝疾患もしくは障害の1つまたは複数の予防および/または処置のための医薬の製造における、本発明1001~1008のいずれかの組成物の使用。
[本発明1010]
脂質およびグルコースの疾患または障害の1つまたは複数の予防および/または処置のための医薬の製造における、本発明1001~1008のいずれかの組成物の使用。
[本発明1011]
脂質異常症、高血糖症、高トリグリセリド血症、高脂血症、糖尿病性脂質異常症、糖尿病性高脂血症、およびスタチン不耐性患者における脂質異常症の1つまたは複数の予防および/または処置のための医薬の製造における、本発明1001~1008のいずれかの組成物の使用。
[本発明1012]
1型および/または2型糖尿病の予防および/または処置のための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1013]
糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、または、心臓発作、卒中、もしくは脚への血流の不足を含む大血管合併症の1つまたは複数の予防および/または処置のための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1014]
脂肪肝、NAFLD、およびNASHの1つまたは複数の予防および/または処置のための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1015]
血糖、総コレステロール(TC)、トリグリセリド(TG)、および低密度リポタンパク質コレステロール(LDL-c)レベルの1つまたは複数を低下させるための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1016]
高密度リポタンパク質コレステロール(HDL-c)レベルを増大させるための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1017]
肝酵素レベルを正常化するための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1018]
インスリンシグナル伝達経路を調整するための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1019]
インスリンの分泌の増大、インスリン感受性の改善、肝臓における糖新生の低減、グルコース吸収の低減、脂質異常症の寛解、および抗炎症の1つまたは複数のための医薬の製造のための、本発明1001~1008のいずれかの組成物の使用。
[本発明1020]
本発明1001~1008のいずれかの組成物と、薬学的に許容される賦形剤、担体、または希釈剤とを含む、薬学的調製物。
[本発明1021]
ソフトゲルカプセル用である、本発明1020の薬学的調製物。
[本発明1022]
100 mg~300 mgの範囲にわたる重量の構成要素(a)と、100 mg~800 mgの範囲にわたる重量の構成要素(b)とを含む、本発明1020または1021の薬学的調製物。
図面および実施例に関連する以下の説明は、本発明によって解決される問題および本発明の有益な実施を例示するものであり、本発明を限定するものではない。
本実施例は、本発明において開示するベルベリン(BBR)とEPAおよび/またはDHAとの組み合わせの薬物動態(PK)特性についての、ラットおよびイヌにおけるインビボ研究を記載する。
Claims (22)
- (a)ベルベリンまたはその薬学的に許容される塩;および
(b)オメガ-3脂肪酸またはその許容されるエステル
を含む、組成物。 - 構成要素(b)が、ドコサヘキサエン酸またはその許容されるエステル、エイコサペンタエン酸またはその許容されるエステル、ドコサペンタエン酸またはその許容されるエステル、α-リノレン酸またはその許容されるエステル、エイコサトリエン酸またはその許容されるエステル、ヘキサデカトリエン酸またはその許容されるエステル、ステアリドン酸またはその許容されるエステル、エイコサテトラエン酸またはその許容されるエステル、ヘンエイコサペンタエン酸またはその許容されるエステル、テトラコサペンタエン酸またはその許容されるエステル、およびニシン酸またはその許容されるエステルからなる群の1つまたは複数より選択される、請求項1に記載の組成物。
- 構成要素(b)が、エイコサペンタエン酸もしくはその許容されるエステル、およびドコサヘキサエン酸もしくはその許容されるエステルの両方を含むか;または、構成要素(b)が、エイコサペンタエン酸もしくはその許容されるエステル、およびドコサヘキサエン酸もしくはその許容されるエステルのうちの1つを含む、請求項1に記載の組成物。
- エイコサペンタエン酸の許容されるエステルが、エイコサペンタエン酸のエチルエステルであり、ドコサヘキサエン酸の許容されるエステルが、ドコサヘキサエン酸のエチルエステルである、請求項3に記載の組成物。
- 構成要素(b)が、ドコサペンタエン酸またはその許容されるエステル、α-リノレン酸またはその許容されるエステル、エイコサトリエン酸またはその許容されるエステル、ヘキサデカトリエン酸またはその許容されるエステル、ステアリドン酸またはその許容されるエステル、エイコサテトラエン酸またはその許容されるエステル、ヘンエイコサペンタエン酸またはその許容されるエステル、テトラコサペンタエン酸またはその許容されるエステル、およびニシン酸またはその許容されるエステルの1つまたは複数をさらに含む、請求項3または4に記載の組成物。
- 組成物における構成要素(a)対構成要素(b)の重量比が、3:1~1:8の範囲にわたる、請求項1~4のいずれか一項に記載の組成物。
- ビタミンD、ビタミンC、ビタミンE、ビタミンB12、ビタミンA、ベンフォチアミン、ピコリン酸クロム、およびバナジウムの1つまたは複数をさらに含む、請求項1~4および6のいずれか一項に記載の組成物。
- ベルベリンの薬学的に許容される塩が、塩酸ベルベリン、硫酸ベルベリン、クエン酸ベルベリン、または他のベルベリン有機酸塩の1つまたは複数である、請求項1~4のいずれか一項に記載の組成物。
- 代謝疾患もしくは障害、心疾患もしくは障害、アテローム性動脈硬化症、神経変性疾患もしくは障害、サルコペニア、筋萎縮症、炎症、がん、および/または肝疾患もしくは障害の1つまたは複数の予防および/または処置のための医薬の製造における、請求項1~8のいずれか一項に記載の組成物の使用。
- 脂質およびグルコースの疾患または障害の1つまたは複数の予防および/または処置のための医薬の製造における、請求項1~8のいずれか一項に記載の組成物の使用。
- 脂質異常症、高血糖症、高トリグリセリド血症、高脂血症、糖尿病性脂質異常症、糖尿病性高脂血症、およびスタチン不耐性患者における脂質異常症の1つまたは複数の予防および/または処置のための医薬の製造における、請求項1~8のいずれか一項に記載の組成物の使用。
- 1型および/または2型糖尿病の予防および/または処置のための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 糖尿病性神経障害、糖尿病性腎症、糖尿病性網膜症、または、心臓発作、卒中、もしくは脚への血流の不足を含む大血管合併症の1つまたは複数の予防および/または処置のための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 脂肪肝、NAFLD、およびNASHの1つまたは複数の予防および/または処置のための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 血糖、総コレステロール(TC)、トリグリセリド(TG)、および低密度リポタンパク質コレステロール(LDL-c)レベルの1つまたは複数を低下させるための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 高密度リポタンパク質コレステロール(HDL-c)レベルを増大させるための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 肝酵素レベルを正常化するための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- インスリンシグナル伝達経路を調整するための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- インスリンの分泌の増大、インスリン感受性の改善、肝臓における糖新生の低減、グルコース吸収の低減、脂質異常症の寛解、および抗炎症の1つまたは複数のための医薬の製造のための、請求項1~8のいずれか一項に記載の組成物の使用。
- 請求項1~8のいずれか一項に記載の組成物と、薬学的に許容される賦形剤、担体、または希釈剤とを含む、薬学的調製物。
- ソフトゲルカプセル用である、請求項20に記載の薬学的調製物。
- 100 mg~300 mgの範囲にわたる重量の構成要素(a)と、100 mg~800 mgの範囲にわたる重量の構成要素(b)とを含む、請求項20または21に記載の薬学的調製物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2023189115A JP2024014894A (ja) | 2015-11-13 | 2023-11-06 | 組成物、ならびにその適用および薬学的調製の方法 |
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201562254739P | 2015-11-13 | 2015-11-13 | |
CN201610303976.5 | 2016-05-10 | ||
CN201610303976.5A CN106692973A (zh) | 2015-11-13 | 2016-05-10 | 一种组合物及其用途、药物制剂 |
PCT/CN2016/105294 WO2017193563A1 (zh) | 2015-11-13 | 2016-11-10 | 一种组合物及其用途、药物制剂 |
JP2018559306A JP2019518738A (ja) | 2015-11-13 | 2016-11-10 | 組成物、ならびにその適用および薬学的調製の方法 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018559306A Division JP2019518738A (ja) | 2015-11-13 | 2016-11-10 | 組成物、ならびにその適用および薬学的調製の方法 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023189115A Division JP2024014894A (ja) | 2015-11-13 | 2023-11-06 | 組成物、ならびにその適用および薬学的調製の方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2022017496A true JP2022017496A (ja) | 2022-01-25 |
JP7448511B2 JP7448511B2 (ja) | 2024-03-12 |
Family
ID=58939703
Family Applications (3)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018559306A Pending JP2019518738A (ja) | 2015-11-13 | 2016-11-10 | 組成物、ならびにその適用および薬学的調製の方法 |
JP2021180724A Active JP7448511B2 (ja) | 2015-11-13 | 2021-11-05 | 組成物、ならびにその適用および薬学的調製の方法 |
JP2023189115A Pending JP2024014894A (ja) | 2015-11-13 | 2023-11-06 | 組成物、ならびにその適用および薬学的調製の方法 |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2018559306A Pending JP2019518738A (ja) | 2015-11-13 | 2016-11-10 | 組成物、ならびにその適用および薬学的調製の方法 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2023189115A Pending JP2024014894A (ja) | 2015-11-13 | 2023-11-06 | 組成物、ならびにその適用および薬学的調製の方法 |
Country Status (5)
Country | Link |
---|---|
US (1) | US11883539B2 (ja) |
JP (3) | JP2019518738A (ja) |
KR (1) | KR20230019269A (ja) |
CN (2) | CN106692973A (ja) |
IL (2) | IL300237A (ja) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN108159037A (zh) * | 2017-12-29 | 2018-06-15 | 广东海洋大学 | 一种用于提高神经保护功能的不饱和脂肪酸组合物及其应用 |
CN108042522A (zh) * | 2017-12-29 | 2018-05-18 | 广东海洋大学 | 一种用于提高抗炎症功能的不饱和脂肪酸组合物及其应用 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20080306154A1 (en) * | 2006-11-03 | 2008-12-11 | My Svensson | Treatment and prevention of major adverse cardiovascular events or major coronary evens by administering Omega-3 fatty acids |
WO2009028457A1 (ja) * | 2007-08-29 | 2009-03-05 | Shinshu University | 非アルコール性脂肪肝炎治療薬 |
JP2009525990A (ja) * | 2006-02-09 | 2009-07-16 | ナショナル・リサーチ・カウンシル・オブ・カナダ | 医薬組成物 |
WO2010104595A1 (en) * | 2009-03-11 | 2010-09-16 | Xintria Pharmaceutical Corporation, Inc. | Methods and compositions for the treatment of metabolic and cardiovascular disorders |
CN101879162A (zh) * | 2010-02-23 | 2010-11-10 | 江苏格林生物科技有限公司 | 一种α-亚麻酸乙酯配伍小檗碱的减肥物 |
JP2014506891A (ja) * | 2011-02-16 | 2014-03-20 | ピヴォタル セラピューティクス インコーポレイテッド | 心血管疾患(CVD)患者の食事管理のためのω3脂肪酸診断アッセイ |
WO2014143272A1 (en) * | 2013-03-13 | 2014-09-18 | Matinas Biopharma Inc. | Omega-3 pentaenoic acid compositions and methods of use |
US20140322314A1 (en) * | 2013-04-29 | 2014-10-30 | Matinas Biopharma, Inc. | Omega-3 Fatty Acid Formulations for Use as Pharmaceutical Treatment |
JP2015514083A (ja) * | 2012-03-30 | 2015-05-18 | サンシリオ アンド カンパニー, インコーポレイテッドSancilio & Company, Inc. | ω−3脂肪酸エステル組成物 |
WO2016015634A1 (en) * | 2014-07-29 | 2016-02-04 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
Family Cites Families (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US9119826B2 (en) * | 2011-02-16 | 2015-09-01 | Pivotal Therapeutics, Inc. | Omega 3 fatty acid for use as a prescription medical food and omega 3 fatty acid diagniostic assay for the dietary management of cardiovascular patients with cardiovascular disease (CVD) who are deficient in blood EPA and DHA levels |
CN102580087B (zh) * | 2012-03-08 | 2013-08-21 | 董萍 | 一种可用于人体局部减肥和美体的原位脂肪细胞系复合抑制剂及其制备方法 |
US8652518B2 (en) * | 2012-04-15 | 2014-02-18 | Jahahreeh Finley | Compositions and methods for the prevention and treatment of diseases or conditions associated with oxidative stress, inflammation, and metabolic dysregulation |
US11026913B2 (en) * | 2013-09-05 | 2021-06-08 | Emory University | Nutritional formulas comprising medium chain fatty acids or esters thereof and methods related thereto |
MA40846A (fr) * | 2014-10-10 | 2017-09-05 | Sancilio & Company Inc | Compositions d'acides gras et d'esters d'acides gras auto-micellisantes, ainsi que leur utilisation dans le traitement d'états pathologiques |
US9446100B2 (en) * | 2015-02-13 | 2016-09-20 | Eastern Vision Limited | Dietary supplements and formulations |
-
2016
- 2016-05-10 CN CN201610303976.5A patent/CN106692973A/zh active Pending
- 2016-05-10 CN CN202310452983.1A patent/CN116492339A/zh active Pending
- 2016-11-10 KR KR1020187034961A patent/KR20230019269A/ko not_active Application Discontinuation
- 2016-11-10 IL IL300237A patent/IL300237A/en unknown
- 2016-11-10 JP JP2018559306A patent/JP2019518738A/ja active Pending
-
2018
- 2018-11-11 IL IL262929A patent/IL262929B2/en unknown
-
2021
- 2021-11-05 JP JP2021180724A patent/JP7448511B2/ja active Active
-
2022
- 2022-05-15 US US17/744,685 patent/US11883539B2/en active Active
-
2023
- 2023-11-06 JP JP2023189115A patent/JP2024014894A/ja active Pending
Patent Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2009525990A (ja) * | 2006-02-09 | 2009-07-16 | ナショナル・リサーチ・カウンシル・オブ・カナダ | 医薬組成物 |
US20080306154A1 (en) * | 2006-11-03 | 2008-12-11 | My Svensson | Treatment and prevention of major adverse cardiovascular events or major coronary evens by administering Omega-3 fatty acids |
WO2009028457A1 (ja) * | 2007-08-29 | 2009-03-05 | Shinshu University | 非アルコール性脂肪肝炎治療薬 |
WO2010104595A1 (en) * | 2009-03-11 | 2010-09-16 | Xintria Pharmaceutical Corporation, Inc. | Methods and compositions for the treatment of metabolic and cardiovascular disorders |
CN101879162A (zh) * | 2010-02-23 | 2010-11-10 | 江苏格林生物科技有限公司 | 一种α-亚麻酸乙酯配伍小檗碱的减肥物 |
JP2014506891A (ja) * | 2011-02-16 | 2014-03-20 | ピヴォタル セラピューティクス インコーポレイテッド | 心血管疾患(CVD)患者の食事管理のためのω3脂肪酸診断アッセイ |
JP2015514083A (ja) * | 2012-03-30 | 2015-05-18 | サンシリオ アンド カンパニー, インコーポレイテッドSancilio & Company, Inc. | ω−3脂肪酸エステル組成物 |
WO2014143272A1 (en) * | 2013-03-13 | 2014-09-18 | Matinas Biopharma Inc. | Omega-3 pentaenoic acid compositions and methods of use |
US20140322314A1 (en) * | 2013-04-29 | 2014-10-30 | Matinas Biopharma, Inc. | Omega-3 Fatty Acid Formulations for Use as Pharmaceutical Treatment |
WO2016015634A1 (en) * | 2014-07-29 | 2016-02-04 | Shenzhen Hightide Biopharmaceutical, Ltd. | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof |
Also Published As
Publication number | Publication date |
---|---|
IL262929B1 (en) | 2023-03-01 |
US11883539B2 (en) | 2024-01-30 |
JP2024014894A (ja) | 2024-02-01 |
JP7448511B2 (ja) | 2024-03-12 |
US20220296528A1 (en) | 2022-09-22 |
CN116492339A (zh) | 2023-07-28 |
CN106692973A (zh) | 2017-05-24 |
JP2019518738A (ja) | 2019-07-04 |
IL262929B2 (en) | 2023-07-01 |
IL300237A (en) | 2023-03-01 |
IL262929A (en) | 2018-12-31 |
KR20230019269A (ko) | 2023-02-08 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US10988471B2 (en) | Pharmaceutical composition comprising berberine ursodeoxycholic acid salt for the treatment of various diseases or disorders | |
US11369573B2 (en) | Pharmaceutical compositions of berberine with EPA and DHA, and methods thereof | |
JP2024014894A (ja) | 組成物、ならびにその適用および薬学的調製の方法 | |
US20230348457A1 (en) | Berberine salts, ursodeoxycholic salts and combinations, methods of preparation and application thereof | |
AU2023200123B2 (en) | Composition, and application and pharmaceutical preparation thereof | |
TW202122078A (zh) | 使用lta4h抑制劑治療肝臟疾病之方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20211124 |
|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20211124 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20221205 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230228 |
|
A601 | Written request for extension of time |
Free format text: JAPANESE INTERMEDIATE CODE: A601 Effective date: 20230427 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20230605 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20230705 |
|
RD02 | Notification of acceptance of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7422 Effective date: 20231027 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20231106 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A821 Effective date: 20231101 |
|
RD04 | Notification of resignation of power of attorney |
Free format text: JAPANESE INTERMEDIATE CODE: A7424 Effective date: 20231101 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20240110 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20240206 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20240229 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 7448511 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |