CN101590235A - The composition and use thereof that contains calcium antagonist and vitamin B group - Google Patents
The composition and use thereof that contains calcium antagonist and vitamin B group Download PDFInfo
- Publication number
- CN101590235A CN101590235A CNA2008101142146A CN200810114214A CN101590235A CN 101590235 A CN101590235 A CN 101590235A CN A2008101142146 A CNA2008101142146 A CN A2008101142146A CN 200810114214 A CN200810114214 A CN 200810114214A CN 101590235 A CN101590235 A CN 101590235A
- Authority
- CN
- China
- Prior art keywords
- vitamin
- content
- group
- calcium antagonist
- amlodipine
- 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
- 229940127291 Calcium channel antagonist Drugs 0.000 title claims abstract description 37
- 239000000480 calcium channel blocker Substances 0.000 title claims abstract description 37
- 235000019156 vitamin B Nutrition 0.000 title claims abstract description 36
- 239000011720 vitamin B Substances 0.000 title claims abstract description 36
- 229930003270 Vitamin B Natural products 0.000 title claims abstract description 35
- 239000000203 mixture Substances 0.000 title claims abstract description 29
- FFFHZYDWPBMWHY-VKHMYHEASA-N L-homocysteine Chemical compound OC(=O)[C@@H](N)CCS FFFHZYDWPBMWHY-VKHMYHEASA-N 0.000 claims abstract description 71
- 239000003814 drug Substances 0.000 claims abstract description 28
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 22
- 238000002360 preparation method Methods 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 11
- 230000000630 rising effect Effects 0.000 claims abstract description 8
- OVBPIULPVIDEAO-LBPRGKRZSA-N folic acid Chemical compound C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-LBPRGKRZSA-N 0.000 claims description 80
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 claims description 45
- 235000019152 folic acid Nutrition 0.000 claims description 43
- 239000011724 folic acid Substances 0.000 claims description 43
- HTIQEAQVCYTUBX-UHFFFAOYSA-N amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-UHFFFAOYSA-N 0.000 claims description 42
- 229960000528 amlodipine Drugs 0.000 claims description 42
- OVBPIULPVIDEAO-UHFFFAOYSA-N N-Pteroyl-L-glutaminsaeure Natural products C=1N=C2NC(N)=NC(=O)C2=NC=1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 OVBPIULPVIDEAO-UHFFFAOYSA-N 0.000 claims description 36
- 229960000304 folic acid Drugs 0.000 claims description 36
- 229930003779 Vitamin B12 Natural products 0.000 claims description 30
- 235000019163 vitamin B12 Nutrition 0.000 claims description 30
- 239000011715 vitamin B12 Substances 0.000 claims description 30
- RADKZDMFGJYCBB-UHFFFAOYSA-N pyridoxal hydrochloride Natural products CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 claims description 23
- -1 wherein Chemical compound 0.000 claims description 23
- 239000002775 capsule Substances 0.000 claims description 22
- 235000019158 vitamin B6 Nutrition 0.000 claims description 22
- 239000011726 vitamin B6 Substances 0.000 claims description 22
- 229940011671 vitamin b6 Drugs 0.000 claims description 22
- HYIMSNHJOBLJNT-UHFFFAOYSA-N nifedipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1[N+]([O-])=O HYIMSNHJOBLJNT-UHFFFAOYSA-N 0.000 claims description 21
- 229960001597 nifedipine Drugs 0.000 claims description 21
- 229960004340 lacidipine Drugs 0.000 claims description 18
- GKQPCPXONLDCMU-CCEZHUSRSA-N lacidipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1C1=CC=CC=C1\C=C\C(=O)OC(C)(C)C GKQPCPXONLDCMU-CCEZHUSRSA-N 0.000 claims description 18
- 239000003826 tablet Substances 0.000 claims description 16
- HTIQEAQVCYTUBX-KRWDZBQOSA-N (S)-amlodipine Chemical compound CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC=C1Cl HTIQEAQVCYTUBX-KRWDZBQOSA-N 0.000 claims description 11
- 229950008554 levamlodipine Drugs 0.000 claims description 11
- 239000002552 dosage form Substances 0.000 claims description 9
- HMJIYCCIJYRONP-UHFFFAOYSA-N (+-)-Isradipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC2=NON=C12 HMJIYCCIJYRONP-UHFFFAOYSA-N 0.000 claims description 8
- RZTAMFZIAATZDJ-HNNXBMFYSA-N 5-o-ethyl 3-o-methyl (4s)-4-(2,3-dichlorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC(Cl)=C1Cl RZTAMFZIAATZDJ-HNNXBMFYSA-N 0.000 claims description 8
- ZBBHBTPTTSWHBA-UHFFFAOYSA-N Nicardipine Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN(C)CC=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZBBHBTPTTSWHBA-UHFFFAOYSA-N 0.000 claims description 8
- 238000013270 controlled release Methods 0.000 claims description 8
- 229960003580 felodipine Drugs 0.000 claims description 8
- 229960004427 isradipine Drugs 0.000 claims description 8
- 229960001783 nicardipine Drugs 0.000 claims description 8
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 7
- PVHUJELLJLJGLN-INIZCTEOSA-N (S)-nitrendipine Chemical compound CCOC(=O)C1=C(C)NC(C)=C(C(=O)OC)[C@@H]1C1=CC=CC([N+]([O-])=O)=C1 PVHUJELLJLJGLN-INIZCTEOSA-N 0.000 claims description 7
- 239000008187 granular material Substances 0.000 claims description 7
- 229960005425 nitrendipine Drugs 0.000 claims description 7
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 6
- 229960002992 barnidipine Drugs 0.000 claims description 6
- VXMOONUMYLCFJD-DHLKQENFSA-N barnidipine Chemical compound C1([C@@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@@H]2CN(CC=3C=CC=CC=3)CC2)=CC=CC([N+]([O-])=O)=C1 VXMOONUMYLCFJD-DHLKQENFSA-N 0.000 claims description 6
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical compound C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 6
- 229960004166 diltiazem Drugs 0.000 claims description 6
- 239000012528 membrane Substances 0.000 claims description 6
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 claims description 6
- 229960000227 nisoldipine Drugs 0.000 claims description 6
- 229960001722 verapamil Drugs 0.000 claims description 6
- GHOKWGTUZJEAQD-ZETCQYMHSA-N (D)-(+)-Pantothenic acid Chemical compound OCC(C)(C)[C@@H](O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-ZETCQYMHSA-N 0.000 claims description 5
- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 claims description 4
- ZKFQEACEUNWPMT-UHFFFAOYSA-N Azelnidipine Chemical compound CC(C)OC(=O)C1=C(C)NC(N)=C(C(=O)OC2CN(C2)C(C=2C=CC=CC=2)C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 ZKFQEACEUNWPMT-UHFFFAOYSA-N 0.000 claims description 4
- KJEBULYHNRNJTE-DHZHZOJOSA-N Cinalong Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC\C=C\C=2C=CC=CC=2)C1C1=CC=CC([N+]([O-])=O)=C1 KJEBULYHNRNJTE-DHZHZOJOSA-N 0.000 claims description 4
- FAIIFDPAEUKBEP-UHFFFAOYSA-N Nilvadipine Chemical compound COC(=O)C1=C(C#N)NC(C)=C(C(=O)OC(C)C)C1C1=CC=CC([N+]([O-])=O)=C1 FAIIFDPAEUKBEP-UHFFFAOYSA-N 0.000 claims description 4
- 229950004646 azelnidipine Drugs 0.000 claims description 4
- 229960003020 cilnidipine Drugs 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 4
- VZWXXKDFACOXNT-UHFFFAOYSA-N niludipine Chemical compound CCCOCCOC(=O)C1=C(C)NC(C)=C(C(=O)OCCOCCC)C1C1=CC=CC([N+]([O-])=O)=C1 VZWXXKDFACOXNT-UHFFFAOYSA-N 0.000 claims description 4
- 229950000109 niludipine Drugs 0.000 claims description 4
- 229960005366 nilvadipine Drugs 0.000 claims description 4
- 229960000715 nimodipine Drugs 0.000 claims description 4
- GHOKWGTUZJEAQD-UHFFFAOYSA-N Chick antidermatitis factor Natural products OCC(C)(C)C(O)C(=O)NCCC(O)=O GHOKWGTUZJEAQD-UHFFFAOYSA-N 0.000 claims description 3
- AUNGANRZJHBGPY-UHFFFAOYSA-N D-Lyxoflavin Natural products OCC(O)C(O)C(O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-UHFFFAOYSA-N 0.000 claims description 3
- AUNGANRZJHBGPY-SCRDCRAPSA-N Riboflavin Chemical compound OC[C@@H](O)[C@@H](O)[C@@H](O)CN1C=2C=C(C)C(C)=CC=2N=C2C1=NC(=O)NC2=O AUNGANRZJHBGPY-SCRDCRAPSA-N 0.000 claims description 3
- 229930003451 Vitamin B1 Natural products 0.000 claims description 3
- 229930003471 Vitamin B2 Natural products 0.000 claims description 3
- 239000007950 delayed release tablet Substances 0.000 claims description 3
- 239000007919 dispersible tablet Substances 0.000 claims description 3
- 239000007788 liquid Substances 0.000 claims description 3
- 239000007937 lozenge Substances 0.000 claims description 3
- 210000000214 mouth Anatomy 0.000 claims description 3
- 235000019161 pantothenic acid Nutrition 0.000 claims description 3
- 239000011713 pantothenic acid Substances 0.000 claims description 3
- 229960002477 riboflavin Drugs 0.000 claims description 3
- 229960003495 thiamine Drugs 0.000 claims description 3
- DPJRMOMPQZCRJU-UHFFFAOYSA-M thiamine hydrochloride Chemical compound Cl.[Cl-].CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N DPJRMOMPQZCRJU-UHFFFAOYSA-M 0.000 claims description 3
- 235000010374 vitamin B1 Nutrition 0.000 claims description 3
- 239000011691 vitamin B1 Substances 0.000 claims description 3
- 235000019164 vitamin B2 Nutrition 0.000 claims description 3
- 239000011716 vitamin B2 Substances 0.000 claims description 3
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 claims description 2
- 235000020958 biotin Nutrition 0.000 claims description 2
- 239000011616 biotin Substances 0.000 claims description 2
- 229960002685 biotin Drugs 0.000 claims description 2
- 229940055726 pantothenic acid Drugs 0.000 claims description 2
- 235000019160 vitamin B3 Nutrition 0.000 claims description 2
- 239000011708 vitamin B3 Substances 0.000 claims description 2
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(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+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 claims 6
- 230000006378 damage Effects 0.000 abstract description 6
- 230000009467 reduction Effects 0.000 abstract description 4
- 230000001225 therapeutic effect Effects 0.000 abstract description 3
- 229930003231 vitamin Natural products 0.000 abstract 1
- 235000013343 vitamin Nutrition 0.000 abstract 1
- 239000011782 vitamin Substances 0.000 abstract 1
- 229940088594 vitamin Drugs 0.000 abstract 1
- 150000003722 vitamin derivatives Chemical class 0.000 abstract 1
- 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 description 24
- 239000002671 adjuvant Substances 0.000 description 20
- 229920002472 Starch Polymers 0.000 description 18
- 239000008107 starch Substances 0.000 description 18
- 235000019698 starch Nutrition 0.000 description 18
- 239000000463 material Substances 0.000 description 16
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 15
- 239000001856 Ethyl cellulose Chemical class 0.000 description 14
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical class CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 14
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 14
- 229920001249 ethyl cellulose Chemical class 0.000 description 14
- 235000019325 ethyl cellulose Nutrition 0.000 description 14
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 14
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 14
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 150000001875 compounds Chemical class 0.000 description 13
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 12
- 239000008108 microcrystalline cellulose Substances 0.000 description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 description 12
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 10
- 150000003839 salts Chemical class 0.000 description 10
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 9
- 229940127292 dihydropyridine calcium channel blocker Drugs 0.000 description 9
- 229940079593 drug Drugs 0.000 description 9
- 239000002904 solvent Substances 0.000 description 9
- 230000000694 effects Effects 0.000 description 8
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 8
- 239000004925 Acrylic resin Chemical class 0.000 description 7
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 7
- 229940014144 folate Drugs 0.000 description 7
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical class OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 7
- 229960003943 hypromellose Drugs 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- XNGIFLGASWRNHJ-UHFFFAOYSA-N phthalic acid Chemical compound OC(=O)C1=CC=CC=C1C(O)=O XNGIFLGASWRNHJ-UHFFFAOYSA-N 0.000 description 7
- 210000002381 plasma Anatomy 0.000 description 7
- 238000011160 research Methods 0.000 description 7
- 239000011734 sodium Substances 0.000 description 7
- 229910052708 sodium Inorganic materials 0.000 description 7
- NIQCNGHVCWTJSM-UHFFFAOYSA-N Dimethyl phthalate Chemical compound COC(=O)C1=CC=CC=C1C(=O)OC NIQCNGHVCWTJSM-UHFFFAOYSA-N 0.000 description 6
- 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 6
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 6
- 239000011575 calcium Substances 0.000 description 6
- 125000002057 carboxymethyl group Chemical class [H]OC(=O)C([H])([H])[*] 0.000 description 6
- 229960000935 dehydrated alcohol Drugs 0.000 description 6
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 6
- 150000002148 esters Chemical class 0.000 description 6
- 210000002216 heart Anatomy 0.000 description 6
- 239000008101 lactose Substances 0.000 description 6
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 description 6
- 239000011780 sodium chloride Substances 0.000 description 6
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 6
- 125000003929 folic acid group Chemical group 0.000 description 5
- 229920002689 polyvinyl acetate Polymers 0.000 description 5
- 239000011118 polyvinyl acetate Substances 0.000 description 5
- 239000003361 porogen Substances 0.000 description 5
- 208000024172 Cardiovascular disease Diseases 0.000 description 4
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 4
- 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 4
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 4
- 229930195725 Mannitol Natural products 0.000 description 4
- 239000002202 Polyethylene glycol Substances 0.000 description 4
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 235000021355 Stearic acid Nutrition 0.000 description 4
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 4
- 239000002253 acid Substances 0.000 description 4
- 235000010443 alginic acid Nutrition 0.000 description 4
- 229920000615 alginic acid Polymers 0.000 description 4
- 239000000783 alginic acid Substances 0.000 description 4
- 229960001126 alginic acid Drugs 0.000 description 4
- 150000004781 alginic acids Chemical class 0.000 description 4
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 4
- MTHSVFCYNBDYFN-UHFFFAOYSA-N diethylene glycol Chemical compound OCCOCCO MTHSVFCYNBDYFN-UHFFFAOYSA-N 0.000 description 4
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 4
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 4
- 230000000302 ischemic effect Effects 0.000 description 4
- 239000000594 mannitol Substances 0.000 description 4
- 235000010355 mannitol Nutrition 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 4
- 239000004014 plasticizer Substances 0.000 description 4
- 229920001223 polyethylene glycol Polymers 0.000 description 4
- 239000011347 resin Substances 0.000 description 4
- 229920005989 resin Polymers 0.000 description 4
- 201000000980 schizophrenia Diseases 0.000 description 4
- 235000010265 sodium sulphite Nutrition 0.000 description 4
- 239000008117 stearic acid Substances 0.000 description 4
- ZEMPKEQAKRGZGQ-AAKVHIHISA-N 2,3-bis[[(z)-12-hydroxyoctadec-9-enoyl]oxy]propyl (z)-12-hydroxyoctadec-9-enoate Chemical compound CCCCCCC(O)C\C=C/CCCCCCCC(=O)OCC(OC(=O)CCCCCCC\C=C/CC(O)CCCCCC)COC(=O)CCCCCCC\C=C/CC(O)CCCCCC ZEMPKEQAKRGZGQ-AAKVHIHISA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- 206010008190 Cerebrovascular accident Diseases 0.000 description 3
- 206010051055 Deep vein thrombosis Diseases 0.000 description 3
- 206010012289 Dementia Diseases 0.000 description 3
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 3
- 229920003136 Eudragit® L polymer Polymers 0.000 description 3
- 229920003137 Eudragit® S polymer Polymers 0.000 description 3
- 206010020772 Hypertension Diseases 0.000 description 3
- 239000008118 PEG 6000 Substances 0.000 description 3
- 208000018737 Parkinson disease Diseases 0.000 description 3
- 229920002584 Polyethylene Glycol 6000 Polymers 0.000 description 3
- 239000004820 Pressure-sensitive adhesive Substances 0.000 description 3
- 208000006011 Stroke Diseases 0.000 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 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 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 230000009286 beneficial effect Effects 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 230000001149 cognitive effect Effects 0.000 description 3
- XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 description 3
- 235000018417 cysteine Nutrition 0.000 description 3
- 229940099371 diacetylated monoglycerides Drugs 0.000 description 3
- 238000003745 diagnosis Methods 0.000 description 3
- FBSAITBEAPNWJG-UHFFFAOYSA-N dimethyl phthalate Natural products CC(=O)OC1=CC=CC=C1OC(C)=O FBSAITBEAPNWJG-UHFFFAOYSA-N 0.000 description 3
- 229960001826 dimethylphthalate Drugs 0.000 description 3
- 239000003937 drug carrier Substances 0.000 description 3
- 235000013773 glyceryl triacetate Nutrition 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 239000005720 sucrose Substances 0.000 description 3
- 229960002622 triacetin Drugs 0.000 description 3
- 239000001069 triethyl citrate Substances 0.000 description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 3
- 235000013769 triethyl citrate Nutrition 0.000 description 3
- 229940082632 vitamin b12 and folic acid Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- 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 2
- 208000024827 Alzheimer disease Diseases 0.000 description 2
- 206010002383 Angina Pectoris Diseases 0.000 description 2
- 108090000312 Calcium Channels Proteins 0.000 description 2
- 102000003922 Calcium Channels Human genes 0.000 description 2
- 108091006146 Channels Proteins 0.000 description 2
- SFSJZXMDTNDWIX-YFKPBYRVSA-N L-homomethionine Chemical compound CSCCC[C@H](N)C(O)=O SFSJZXMDTNDWIX-YFKPBYRVSA-N 0.000 description 2
- FFEARJCKVFRZRR-BYPYZUCNSA-N L-methionine Chemical compound CSCC[C@H](N)C(O)=O FFEARJCKVFRZRR-BYPYZUCNSA-N 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241001597008 Nomeidae Species 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 239000004698 Polyethylene Substances 0.000 description 2
- 239000004743 Polypropylene Substances 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 241000700159 Rattus Species 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 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 2
- VREFGVBLTWBCJP-UHFFFAOYSA-N alprazolam Chemical compound C12=CC(Cl)=CC=C2N2C(C)=NN=C2CN=C1C1=CC=CC=C1 VREFGVBLTWBCJP-UHFFFAOYSA-N 0.000 description 2
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 description 2
- 210000000709 aorta Anatomy 0.000 description 2
- 206010003119 arrhythmia Diseases 0.000 description 2
- 230000006793 arrhythmia Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- 238000010241 blood sampling Methods 0.000 description 2
- 230000003925 brain function Effects 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 238000003759 clinical diagnosis Methods 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 230000003920 cognitive function Effects 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- RMRCNWBMXRMIRW-BYFNXCQMSA-M cyanocobalamin Chemical compound N#C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 RMRCNWBMXRMIRW-BYFNXCQMSA-M 0.000 description 2
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 230000006870 function Effects 0.000 description 2
- SFSJZXMDTNDWIX-UHFFFAOYSA-N homomethionine Natural products CSCCCC(N)C(O)=O SFSJZXMDTNDWIX-UHFFFAOYSA-N 0.000 description 2
- 230000001771 impaired effect Effects 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 239000002207 metabolite Substances 0.000 description 2
- 229930182817 methionine Natural products 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229920000573 polyethylene Polymers 0.000 description 2
- 229920001155 polypropylene Polymers 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 238000011552 rat model Methods 0.000 description 2
- 239000000080 wetting agent Substances 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OAJLVMGLJZXSGX-NDSREFPTSA-L (2r,3s,4s,5r)-2-(6-aminopurin-9-yl)-5-methanidyloxolane-3,4-diol;cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12 Chemical compound [Co+3].O[C@H]1[C@H](O)[C@@H]([CH2-])O[C@H]1N1C2=NC=NC(N)=C2N=C1.C1([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)[N-]\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 OAJLVMGLJZXSGX-NDSREFPTSA-L 0.000 description 1
- MSTNYGQPCMXVAQ-RYUDHWBXSA-N (6S)-5,6,7,8-tetrahydrofolic acid Chemical compound C([C@H]1CNC=2N=C(NC(=O)C=2N1)N)NC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 MSTNYGQPCMXVAQ-RYUDHWBXSA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical class CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- 229920000178 Acrylic resin Polymers 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- 240000001592 Amaranthus caudatus Species 0.000 description 1
- 235000009328 Amaranthus caudatus Nutrition 0.000 description 1
- 229920001661 Chitosan Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 241000207199 Citrus Species 0.000 description 1
- 235000005979 Citrus limon Nutrition 0.000 description 1
- 244000131522 Citrus pyriformis Species 0.000 description 1
- 206010056370 Congestive cardiomyopathy Diseases 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920000858 Cyclodextrin 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
- 235000000638 D-biotin Nutrition 0.000 description 1
- 239000011665 D-biotin Substances 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
- 108090000790 Enzymes Proteins 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 208000004248 Familial Primary Pulmonary Hypertension Diseases 0.000 description 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 208000008899 Habitual abortion Diseases 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 208000031226 Hyperlipidaemia Diseases 0.000 description 1
- 235000000177 Indigofera tinctoria Nutrition 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- XEEYBQQBJWHFJM-UHFFFAOYSA-N Iron Chemical compound [Fe] XEEYBQQBJWHFJM-UHFFFAOYSA-N 0.000 description 1
- VTAJIXDZFCRWBR-UHFFFAOYSA-N Licoricesaponin B2 Natural products C1C(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2)C(O)=O)C)(C)CC2)(C)C2C(C)(C)CC1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O VTAJIXDZFCRWBR-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- NRGONRDRXCPMIC-GDKBPFBDSA-N N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 Chemical class N1C=2C(=O)NC(N)=NC=2NCC1CNC1=CC=C(C(=O)N[C@@H](CC(C=O)C(O)=O)C(O)=O)C=C1 NRGONRDRXCPMIC-GDKBPFBDSA-N 0.000 description 1
- 206010029350 Neurotoxicity Diseases 0.000 description 1
- 241000233855 Orchidaceae Species 0.000 description 1
- 208000001132 Osteoporosis Diseases 0.000 description 1
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 1
- 229920001030 Polyethylene Glycol 4000 Polymers 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- 108010013381 Porins Proteins 0.000 description 1
- 102000017033 Porins Human genes 0.000 description 1
- 206010064911 Pulmonary arterial hypertension Diseases 0.000 description 1
- 102000054727 Serum Amyloid A Human genes 0.000 description 1
- 108700028909 Serum Amyloid A Proteins 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000004141 Sodium laurylsulphate Substances 0.000 description 1
- UEDUENGHJMELGK-HYDKPPNVSA-N Stevioside Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1O[C@]12C(=C)C[C@@]3(C1)CC[C@@H]1[C@@](C)(CCC[C@]1([C@@H]3CC2)C)C(=O)O[C@H]1[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O1)O)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O UEDUENGHJMELGK-HYDKPPNVSA-N 0.000 description 1
- 206010042434 Sudden death Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 206010044221 Toxic encephalopathy Diseases 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- 229930003571 Vitamin B5 Natural products 0.000 description 1
- 229930003756 Vitamin B7 Natural products 0.000 description 1
- 229930003761 Vitamin B9 Natural products 0.000 description 1
- 208000027418 Wounds and injury Diseases 0.000 description 1
- CGLXTBACLXZPED-UHFFFAOYSA-N [4-(aminomethyl)-5-(hydroxymethyl)-2-methylpyridin-3-yl] dihydrogen phosphate Chemical compound Cc1ncc(CO)c(CN)c1OP(O)(O)=O CGLXTBACLXZPED-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000001785 acacia senegal l. willd gum Substances 0.000 description 1
- 229940022682 acetone Drugs 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
- 230000008484 agonism Effects 0.000 description 1
- 230000001476 alcoholic effect Effects 0.000 description 1
- 239000005030 aluminium foil Substances 0.000 description 1
- 239000004178 amaranth Substances 0.000 description 1
- 235000012735 amaranth Nutrition 0.000 description 1
- 235000001014 amino acid Nutrition 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 230000002253 anti-ischaemic effect Effects 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- FAPWYRCQGJNNSJ-UBKPKTQASA-L calcium D-pantothenic acid Chemical compound [Ca+2].OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O.OCC(C)(C)[C@@H](O)C(=O)NCCC([O-])=O FAPWYRCQGJNNSJ-UBKPKTQASA-L 0.000 description 1
- 229960002079 calcium pantothenate Drugs 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000002327 cardiovascular agent Substances 0.000 description 1
- 229940125692 cardiovascular agent Drugs 0.000 description 1
- 235000012730 carminic acid Nutrition 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 230000004663 cell proliferation Effects 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 235000020971 citrus fruits Nutrition 0.000 description 1
- 208000010877 cognitive disease Diseases 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 230000008602 contraction Effects 0.000 description 1
- 230000001276 controlling effect Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 208000029078 coronary artery disease Diseases 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 230000001086 cytosolic effect Effects 0.000 description 1
- 230000003013 cytotoxicity Effects 0.000 description 1
- 231100000135 cytotoxicity Toxicity 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 230000002950 deficient Effects 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 201000011304 dilated cardiomyopathy 1A Diseases 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 239000002702 enteric coating Substances 0.000 description 1
- 238000009505 enteric coating Methods 0.000 description 1
- 229960004756 ethanol Drugs 0.000 description 1
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 1
- 229960004667 ethyl cellulose Drugs 0.000 description 1
- 239000005038 ethylene vinyl acetate Substances 0.000 description 1
- 229940044949 eucalyptus oil Drugs 0.000 description 1
- 239000010642 eucalyptus oil Substances 0.000 description 1
- 230000003203 everyday effect Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 230000003480 fibrinolytic effect Effects 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
- 239000008103 glucose Substances 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- 239000001685 glycyrrhizic acid Substances 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- YOZNUFWCRFCGIH-BYFNXCQMSA-L hydroxocobalamin Chemical compound O[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 YOZNUFWCRFCGIH-BYFNXCQMSA-L 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229940071826 hydroxyethyl cellulose Drugs 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000001969 hypertrophic effect Effects 0.000 description 1
- 229940097275 indigo Drugs 0.000 description 1
- COHYTHOBJLSHDF-UHFFFAOYSA-N indigo powder Natural products N1C2=CC=CC=C2C(=O)C1=C1C(=O)C2=CC=CC=C2N1 COHYTHOBJLSHDF-UHFFFAOYSA-N 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 230000003834 intracellular effect Effects 0.000 description 1
- 239000010977 jade Substances 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 230000003907 kidney function Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229960005321 mecobalamin Drugs 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 229960002900 methylcellulose Drugs 0.000 description 1
- 235000007672 methylcobalamin Nutrition 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- JEWJRMKHSMTXPP-BYFNXCQMSA-M methylcobalamin Chemical compound C[Co+]N([C@]1([H])[C@H](CC(N)=O)[C@]\2(CCC(=O)NC[C@H](C)OP(O)(=O)OC3[C@H]([C@H](O[C@@H]3CO)N3C4=CC(C)=C(C)C=C4N=C3)O)C)C/2=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 JEWJRMKHSMTXPP-BYFNXCQMSA-M 0.000 description 1
- 239000003094 microcapsule Substances 0.000 description 1
- 230000004089 microcirculation Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 210000000107 myocyte Anatomy 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 230000007135 neurotoxicity Effects 0.000 description 1
- 231100000228 neurotoxicity Toxicity 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000019198 oils Nutrition 0.000 description 1
- 229940014662 pantothenate Drugs 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 230000036513 peripheral conductance Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229960000502 poloxamer Drugs 0.000 description 1
- 229920001983 poloxamer Polymers 0.000 description 1
- 229920001200 poly(ethylene-vinyl acetate) Polymers 0.000 description 1
- 229920002401 polyacrylamide Polymers 0.000 description 1
- 229920001083 polybutene Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 201000008312 primary pulmonary hypertension Diseases 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- NGVDGCNFYWLIFO-UHFFFAOYSA-N pyridoxal 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(C=O)=C1O NGVDGCNFYWLIFO-UHFFFAOYSA-N 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 230000011506 response to oxidative stress Effects 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 239000002002 slurry Substances 0.000 description 1
- 230000000391 smoking effect Effects 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 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
- 239000007779 soft material Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- OHHNJQXIOPOJSC-UHFFFAOYSA-N stevioside Natural products CC1(CCCC2(C)C3(C)CCC4(CC3(CCC12C)CC4=C)OC5OC(CO)C(O)C(O)C5OC6OC(CO)C(O)C(O)C6O)C(=O)OC7OC(CO)C(O)C(O)C7O OHHNJQXIOPOJSC-UHFFFAOYSA-N 0.000 description 1
- 229940013618 stevioside Drugs 0.000 description 1
- 235000019202 steviosides Nutrition 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000005460 tetrahydrofolate Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- BAZVSMNPJJMILC-UHFFFAOYSA-N triadimenol Chemical compound C1=NC=NN1C(C(O)C(C)(C)C)OC1=CC=C(Cl)C=C1 BAZVSMNPJJMILC-UHFFFAOYSA-N 0.000 description 1
- 210000004509 vascular smooth muscle cell Anatomy 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 235000015112 vegetable and seed oil Nutrition 0.000 description 1
- 235000009492 vitamin B5 Nutrition 0.000 description 1
- 239000011675 vitamin B5 Substances 0.000 description 1
- 235000011912 vitamin B7 Nutrition 0.000 description 1
- 239000011735 vitamin B7 Substances 0.000 description 1
- 235000019159 vitamin B9 Nutrition 0.000 description 1
- 239000011727 vitamin B9 Substances 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The present invention relates to contain the pharmaceutical composition and the purposes in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease thereof of calcium antagonist and B group vitamin.Calcium antagonist and vitamin B group share and can further reduce the Hcy level, are better than list and use medicine, show that calcium antagonist class medicine and vitamin B group share the level at reduction Hcy, have synergism thereby alleviate in the Hcy damage.Compositions innovation and creation provided by the invention are selections that treatment Hcy raises, for the treatment of homocysteine provides more effective therapeutic scheme.The invention belongs to pharmaceutical field.
Description
Technical field
The present invention relates to contain the pharmaceutical composition and the purposes in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease thereof of calcium antagonist and vitamin B group.Belong to pharmaceutical field.
Background technology
As far back as people in 1969 hypothesis is just proposed, think homocysteine (Hcy, a kind of sulfur-containing amino acid) may be the risk factor of cardiovascular disease, since then, there is big quantity research to accumulate objective evidence, thinks that Plasma Homocysteine and cardiovascular disease (CVD) and other systemic disease occurrence risk are closely related.
A large amount of dissimilar studies confirm that, Plasma Homocysteine is independent of conventional risk factors such as hypertension, hyperlipidemia, the Hcy 5 μ mol/L that raise, the apoplexy risk increases by 59% (OR, 1.59; 95%CI, 1.30-1.95), the deep venous thrombosis risk increases by 60% (OR, 1.60; 95%CI, 1.15-2.22), ischemic heart desease (comprising coronary heart disease, angina pectoris, arrhythmia, heart infarction, heart failure and sudden death) risk increases by 33% (OR, 1.33; 95%CI, 1.22-1.46); And Hcy reduces by 3 μ mol/L, and the apoplexy risk reduces by 24%, and the deep venous thrombosis risk reduces by 25%, and the ischemic heart desease risk reduces by 16%.Show Hcy and ischemic heart desease, apoplexy, deep venous thrombosis all closely related [Wald DS, et al.Homocysteine and cardiovascular disease:evidence on causality from ameta-analysis.BMJ.2002; 325:1202-1206.].The mechanism of the body injury that high Hcy mass formed by blood stasis causes it is generally acknowledged and response to oxidative stress, the blood coagulation of destruction body and fibrinolytic between balance, cause that vascular smooth muscle cell proliferation and direct cytotoxicity are relevant.
High Hcy except in CVD develops, playing an important role, also and other diseases such as Alzheimer (Alzheimer ' s disease, AD), cognitive dysfunction, dementia (Clarke et al.1998; Morris, 2003), osteoporosis (Verhoef ﹠amp; De Groot, 2005), depression, parkinson disease (PD), schizophrenia, death, the neonate defective, multiple disease such as habitual abortion is closely related.
Since the nineties in 20th century, the high Hcy of a large amount of report prompting blood plasma and brain function go down and the generation of AD relevant.The blood Hcy level that studies show that AD patient in a large number is higher than normally.1998 by people such as Clarke [Clarke R, et al.Folate, vitamin B12, and serum total homocysteine levels in confirmed Alzheimerdisease.Arch Neurol.1998; 55:1449-1455.] being AD to 164 clinical diagnosises more than 55 years old, the patient has carried out comparative study with 148 similar old peoples of age.The result shows, AD patient's Cambridge cognitive competence is checked (the Cambri dge Cognitive Examination, CAMCOG) scoring and simple and easy mental status examination (mini-mental state examination, MMSE) scoring significantly is lower than matched group, and the Plasma Hcy level significantly increases; The maximum characteristics of this research are to have 76 patients to make a definite diagnosis in after death obtaining the histology in the case, the difference of Hcy concentration more remarkable than 164 clinical diagnosis patients between AD patient after making a definite diagnosis and the contrast; There are some researches show the every rising 5mmol/L of Hcy, the danger of suffering from AD just increases by 40%, and thinks and the diagnosis of the Hcy level before 8 years and dementia and AD can be interrelated at least; Postrglion[Postiglione A, et al.Plasma folate, vitamin B12, and totalhomocysteine tetrahydrofolate reducase gene in patients with Alzheimer ' sdementia.A case-control study.Gerontolgy, 2001; 47:324-349.] etc. the people studies confirm that AD patient not only has higher Plasma Hcy level, its course of disease progress also is directly proportional with Hcy, therefore thinks that the Hcy mass formed by blood stasis not only be the independent hazard factor of AD, more develop with its course of disease and the order of severity relevant.More have research to think, the Hcy level can be used as and is independent of beyond age, sex, education degree, renal function, vitamin B6 level, smoking history and the hypertension and self-existent cognitive competence on the horizon descended and the predictive factors of decline degree.Hcy possible mechanism of action in AD, dementia or cognitive function are impaired: Hcy is to neuronic direct infringement; Strengthen the neurotoxicity of amyloid A β; Influence brain function etc. by the infringement microcirculation.
There is research [OpSuilleabhain PE, et al.Arch Neurol, 2004,61:865.] to show that depression takes place the PD patient of high Hcy and Cognitive function damage is tighter.The research that Susser etc. carry out is schizophrenia group and matched group homocysteine level relatively, and they are divided into normal folate level group and low folate level group, found that two groups there were significant differences in low folate level.Prompting supports that there is homocysteine metabolic imbalance hypothesis [Susser E in schizophrenia thus, etal.Lindenbaum J:Schizophrenia and impaired homocysteine metabolism:a possibleassociation[J] .Biol Psychiatry 1998,44:141].Gonzalez S etc. studies show that, in the old people of no any chronic disease, high Hcy and its death closely related [Gonzalez S, et al.Homocysteineincrease the risk of mortality in elderly individuals.BJN.2007; 1-7].
It is generally acknowledged that the infringement that the Hcy level causes with it is proportionate, do not have a tangible dangerous decomposition point.The external about 8-10 μ of Hcy level mol/L.Hughes et al[J Epidemiol Community Health.2000; 54 (1): 31-34.] find, Chinese male Hcy average out to 15.3 μ mol/L, the women is 12.2 μ mol/L.If with blood plasma tHcy＞14 μ mol/L is criterion, the high tHcy incidence rate of Chinese male is 57%, and the women is 31%.Hao et al[J Nutr2007; 137:407-13] research also show that the high Hcy incidence rate of Chinese population is higher.Show that high Hcy is extensive China morbidity crowd, cause important social danger.
Main at present use vitamin B group reduces Hcy.A meta the analysis showed that folic acid is less than 1mg/d (average 0.5mg), and 1-3mg/d (average 1.2mg) is greater than the therapeutic equivalence [BMJ.1998 of 3mg/d (average 5.7mg) reduction Hcy; 316:894-898].
Calcium antagonist claims calcium channel blocker again, can suppress to stride film Ca
2+Interior stream and/or intracellular Ca
2+Discharge, reduce Cytoplasmic Ca
2+Concentration and utilization rate thereof suppress the activity of ATP enzyme, reduce myocardial contraction, make that the myocyte is lax, vasodilation, reduce peripheral vascular resistance, thereby blood pressure is reduced.Calcium antagonist is used for the treatment of angina pectoris, hypertension, arrhythmia, congestive cardiomyopathy and ischemic heart desease etc. clinically.Can be used for primary pulmonary hypertension, cerebral infarction, hypertrophic neuropathy etc. in addition, is the widely used cardiovascular drugs of a class.Dihydropyridine type calcium antagonists is selectivity Ca
2+The channel blocking medicine, its significant feature position is at the porin (dihydropyridines point position) in voltage dependent form passage (PDC), regulating and controlling voltage type passage (VOC) and receptor agonism type passage (ROC) outside and the α l subunit (dihydropyridines responsive type) of L type PDC, its exercising result is to make calcium channel exempt to be activated or gate can not be opened, reduce open calcium channel number, retardance Ca
2+Enter in the cell, and correspondingly show Ca at heart, kidney, blood vessel, smooth muscle etc.
2+The channel blocking effect.Dihydropyridine type calcium antagonists comprises nifedipine (nifedipine), amlodipine (amlodipine), Levamlodipine, nimodipine (nimodipine), nicardipine (nicardipine), lacidipine (lacidipine), nisoldipine (nisoldipine), nitrendipine (nitrendipine), felodipine (felodipine), nilvadipine (nilvadipine), isradipine (isradipine), barnidipine (barnidipine), cilnidipine (cilnidipine), niludipine (niludipine), azelnidipine (azelnidipine) etc.United States Patent (USP) 4572909 discloses amlodipine and relevant dihydropyridine compound thereof, and they are effective anti-ischemic and antihypertensive.United States Patent (USP) 4879303 discloses amlodipine benzenesulphonate.Amlodipine benzenesulphonate is at present with trade name
Sell.Nicardipine, nicardipine hydrochlorate are effective dihydropyridine type calcium antagonists.Barnidipine, barnidipine hydrochlorate are effective dihydropyridine type calcium antagonists.Nifedipine has following structural formula.
Summary of the invention
The objective of the invention is to overcome the deficiency of existing medicine when the high Hcy of treatment, a kind of pharmaceutical composition and purposes in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease thereof that contains calcium antagonist and vitamin B group is provided.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition comprises:
(1) one or more in the calcium antagonist of pharmaceutical dosage, calcium antagonist isomer, calcium antagonist activity metabolite or the calcium antagonist officinal salt;
(2) one or more in the vitamin B group of pharmaceutical dosage; And
(3) acceptable carrier on the pharmaceutics.
In compositions provided by the invention, described calcium antagonist comprises dihydropyridine type calcium antagonists and non-dihydropyridine type calcium antagonists, preferred dihydropyridine type calcium antagonists.Dihydropyridine type calcium antagonists comprises nifedipine, amlodipine, Levamlodipine, nimodipine, nicardipine, lacidipine, nisoldipine, nitrendipine, felodipine, nilvadipine, isradipine, barnidipine, cilnidipine, niludipine, azelnidipine, preferred nifedipine, amlodipine, Levamlodipine, nitrendipine are more preferably amlodipine, Levamlodipine, lacidipine and nifedipine; Non-dihydropyridine type calcium antagonists comprises diltiazem, verapamil etc.Wherein, nifedipine content is that 20-120mg, amlodipine content are that 2.5-20mg, Levamlodipine content are that 2.5-10mg, nicardipine content are that 30-240mg, lacidipine content are that 2-8mg, nisoldipine content are that 5-60mg, nitrendipine content are that 10-60mg, felodipine content are that 2.5-40mg, isradipine content are that 2.5-20mg, diltiazem content are that 30-240mg, verapamil content are 40-480mg.The better content of said medicine is respectively: nifedipine 20-60mg, amlodipine 2.5-10mg, Levamlodipine 2.5-5mg, nicardipine 60-120mg, lacidipine 4-6mg, nisoldipine 10-60mg, nitrendipine 20-60mg, felodipine 2.5-20mg, isradipine 2.5-10mg, diltiazem 90-240mg, verapamil 80-360mg, the isomer of above-mentioned substance, active metabolite or its officinal salt content can be tried to achieve according to of equal value conversion of above-mentioned substance.
In compositions provided by the invention, described vitamin B group comprises vitamin B1 (vitamin B1), vitamin B2 (vitamin B2), vitamin PP, vitamin B6 (vitamin B6), vitamin B12 (vitamin B12), biotin (D-biotin, vitamin H), folic acid (folic acid, vitamin B9) and pantothenic acid (pantothenate, vitamin B5) etc.
In compositions provided by the invention, one or both in described vitamin B group preferred vitamin B12, the vitamin B6.Further comprise folic acid.Wherein, vitamin B12 comprises the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and other cobalamine and can discharge/generate the material of cobalamine in vivo.Vitamin B6 comprises the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and can discharge/generate the material of this compounds in vivo.Folic acid comprises the active metabolite of formyl tetrahydrofolic acid, L-methopterin, folate, folic acid or folate and can discharge/generate the material of folic acid in vivo.
According to the present invention, the content of described vitamin B12 is 1 μ g～2mg, and the content of vitamin B6 is 0.5～50mg.The content of folic acid is 0.2～15mg.Its better content is: vitamin B12 1 μ g～0.25mg, vitamin B6 1～50mg, folic acid 0.2～5mg.Wherein folic acid is treated preferred 0.4mg of effective dose or 0.8mg.
According to the present invention, described vitamin B group is a vitamin B12, and content is 1 μ g～2mg, preferred 1 μ g～0.25mg.
In compositions of the present invention, the component of preferred following content is as active component:
Calcium antagonist is an amlodipine, and vitamin B group is a vitamin B6; Wherein the content of amlodipine is 2.5-10mg, and the content of vitamin B6 is 5-50mg; Or
Calcium antagonist is an amlodipine, and vitamin B group is vitamin B12 and folic acid; Wherein the content of amlodipine is 2.5-10mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of folic acid is 0.2～5mg; Or
Calcium antagonist is an amlodipine, and vitamin B group is a vitamin B12; Wherein the content of amlodipine is 2.5-10mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg; Or
Calcium antagonist is an amlodipine, and vitamin B group is vitamin B12, vitamin B6 and folic acid; Wherein the content of amlodipine is 2.5-10mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of vitamin B6 is 5-50mg, the content of folic acid is 0.2～5mg; Or
Calcium antagonist is a nifedipine, and vitamin B group is a vitamin B6; Wherein the content of nifedipine is 20-60mg, and the content of vitamin B6 is 5-50mg; Or
Calcium antagonist is a nifedipine, and vitamin B group is vitamin B12 and folic acid; Wherein the content of nifedipine is 20-60mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of folic acid is 0.2～5mg; Or
Calcium antagonist is a nifedipine, and vitamin B group is a vitamin B12; Wherein the content of nifedipine is 20-60mg, and the content of vitamin B12 is 0.25-2mg, preferred 1 μ g～0.25mg; Or
Calcium antagonist is a nifedipine, and vitamin B group is vitamin B12, vitamin B6 and folic acid; Wherein the content of nifedipine is 20-60mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of vitamin B6 is 5-50mg, the content of folic acid is 0.2～5mg; Or
Calcium antagonist is a lacidipine, and vitamin B group is a vitamin B6; Wherein the content of lacidipine is 2-8mg, and the content of vitamin B6 is 5-50mg; Or
Calcium antagonist is a lacidipine, and vitamin B group is vitamin B12 and folic acid; Wherein the content of lacidipine is 2-8mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of folic acid is 0.2～5mg; Or
Calcium antagonist is a lacidipine, and vitamin B group is a vitamin B12; Wherein the content of lacidipine is 2-8mg, and the content of vitamin B12 is 0.25-2mg, preferred 1 μ g～0.25mg; Or
Calcium antagonist is a lacidipine, and vitamin B group is vitamin B12, vitamin B6 and folic acid; Wherein the content of lacidipine is 2-8mg, and the content of vitamin B12 is 1 μ g～2mg, preferred 1 μ g～0.25mg, and the content of vitamin B6 is 5-50mg, the content of folic acid is 0.2～5mg.
Among the present invention, described various content of medicines are the dosage of every day.
According to the present invention, active component in the pharmaceutical composition is the solvent in the compositions, one of them active component comes from a kind of in the calcium antagonist, another active component is from one or more vitamin B group, the dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/the position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, oral liquid, membrane or patch, what should particularly point out is that the pharmaceutical composition that will contain calcium antagonist and vitamin B group is made tablet or capsule.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutically suitable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc. belongs to this area general knowledge.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing preparation, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is that the solubility/insoluble salt of hydroxypropyl methylcellulose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid and/or ethyl cellulose and/or other play the adjuvant of slow releasing function, the hypromellose employing includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and polyacrylic resin adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release preparation, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose, chitosan, sodium alginate, methylcellulose, ethyl cellulose, starch slurry, arabic gum, gelatin, sucrose, polyvinyl alcohol etc.; Wetting agent can adopt the ethanol-water solution of dehydrated alcohol, water, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt natural pigment such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide and synthetic dyestuff or the like; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose acetic acid succinate, beautiful jade Cellulose Acetate Phthalate, poly-phthalic acid vinyl acetate cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.
Also contain the pharmaceutics acceptable carrier in the said composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc.; Comprise excipient and adjuvant etc.Described excipient and adjuvant have mannitol, sorbitol, maltose alcohol, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar, cyclodextrin, glycyrrhizic acid, stevioside, citric acid, Oleum menthae, eucalyptus oil, Oleum Caryophylli, Fructus Citri Limoniae oil, citrus seed oil and some other correctives that wraps up with microcapsule etc.
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into enteric coatel tablets or enteric coated capsule etc.; comprise excipient and adjuvant etc.; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc.; enteric-coating material comprises: Lac; the cellulose acetate phthalate ester; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into delayed-release tablet or timing (position) releasing piece; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., described coating material that postpones release or regularly (position) release comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen (as PEGi000; PEG4000; various medicaments adjuvant such as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).
Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into dosage forms such as granule, oral liquid, membrane, patch.Described pharmaceutically acceptable carrier includes excipient and the adjuvant that helps reactive compound is mixed with pharmaceutical formulation when making the patch membrane; as polyvinyl alcohol, Triafol T, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone, polyacrylamide, polybutene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc.; and back lining materials such as polrvinyl chloride, polyethylene, aluminium foil, polypropylene, polyester, the compositions of one or more materials of protecting film such as polyethylene, polystyrene, polypropylene etc.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in identical preparation, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions can mix and be present in the same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.The compound tablet of a kind of composition in a kind of and described vitamin B group in the preferred in the present invention described calcium antagonist class medicine.
Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in preparation inequality, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss that brings beneficial effect.If grant diseased individuals simultaneously, the chemical compound in the compositions independently exists with different dosage forms, and pharmaceutical composition also can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.
Another object of the present invention provides the purposes of pharmaceutical composition in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease that contains calcium antagonist and vitamin B group.
Beneficial effect of the present invention:
The at present clinical medicine that does not still have the rising of efficient treatment homocysteine, single with vitamin B group (folk prescription or compound recipe) unsatisfactory curative effect, do not reach certain degree owing to reduce the degree of Hcy, often unhelpful to terminal point; Calcium antagonist and vitamin B group share and can further reduce Hcy, thereby reduce the Hcy damage, have synergism, can solve the clinical blank of present treatment Hcy.
The present invention will be further described below in conjunction with the specific embodiment, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
Embodiment 1: preparation amlodipine VB12 sheet (1000)
Prescription is formed:
Amlodipine 5g
VB12 6mg
Starch 10g
Microcrystalline Cellulose 50g
Carboxymethyl starch sodium (CMSNa) 30g
10% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of
Magnesium stearate is an amount of
Preparation technology:
5g amlodipine, 6mgVB12,50g lactose, 50g microcrystalline Cellulose, 10g starch are pulverized, cross 120 mesh sieves, according to the equivalent method mix homogeneously that progressively increases, poly-ly make soft material for the ketone alcoholic solution with an amount of 10%, granulation, dry, granulate, with water content is about 3% granule and an amount of magnesium stearate mix homogeneously, makes 1000 according to a conventional method promptly.Embodiment 2: preparation amlodipine folic acid, VB12 sheet (1000)
Prescription is formed:
Amlodipine 10.0g
Folic acid 0.8g
VB12 0.1g
Starch 45.0g
Microcrystalline Cellulose 45.0g
Carboxymethyl starch sodium (CMSNa) 5.0g
5% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of
Magnesium stearate is an amount of
Preparation technology is with embodiment 1.
Embodiment 3: preparation amlodipine folic acid, VB12, VB6 sheet (1000)
Prescription is formed:
Amlodipine 10.0g
Folic acid 0.8g
VB12 0.1g
VB6 6.0g
Starch 45.0g
Microcrystalline Cellulose 45.0g
Carboxymethyl starch sodium (CMSNa) 5.0g
5% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of
Magnesium stearate is an amount of
Preparation technology is with embodiment 1.
Embodiment 4: preparation nifedipine folic acid VB12 capsule (1000)
Prescription is formed:
Nifedipine 30.0g
Folic acid 0.8g
VB12 0.1g
Lactose 30.0g
Microcrystalline Cellulose 15.0g
Starch 20.0g
Carboxymethyl starch sodium 5.0g
Magnesium stearate is an amount of
Preparation technology:
According to the prescription proportioning, get lactose, microcrystalline Cellulose, starch, carboxymethylstach sodium and in about 100 ℃, distinguish dry about 2 hours, cross 100 mesh sieves; With crude drug cross behind 100 mesh sieves with above-mentioned adjuvant by equivalent incremental method mix homogeneously, with No. 3 capsule fills.
Embodiment 5: preparation Levamlodipine folic acid VB12 capsule (1000)
Prescription is formed:
Levamlodipine 2.5g
Folic acid 0.8g
VB12 0.1g
Starch 10.0g
Microcrystalline Cellulose 50.0g
Carboxymethyl starch sodium (CMSNa) 30.0g
5% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of
Magnesium stearate is an amount of
Preparation technology is with embodiment 7.
Embodiment 6: amlodipine VB12 compound recipe is to the curative effect of high Hcy rat model
1, method
90 of 250～300g male rats are got in animal and high Hcy modelling, are divided into 6 groups at random, 15/group.Wherein 1 group gives normal feedstuff, and other groups give the feedstuff of homomethionin, continuous 12 weeks.
Each group of grouping and administration gives amlodipine (0.5mg/kg), amlodipine (1mg/kg), VB12 (0.01mg/kg), amlodipine+VB12 (0.5mg+0.01mg/kg) respectively, and all the other two group model groups and normal group give the equivalent normal saline respectively.In continuous 8 weeks, the mensuration of required index is carried out in the ventral aorta blood sampling after the last administration.
2, result
The result shows, compares with normal group, and methionine feed group Hcy all significantly raises.Amlodipine list medicine group does not make significant difference to Hcy, and the folic acid group all can significantly reduce the Hcy level; Amlodipine+folic acid group can significantly reduce the Hcy level, is better than list with amlodipine group and folic acid group, shows that the two has significant synergism on reduction Hcy.
Embodiment 7: amlodipine folic acid VB12 compound recipe is to the curative effect of high Hcy rat model
1, method
90 of 250～300g male rats are got in animal and high Hcy modelling, are divided into 6 groups at random, 15/group.Wherein 1 group gives normal feedstuff, and other groups give the feedstuff of homomethionin, continuous 12 weeks.
Each group of grouping and administration gives amlodipine (0.5mg/kg), amlodipine (1mg/kg), folic acid+VB12 (0.08mg+0.01mg/kg), amlodipine+folic acid+VB12 (0.5mg+0.08mg+0.01mg/kg) respectively, and all the other two group model groups and normal group give the equivalent normal saline respectively.In continuous 8 weeks, the mensuration of required index is carried out in the ventral aorta blood sampling after the last administration.
2, result
The result shows, compares with normal group, and methionine feed group Hcy all significantly raises.Amlodipine list medicine group does not make significant difference to Hcy, and folic acid+VB12 group all can significantly reduce the Hcy level; Amlodipine folic acid VB12 group also can significantly reduce the Hcy level, is better than list with amlodipine group and folic acid group, shows that amlodipine and vitamin B group have significant synergism on reduction Hcy.
It is the independent hazard factor of body that brief summary: Hcy raises, single at present unsatisfactory with folic acid or Compound B vitamin effect in the treatment of clinical high Hcy, the compound medicine of this invention can further reduce Hcy, thereby reduce the Hcy damage, to be better selection, for the treatment of homocysteine provides more effective therapeutic scheme.
Claims (10)
1. pharmaceutical composition for the treatment of hyperhomocysteinemiainjury or homocysteine rising disease comprises:
(1) calcium antagonist of pharmaceutical dosage;
(2) vitamin B group of pharmaceutical dosage; And
(3) acceptable carrier on the pharmaceutics;
Wherein, described calcium antagonist is selected from a kind of in nifedipine, amlodipine, Levamlodipine, nimodipine, nicardipine, lacidipine, nisoldipine, nitrendipine, felodipine, nilvadipine, isradipine, barnidipine, cilnidipine, niludipine, azelnidipine, diltiazem, the verapamil; Described vitamin B group is selected from one or more in folic acid, vitamin B6, vitamin B12, vitamin B1, vitamin B2, vitamin PP, biotin and the pantothenic acid.
2. the described compositions of claim 1, it is characterized in that: described calcium antagonist is selected from nifedipine, amlodipine, Levamlodipine, lacidipine, felodipine, isradipine, diltiazem, a kind of in the verapamil, wherein, nifedipine content is 20～120mg, amlodipine content is 2.5～20mg, Levamlodipine content is 2.5～10mg, lacidipine content is 2～8mg, felodipine content is 2.5～40mg, isradipine content is 2.5-20mg, diltiazem content is 30-240mg, verapamil content is 40-480mg; Described vitamin B group is one or both in vitamin B12, the vitamin B6, and wherein, vitamin B12 content is 1 μ g～2mg, and vitamin B6 content is 5-50mg.
3. the described compositions of claim 2, it is characterized in that: described vitamin B12 content is 1 μ g～0.25mg.
4. claim 2,3 each described compositionss further comprise folic acid, and content is 0.2～5mg, preferred 0.2～1.0mg.
5. the described compositions of claim 4, it is characterized in that: the content of described folic acid is 0.4mg or 0.8mg.
6. the described compositions of claim 2, it is characterized in that: described calcium antagonist is an amlodipine, content is 2.5～20mg; Described vitamin B group is a vitamin B12, and content is 1 μ g～0.25mg.
7. the described compositions of claim 2, it is characterized in that: described calcium antagonist is a lacidipine, content is 2～8mg; Described vitamin B group is a vitamin B12, and content is 1 μ g～0.25mg.
8. claim 6,7 each described compositionss further comprise folic acid, and content is 0.2～1.0mg.
9. any one described compositions in the claim 1 to 8 is characterized in that: said composition make conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain pH dependent form capsule, granule, oral liquid, membrane, the patch dosage form of micropill or small pieces.
10. the purposes of any one described compositions in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease in the claim 1 to 9.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101142146A CN101590235A (en) | 2008-05-30 | 2008-05-30 | The composition and use thereof that contains calcium antagonist and vitamin B group |
| PCT/CN2008/001681 WO2009143662A1 (en) | 2008-05-30 | 2008-09-28 | Pharmaceutical composition comprising calcium blocker and b family vitamins and the use thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2008101142146A CN101590235A (en) | 2008-05-30 | 2008-05-30 | The composition and use thereof that contains calcium antagonist and vitamin B group |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101590235A true CN101590235A (en) | 2009-12-02 |
Family
ID=41405234
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2008101142146A Pending CN101590235A (en) | 2008-05-30 | 2008-05-30 | The composition and use thereof that contains calcium antagonist and vitamin B group |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101590235A (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109498643A (en) * | 2018-12-06 | 2019-03-22 | 北京斯利安药业有限公司 | A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement |
| CN111481554A (en) * | 2019-01-29 | 2020-08-04 | 深圳奥萨医药有限公司 | Tablet containing amlodipine and folic acid and preparation method thereof |
-
2008
- 2008-05-30 CN CNA2008101142146A patent/CN101590235A/en active Pending
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109498643A (en) * | 2018-12-06 | 2019-03-22 | 北京斯利安药业有限公司 | A kind of folate composition and its application in the old mistake intelligence drug of preparation improvement |
| CN111481554A (en) * | 2019-01-29 | 2020-08-04 | 深圳奥萨医药有限公司 | Tablet containing amlodipine and folic acid and preparation method thereof |
| CN111481554B (en) * | 2019-01-29 | 2022-11-25 | 深圳奥萨医药有限公司 | Tablet containing amlodipine and folic acid and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU2006241771B2 (en) | Composition containing anti-dementia drug | |
| JP5604304B2 (en) | Orally disintegrating solid preparation | |
| CN101897706A (en) | Composition containing folic acid and B vitamins and applications thereof | |
| KR101230731B1 (en) | Pharmaceutical formulation | |
| KR20090091077A (en) | Pharmaceutical preparations for the treatment of cardiovascular diseases | |
| US20060246003A1 (en) | Composition containing anti-dementia drug | |
| CN102065847A (en) | Pharmaceutical formulation containing angiotensin-II receptor blocker | |
| US8865213B2 (en) | Modified release pharmaceutical compositions | |
| WO2010128525A2 (en) | A formulation of ivabradine for treating the cardiovascular disease | |
| CN106310278A (en) | Multi-cascade antihypertensive drug composition containing folic acid | |
| KR20160128449A (en) | Pharmaceutical preparation containing calcium antagonist/angiotensin ii receptor antagonist | |
| US20080241240A1 (en) | Combined pharmaceutical formulation with controlled-release comprising dihydropyridine calcium channel blockers and hmg-coa reductase inhibitors | |
| US20060160852A1 (en) | Composition containing anti-dementia drug | |
| CN101590235A (en) | The composition and use thereof that contains calcium antagonist and vitamin B group | |
| KR101414814B1 (en) | Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof | |
| CN101590040A (en) | The composition and use thereof that contains indopamide and vitamin B group | |
| CN101590237A (en) | The purposes that contains the compositions of calcium antagonist and folic acid | |
| CN101590233A (en) | The composition and use thereof that contains calcium antagonist, statins and vitamin B group | |
| CN101897709A (en) | Drug composition containing small dosage of folic acid and aspirin and application thereof | |
| CN116327781A (en) | Afabixing preparation and preparation method thereof | |
| WO2009143662A1 (en) | Pharmaceutical composition comprising calcium blocker and b family vitamins and the use thereof | |
| CN104224788A (en) | Medicinal composition of indapamide and folic acid and application of medicinal composition | |
| CN101590084B (en) | Pharmaceutical composition containing angiotensin converting enzyme inhibitors, B vitamins and ginkgo biloba extracts | |
| CN101590236A (en) | The composition and use thereof that contains calcium antagonist, statins | |
| WO2018028841A1 (en) | Solid pharmaceutical composition of abacavir, lamivudine, and efavirenz |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Open date: 20091202 |