CN104013964B - 含有口服抗凝药和b族维生素的药物组合物及其用途 - Google Patents
含有口服抗凝药和b族维生素的药物组合物及其用途 Download PDFInfo
- Publication number
- CN104013964B CN104013964B CN201410257801.6A CN201410257801A CN104013964B CN 104013964 B CN104013964 B CN 104013964B CN 201410257801 A CN201410257801 A CN 201410257801A CN 104013964 B CN104013964 B CN 104013964B
- Authority
- CN
- China
- Prior art keywords
- vitamin
- group
- pharmaceutical composition
- content
- apoplexy
- 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.)
- Active
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 230000010100 anticoagulation Effects 0.000 title claims abstract description 15
- 229930003270 Vitamin B Natural products 0.000 title abstract description 16
- 235000019156 vitamin B Nutrition 0.000 title abstract description 16
- 239000011720 vitamin B Substances 0.000 title abstract description 16
- OVBPIULPVIDEAO-LBPRGKRZSA-N Folic acid Natural products 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 abstract description 38
- 229960003850 dabigatran Drugs 0.000 claims abstract description 26
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 claims abstract description 26
- 235000019152 folic acid Nutrition 0.000 claims abstract description 26
- 239000011724 folic acid Substances 0.000 claims abstract description 26
- 239000003814 drug Substances 0.000 claims abstract description 24
- 206010003658 Atrial Fibrillation Diseases 0.000 claims abstract description 20
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 claims abstract description 19
- 208000006011 Stroke Diseases 0.000 claims abstract description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 17
- OFJRNBWSFXEHSA-UHFFFAOYSA-N 2-(3-amino-1,2-benzoxazol-5-yl)-n-[4-[2-[(dimethylamino)methyl]imidazol-1-yl]-2-fluorophenyl]-5-(trifluoromethyl)pyrazole-3-carboxamide Chemical compound CN(C)CC1=NC=CN1C(C=C1F)=CC=C1NC(=O)C1=CC(C(F)(F)F)=NN1C1=CC=C(ON=C2N)C2=C1 OFJRNBWSFXEHSA-UHFFFAOYSA-N 0.000 claims abstract description 15
- 206010008190 Cerebrovascular accident Diseases 0.000 claims abstract description 15
- -1 folacin compound Chemical class 0.000 claims abstract description 15
- 229950010535 razaxaban Drugs 0.000 claims abstract description 15
- 229940047562 eliquis Drugs 0.000 claims abstract description 14
- 229940064302 folacin Drugs 0.000 claims abstract description 8
- 150000003839 salts Chemical class 0.000 claims abstract description 6
- 239000003826 tablet Substances 0.000 claims description 21
- 239000008187 granular material Substances 0.000 claims description 20
- 239000002775 capsule Substances 0.000 claims description 17
- 238000002360 preparation method Methods 0.000 claims description 17
- 239000003146 anticoagulant agent Substances 0.000 claims description 16
- 229940127219 anticoagulant drug Drugs 0.000 claims description 14
- 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 12
- 229960000304 folic acid Drugs 0.000 claims description 12
- 238000002560 therapeutic procedure Methods 0.000 claims description 10
- ZNOVTXRBGFNYRX-ABLWVSNPSA-N levomefolic acid Chemical compound C1NC=2NC(N)=NC(=O)C=2N(C)C1CNC1=CC=C(C(=O)N[C@@H](CCC(O)=O)C(O)=O)C=C1 ZNOVTXRBGFNYRX-ABLWVSNPSA-N 0.000 claims description 9
- 235000007635 levomefolic acid Nutrition 0.000 claims description 9
- 239000011578 levomefolic acid Substances 0.000 claims description 9
- 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 compound 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 claims description 5
- 150000002148 esters Chemical class 0.000 claims description 4
- 229950011103 betrixaban Drugs 0.000 claims description 3
- XHOLNRLADUSQLD-UHFFFAOYSA-N betrixaban Chemical compound C=1C=C(Cl)C=NC=1NC(=O)C1=CC(OC)=CC=C1NC(=O)C1=CC=C(C(=N)N(C)C)C=C1 XHOLNRLADUSQLD-UHFFFAOYSA-N 0.000 claims description 3
- 239000003795 chemical substances by application Substances 0.000 claims description 3
- 230000002265 prevention Effects 0.000 claims description 3
- VVIAGPKUTFNRDU-UHFFFAOYSA-N 6S-folinic acid Natural products C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)NC(CCC(O)=O)C(O)=O)C=C1 VVIAGPKUTFNRDU-UHFFFAOYSA-N 0.000 claims description 2
- MPJKWIXIYCLVCU-UHFFFAOYSA-N Folinic acid Natural products NC1=NC2=C(N(C=O)C(CNc3ccc(cc3)C(=O)NC(CCC(=O)O)CC(=O)O)CN2)C(=O)N1 MPJKWIXIYCLVCU-UHFFFAOYSA-N 0.000 claims description 2
- KVUAALJSMIVURS-ZEDZUCNESA-L calcium folinate Chemical compound [Ca+2].C1NC=2NC(N)=NC(=O)C=2N(C=O)C1CNC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-ZEDZUCNESA-L 0.000 claims description 2
- 229960001921 calcium levofolinate Drugs 0.000 claims description 2
- KVUAALJSMIVURS-QNTKWALQSA-L calcium;(2s)-2-[[4-[[(6s)-2-amino-5-formyl-4-oxo-1,6,7,8-tetrahydropteridin-6-yl]methylamino]benzoyl]amino]pentanedioate Chemical compound [Ca+2].C([C@@H]1N(C=O)C=2C(=O)N=C(NC=2NC1)N)NC1=CC=C(C(=O)N[C@@H](CCC([O-])=O)C([O-])=O)C=C1 KVUAALJSMIVURS-QNTKWALQSA-L 0.000 claims description 2
- 235000008191 folinic acid Nutrition 0.000 claims description 2
- 239000011672 folinic acid Substances 0.000 claims description 2
- 229960001691 leucovorin Drugs 0.000 claims description 2
- 206010008088 Cerebral artery embolism Diseases 0.000 claims 1
- 201000010849 intracranial embolism Diseases 0.000 claims 1
- 239000011715 vitamin B12 Substances 0.000 abstract description 8
- 229940127066 new oral anticoagluant drug Drugs 0.000 abstract description 7
- 239000011726 vitamin B6 Substances 0.000 abstract description 7
- 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 abstract description 5
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 4
- 239000002243 precursor Substances 0.000 abstract description 3
- 210000004556 brain Anatomy 0.000 abstract description 2
- 239000002207 metabolite Substances 0.000 abstract description 2
- 239000003937 drug carrier Substances 0.000 abstract 1
- 238000000034 method Methods 0.000 description 13
- 150000001875 compounds Chemical class 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 8
- 210000004731 jugular vein Anatomy 0.000 description 8
- 241001465754 Metazoa Species 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 239000011812 mixed powder Substances 0.000 description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- 208000007536 Thrombosis Diseases 0.000 description 6
- 229940014144 folate Drugs 0.000 description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 6
- 239000008108 microcrystalline cellulose Substances 0.000 description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 description 6
- 239000013641 positive control Substances 0.000 description 6
- 235000002639 sodium chloride Nutrition 0.000 description 6
- 210000003462 vein Anatomy 0.000 description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 6
- 241000283973 Oryctolagus cuniculus Species 0.000 description 5
- 239000002671 adjuvant Substances 0.000 description 5
- 238000013270 controlled release Methods 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000000546 pharmaceutical excipient Substances 0.000 description 5
- 239000007779 soft material Substances 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 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 4
- 230000002785 anti-thrombosis Effects 0.000 description 4
- 230000001276 controlling effect Effects 0.000 description 4
- 238000001514 detection method Methods 0.000 description 4
- 210000003191 femoral vein Anatomy 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 230000004060 metabolic process Effects 0.000 description 4
- 238000012856 packing Methods 0.000 description 4
- 229920003023 plastic Polymers 0.000 description 4
- 239000004033 plastic Substances 0.000 description 4
- 230000009467 reduction Effects 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 229910052708 sodium Inorganic materials 0.000 description 4
- 206010002091 Anaesthesia Diseases 0.000 description 3
- 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 3
- 239000004698 Polyethylene Substances 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 230000037005 anaesthesia Effects 0.000 description 3
- 230000037396 body weight Effects 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000015271 coagulation Effects 0.000 description 3
- 238000005345 coagulation Methods 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 230000002526 effect on cardiovascular system Effects 0.000 description 3
- 238000001727 in vivo Methods 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 229920000573 polyethylene Polymers 0.000 description 3
- 239000011780 sodium chloride Substances 0.000 description 3
- 239000008107 starch Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- 230000001732 thrombotic effect Effects 0.000 description 3
- 229960005080 warfarin Drugs 0.000 description 3
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-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
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 description 2
- 241000283977 Oryctolagus Species 0.000 description 2
- 229920001363 Polidocanol Polymers 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 239000004141 Sodium laurylsulphate Substances 0.000 description 2
- 108090000190 Thrombin Proteins 0.000 description 2
- 208000027418 Wounds and injury Diseases 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
- 230000008901 benefit Effects 0.000 description 2
- 230000002146 bilateral effect Effects 0.000 description 2
- 230000023555 blood coagulation Effects 0.000 description 2
- 230000008081 blood perfusion Effects 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000013339 cereals Nutrition 0.000 description 2
- 230000000875 corresponding effect Effects 0.000 description 2
- 238000004132 cross linking Methods 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
- IJNIQYINMSGIPS-UHFFFAOYSA-N darexaban Chemical compound C1=CC(OC)=CC=C1C(=O)NC1=CC=CC(O)=C1NC(=O)C1=CC=C(N2CCN(C)CCC2)C=C1 IJNIQYINMSGIPS-UHFFFAOYSA-N 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 229960000622 edoxaban Drugs 0.000 description 2
- 230000003203 everyday effect Effects 0.000 description 2
- 238000011010 flushing procedure Methods 0.000 description 2
- 229940083626 folic acid 0.4 mg Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 238000007689 inspection Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 230000007774 longterm Effects 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- VYNKVNDKAOGAAQ-RUZDIDTESA-N n-[(1r)-2-[4-(1-methylpiperidin-4-yl)piperazin-1-yl]-2-oxo-1-phenylethyl]-1h-indole-6-carboxamide Chemical compound C1CN(C)CCC1N1CCN(C(=O)[C@H](NC(=O)C=2C=C3NC=CC3=CC=2)C=2C=CC=CC=2)CC1 VYNKVNDKAOGAAQ-RUZDIDTESA-N 0.000 description 2
- ONJQDTZCDSESIW-UHFFFAOYSA-N polidocanol Chemical compound CCCCCCCCCCCCOCCOCCOCCOCCOCCOCCOCCOCCOCCO ONJQDTZCDSESIW-UHFFFAOYSA-N 0.000 description 2
- 229960002226 polidocanol Drugs 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- NHZMQXZHNVQTQA-UHFFFAOYSA-N pyridoxamine Chemical compound CC1=NC=C(CO)C(CN)=C1O NHZMQXZHNVQTQA-UHFFFAOYSA-N 0.000 description 2
- 230000002829 reductive effect Effects 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- GEHJYWRUCIMESM-UHFFFAOYSA-L sodium sulfite Chemical compound [Na+].[Na+].[O-]S([O-])=O GEHJYWRUCIMESM-UHFFFAOYSA-L 0.000 description 2
- 238000000528 statistical test Methods 0.000 description 2
- 239000000829 suppository Substances 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229960004072 thrombin Drugs 0.000 description 2
- 229940088594 vitamin Drugs 0.000 description 2
- 229930003231 vitamin Natural products 0.000 description 2
- 235000013343 vitamin Nutrition 0.000 description 2
- 239000011782 vitamin Substances 0.000 description 2
- 150000003722 vitamin derivatives Chemical class 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-N 0.000 description 1
- 206010061623 Adverse drug reaction Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 208000030453 Drug-Related Side Effects and Adverse reaction Diseases 0.000 description 1
- 108010029144 Factor IIa Proteins 0.000 description 1
- 108010074860 Factor Xa 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
- 208000032843 Hemorrhage Diseases 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- QGMRQYFBGABWDR-UHFFFAOYSA-M Pentobarbital sodium Chemical compound [Na+].CCCC(C)C1(CC)C(=O)NC(=O)[N-]C1=O QGMRQYFBGABWDR-UHFFFAOYSA-M 0.000 description 1
- 208000035992 Postmortem Changes Diseases 0.000 description 1
- RADKZDMFGJYCBB-UHFFFAOYSA-N Pyridoxal Chemical compound CC1=NC=C(CO)C(C=O)=C1O RADKZDMFGJYCBB-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 108010000499 Thromboplastin Proteins 0.000 description 1
- 102000002262 Thromboplastin Human genes 0.000 description 1
- 206010047249 Venous thrombosis 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
- 239000002253 acid Substances 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000013543 active substance Substances 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 150000001336 alkenes Chemical class 0.000 description 1
- 229910052782 aluminium Inorganic materials 0.000 description 1
- 229960003886 apixaban Drugs 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 210000001168 carotid artery common Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 239000011789 cobamamide Substances 0.000 description 1
- 235000006279 cobamamide Nutrition 0.000 description 1
- ZIHHMGTYZOSFRC-UWWAPWIJSA-M cobamamide Chemical compound C1(/[C@](C)(CCC(=O)NC[C@H](C)OP(O)(=O)OC2[C@H]([C@H](O[C@@H]2CO)N2C3=CC(C)=C(C)C=C3N=C2)O)[C@@H](CC(N)=O)[C@]2(N1[Co+]C[C@@H]1[C@H]([C@@H](O)[C@@H](O1)N1C3=NC=NC(N)=C3N=C1)O)[H])=C(C)\C([C@H](C/1(C)C)CCC(N)=O)=N\C\1=C/C([C@H]([C@@]\1(CC(N)=O)C)CCC(N)=O)=N/C/1=C(C)\C1=N[C@]2(C)[C@@](C)(CC(N)=O)[C@@H]1CCC(N)=O ZIHHMGTYZOSFRC-UWWAPWIJSA-M 0.000 description 1
- 230000002301 combined effect Effects 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 239000011666 cyanocobalamin Substances 0.000 description 1
- 235000000639 cyanocobalamin Nutrition 0.000 description 1
- 229960002104 cyanocobalamin Drugs 0.000 description 1
- 229960000288 dabigatran etexilate Drugs 0.000 description 1
- KSGXQBZTULBEEQ-UHFFFAOYSA-N dabigatran etexilate Chemical compound C1=CC(C(N)=NC(=O)OCCCCCC)=CC=C1NCC1=NC2=CC(C(=O)N(CCC(=O)OCC)C=3N=CC=CC=3)=CC=C2N1C KSGXQBZTULBEEQ-UHFFFAOYSA-N 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 239000007950 delayed release tablet Substances 0.000 description 1
- 238000000151 deposition Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- GLUUGHFHXGJENI-UHFFFAOYSA-N diethylenediamine Natural products C1CNCCN1 GLUUGHFHXGJENI-UHFFFAOYSA-N 0.000 description 1
- 125000000118 dimethyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 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 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000003511 endothelial effect Effects 0.000 description 1
- 210000003038 endothelium Anatomy 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 230000001815 facial effect Effects 0.000 description 1
- 239000012467 final product Substances 0.000 description 1
- 125000003929 folic acid group Chemical group 0.000 description 1
- 150000002224 folic acids Chemical class 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000011704 hydroxocobalamin Substances 0.000 description 1
- 235000004867 hydroxocobalamin Nutrition 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
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 1
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000006698 induction Effects 0.000 description 1
- 238000001802 infusion Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 238000007912 intraperitoneal administration Methods 0.000 description 1
- 231100000518 lethal Toxicity 0.000 description 1
- 230000001665 lethal effect Effects 0.000 description 1
- 239000007937 lozenge Substances 0.000 description 1
- 229960005321 mecobalamin Drugs 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 239000011585 methylcobalamin Substances 0.000 description 1
- 235000007672 methylcobalamin Nutrition 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
- 238000012544 monitoring process Methods 0.000 description 1
- 210000000214 mouth Anatomy 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 229960002275 pentobarbital sodium Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 230000035479 physiological effects, processes and functions Effects 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 229940002612 prodrug Drugs 0.000 description 1
- 239000000651 prodrug Substances 0.000 description 1
- 230000004224 protection Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 238000010298 pulverizing process Methods 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
- 239000011589 pyridoxal 5'-phosphate Substances 0.000 description 1
- 235000007682 pyridoxal 5'-phosphate Nutrition 0.000 description 1
- 229960001327 pyridoxal phosphate Drugs 0.000 description 1
- 239000011699 pyridoxamine Substances 0.000 description 1
- 235000008151 pyridoxamine Nutrition 0.000 description 1
- LXNHXLLTXMVWPM-UHFFFAOYSA-N pyridoxine Chemical compound CC1=NC=C(CO)C(CO)=C1O LXNHXLLTXMVWPM-UHFFFAOYSA-N 0.000 description 1
- 239000011677 pyridoxine Substances 0.000 description 1
- 235000008160 pyridoxine Nutrition 0.000 description 1
- WHOMFKWHIQZTHY-UHFFFAOYSA-N pyridoxine 5'-phosphate Chemical compound CC1=NC=C(COP(O)(O)=O)C(CO)=C1O WHOMFKWHIQZTHY-UHFFFAOYSA-N 0.000 description 1
- 238000011555 rabbit model Methods 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 229960001148 rivaroxaban Drugs 0.000 description 1
- KGFYHTZWPPHNLQ-AWEZNQCLSA-N rivaroxaban Chemical compound S1C(Cl)=CC=C1C(=O)NC[C@@H]1OC(=O)N(C=2C=CC(=CC=2)N2C(COCC2)=O)C1 KGFYHTZWPPHNLQ-AWEZNQCLSA-N 0.000 description 1
- 239000011265 semifinished product Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 229920002545 silicone oil Polymers 0.000 description 1
- 206010040882 skin lesion Diseases 0.000 description 1
- 231100000444 skin lesion Toxicity 0.000 description 1
- 235000010265 sodium sulphite Nutrition 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000001502 supplementing effect Effects 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 230000002195 synergetic effect Effects 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 238000004448 titration Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000020985 whole grains Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
本发明涉及一种含有新型口服抗凝药物和B族维生素的药物组合物，由治疗有效量的口服抗凝药及其药用前体、活性代谢产物或盐类中的一种、治疗有效量的B族维生素的一种或几种、和药学上可接受的载体组成。其中，新型口服抗凝药主要包括达比加群酯、利伐沙班、阿哌沙班、依度沙班，含量为2.5～200mg；B族维生素主要包括叶酸类化合物(优选)、维生素B6、维生素B12，含量为0.1～50mg。本发明还涉及该组合物在制备用于预防房颤患者发生脑卒中的药物中的用途。由本发明提供的药物组合物制成的药物具有更佳的预防脑卒中效果；此外，本发明还可使患者服药方便，增加依从性。
Description
技术领域
本发明涉及一种含有口服抗凝药和B族维生素的药物组合物，用于在心房颤动患者中预防脑卒中的抗凝治疗。本发明属于药学领域。
背景技术
心房颤动(房颤)是一种心血管“流行病”。在我国同期心血管住院患者中，房颤患者所占比例接近10％。房颤可能导致多种不良后果，脑卒中是最严重的并发症之一，房颤可使脑卒中发生率至少增高4～5倍【Hu D,et al.Epidemiology,Risk Factors for Stroke,and Management of Atrial Fibrillation in China.J Am Coll Cardiol,2008；52:865】。研究显示，全球每年有多达300万人罹患与房颤有关的脑卒中。房颤相关性卒中的致残程度更严重，致死危险性更大，半数患者在一年内死亡。
抗凝治疗是降低房颤相关卒中死亡率的关键。我国首部由中华医学会心血管病学分会牵头制定的《心房颤动抗凝治疗中国专家共识》明确指出，若无禁忌证，CHADS2评分≥2分的房颤患者，卒中风险较高，应进行长期口服抗凝治疗【胡大一，等.心房颤动抗凝治疗中国专家共识.心脑血管病防治，2012；12(3)：173】。
口服抗凝治疗的经典老药华法林本身有其短板，如治疗窗窄、在降低卒中风险的同时可能导致出血风险、需要频繁监测凝血功能并调整药物剂量、可能与多种食物及药物相互作用等，这都在一定程度上限制了房颤患者抗凝治疗的依从性。科学家一直致力于寻找替代华法林的新型口服抗凝药物，达比加群酯(dabigatran etexilate)和沙班类抗凝药物的相继问市，为房颤患者带来了抗凝治疗的信心和前景。
达比加群酯是一种直接的凝血酶(因子IIa)抑制剂，是达比加群(dabigatran)的前体药物，而沙班类抗凝药是一类高选择性、可逆地直接抑制凝血因子Xa的药物，已上市的有利伐沙班(rivaroxaban,阿哌沙班(apixaban， 和依度沙班(edoxaban，在研的有betrixaban、LY517717、YM150、DU-176b等。这两类药物通过抑制相应的凝血因子而阻断内源性和外源性凝血途径，均适用于房颤患者预防卒中的长期口服抗凝治疗，且与华法林相比具有不需要常规血液学监测及剂量调整、不受食物影响、出血发生风险低等优势【①Miller CS,et al.Meta-analysis of efficacy andsafety of new oral anticoagulants(dabigatran,rivaroxaban,apixaban)versuswarfarin in patients with atrial fibrillation.Am J Cardiol.2012；110:453.②Patel MR,et al.Rivaroxaban versus warfarin in nonvalvular atrialfibrillation.N Engl JMed,2011；365:883】。
新型口服抗凝药物在临床应用上仍存在一定问题，比较突出的仍旧是治疗过程中不可避免发生的出血倾向，尤其在剂量加大时，出血发生率比较高，因此仍需要进一步改善。对于房颤患者来说，心房血栓形成、脱落固然是引发卒中的直接原因，但其病理过程并非单一，其中可能涉及其它危险因素。流行病学调研显示，我国卒中发病率远高于欧美国家，但居民携带卒中危险因素(高血压、高血脂、肥胖及糖尿病)比率却低于欧美居民，提示我国存在其它重要危险因素；另一方面，从药理协同作用角度看，药物组合物具有临床价值，每种药物的剂量可有所减少，故不良反应可减轻或部分抵消，而药物治疗作用可相加乃至协同。
B族维生素包括维生素B1、维生素B2、维生素PP、维生素B6、维生素B12、叶酸、泛酸和生物素等，对机体新陈代谢、红细胞形成、保持神经系统和免疫系统功能具有重要作用。B族维生素属于水溶性维生素，经人体肠道吸收，由尿排出体外，在体内存留时间短暂，很少蓄积，所以必须经常从体外摄取以满足机体营养和代谢需要。B族维生素缺乏可导致诸多不良后果，包括肌无力、精神及神经系统紊乱、消化障碍、皮肤皱裂、严重贫血和心脏损害等。其中，叶酸、维生素B6、维生素B12缺乏时影响人体内同型半胱氨酸(Homocysteine，Hcy)的生化代谢，研究提示血液Hcy水平升高或叶酸水平降低与卒中风险升高呈显著相关【①Wang X,et al.Efficacy of folic acid supplementation in stroke prevention:a metaanalysis.Lancet,2007,369:1876.②Sun Y,et al.Use of serum homocysteine topredict stroke,coronary heart disease and death in Ethnic Chinese:a12-yearprospective cohort study.Circ J.2009；73:1423】。
发明内容
本发明的目的是克服新型口服抗凝药物存在的不足，提供一种在抗凝疗效或预防卒中方面优于这些抗凝药物、而毒副作用不增加或减少的药物组合物。
为实现上述目的，本发明采用以下技术方案：
一种药物组合物，包括
(1)药用剂量的新型口服抗凝药物及其药用前体、活性代谢产物、或盐类中的 一种；
(2)药用剂量的B族维生素的一种或多种；
(3)药剂学上可接受的载体。
上述的“药用剂量”是指具有协同、预防或治疗的药理作用的量。上述新型口服抗凝药物选自达比加群酯、利伐沙班、阿哌沙班、依度沙班、Betrixaban、LY517717、YM150、DU-176b的一种，B族维生素选自维生素B6、维生素B12和叶酸类化合物的一种或多种，其中维生素B6包括吡哆醇、吡哆醛、吡哆胺、磷酸吡哆醇、磷酸吡哆醛、磷酸吡哆胺及上述物质的衍生物和可在体内代谢和/或生成该类化合物的物质，维生素B12包括钴胺素、甲钴胺素、5′-脱氧腺苷钴胺素、羟钴胺素、氰钴胺素及上述物质的衍生物和可在体内代谢和/或生成该类化合物的物质,叶酸类化合物包括叶酸、5-甲基四氢叶酸、甲酰四氢叶酸、亚叶酸、左亚叶酸钙、叶酸可药用盐或叶酸可药用盐的活性代谢产物和可在体内生成叶酸的物质。
在本发明中，口服抗凝药物的药用剂量范围分别为达比加群酯(50～220mg)、利伐沙班(2.5～20mg)、阿哌沙班(1～10mg)、依度沙班(10～60mg)；这些药物更佳的安全有效剂量分别为达比加群酯(75～175mg)、利伐沙班(5～15mg)、阿哌沙班(2.5～7.5mg)、依度沙班(15～30mg)。
在本发明中，B族维生素的药用剂量范围分别为维生素B6(1～50mg)、维生素B12(0.05～2mg)、叶酸类化合物(0.1～5mg)；这些药物更佳的治疗有效量分别为维生素B6(10～40mg)、维生素B12(0.1～1mg)、叶酸类化合物(0.4～2mg)。
本研究发现，B族维生素单用(尤其叶酸)对血管内皮具有一定保护作用，与口服抗凝药物合用能增强对血栓形成的抑制作用。
根据本发明，药物组合物中的活性成分是组合物中的基本组分，其中一个活性成分来自于新型口服抗凝药物中的一种，另一个活性成分为B族维生素的一种或多种，该药物组合物的剂型包括但不限于普通片剂、双层片剂、多层片剂、缓释片剂、单室控释片剂、双室控释片剂、微孔型控释片剂、舌下含片、口腔速崩片、分散片、肠溶片、延迟释放片、定时/位释放片、普通胶囊、肠溶胶囊、缓释胶囊、控释胶囊、含有微丸或小片的胶囊、含有微丸或小片的pH依赖型胶囊、颗粒剂、丸剂、口服液、膜剂或贴剂。
在本发明中，可药用载体或赋形剂可制成普通口服制剂，包括普通片剂、普通胶囊、颗粒剂等，制成片剂时所述可药用载体包括有助于将活性化合物配制成药用制剂的赋形剂和辅料，如微晶纤维素、无机盐类、乳糖、氯化钠、柠檬酸、亚硫酸钠、淀粉、纤维素衍生物、预胶化淀粉，羧甲基淀粉钠，羟丙基淀粉，低取代羟丙基纤维素，交联羧甲基淀粉钠，交联聚乙烯吡咯烷酮，蔗糖、糊精、糖粉、葡萄糖等的一种或几种物质的组合物，属于本领域常识。
在本发明中，可药用载体或赋形剂可制成缓释制剂，包括赋形剂和辅料等。
在本发明中，可药用载体或赋形剂可制成缓释胶囊、控释胶囊，含有微丸或小片的胶囊，含有微丸或小片的pH依赖型胶囊，二联胶囊等，包括赋形剂和辅料等。
术语“药用剂量”是指为达到有效控制或治疗疾病的目的，临床医生根据患病个体病情严重程度对患病个体施与药物的剂量。应当理解本发明提供的药物药用剂量不是对本发明的限制，而是对本发明的优选，通常情况下，在该剂量优选范围内，该药物能够对患病个体产生有效的治疗效果。患病个体是指患有疾病的独立存在的生命体，在本发明中，生命体尤指人类。应当理解，现有技术中，人类药用剂量或药用剂量范围可与哺乳动物，如大鼠、小鼠等进行换算以得出适合相应动物适用的药用剂量或剂量范围。
本发明提供的药物组合物中的化合物在相同的制剂中可以同时施与患病个体，也可分别地相继施与患病个体。若是相继施与患病个体，则第二个(或附加的)活性成分施与的延迟不应当导致活性成分联合带来的有益效果的损失。若是同时施与患病个体，组合物中的化合物可以混合存在于同一个药物制剂形式中，也可以以同样的制剂形式分别独立存在。若是以同样的制剂形式分别独立存在，则药物组合物可以变通的以“组合药盒”形式存在。“组合药盒”是一种盒状容器，内置一种或多种剂量形式的药物组合及其使用说明书，在本发明中优选所述的新型口服抗凝药物中的一种和B族维生素的一种或多种。
本发明的另一个目的是提供含有药用剂量的新型口服抗凝药物及其活性代谢产物或其盐类中的一种、药用剂量的B族维生素的一种或多种和可药用载体的药物组合物在制备用于房颤患者预防卒中的抗凝治疗中的用途，更具体地说，是提供在制备用于治疗房颤患者、降低卒中发生危险性的药物的用途。
本发明的优点：本发明提供了含有药用剂量的新型口服抗凝药物及其活性代谢产物或其盐类中的一种、药用剂量的B族维生素的一种或多种和可药用载体的药物组合 物。口服抗凝药物和B族维生素的联合效果并不是各个活性物质的各自作用的简单相加，而是在患者凝血功能得到更佳改善的基础上减少药物副作用、更加有效地降低卒中风险。也就是说，口服抗凝药物和B族维生素联合用药取得了协同治疗效果，因此是更适宜的抗凝治疗药物。
下面结合具体实施方式对本发明做进一步说明，并非对本发明的限定，凡依照本发明内容进行的任何本领域的等同替换，均属于本发明的保护范围。
具体实施方式
实施例1.制备复方利伐沙班/叶酸片(1000片量)
制备方法：取处方量叶酸、利伐沙班按照等量递增法混合均匀，备用；称取处方量的微晶纤维素、交联羧甲基纤维素钠、乳糖、十二烷基硫酸钠，与原料药混合粉充分混匀，过80目筛，加入适量5％羟丙甲纤维素溶液制成软材，20目筛制粒，50℃干燥约6h，20目筛整粒，控制颗粒的含水量为2-3％，将干燥后的颗粒与处方量的硬脂酸镁混合均匀，中间体进行检测，压片。制备过程中注意避光，制成的片剂需铝塑泡罩包装。制成的复方片剂中每片含利伐沙班5mg、叶酸0.4mg。
实施例2.制备复方达比加群酯/叶酸片(1000片量)
制备方法：取处方量叶酸、达比加群酯按照等量递增法混合均匀，备用；称取处方量的微晶纤维素、乳糖、阿拉伯树胶，与原料药混合粉充分混匀，过80目筛，加入适量二甲基硅油、10％羟丙纤维素溶液制成软材，20目筛制粒，50℃干燥约6h，20目筛整粒，控制颗粒的含水量为2-3％，将干燥后的颗粒与处方量的滑石粉和硬脂酸镁混合均匀，中间体进行检测，压片。制备过程中注意避光，制成的片剂需铝塑泡罩包装，避光保存。制成的复方片剂中每片含达比加群酯75mg、叶酸0.4mg。
实施例3.制备复方阿哌沙班/5-甲基四氢叶酸片(1000片量)
制备方法：辅料为直压辅料，干燥备用。取处方量的5-甲基四氢叶酸及微晶纤维素混合均匀，得到混粉中间体1；称取无水乳糖、交联羧甲基纤维素钠、十二烷基硫酸钠，与阿哌沙班充分混匀，得到混粉中间体2；将混粉中间体1和混粉中间体2与处方量的硬脂酸镁按照等量递增法混合均匀，得最终混粉中间体，检测混粉中间体，压片。制成的片剂需铝塑泡罩包装，每片含阿哌沙班2.5mg、5-甲基四氢叶酸0.45mg。
实施例4.制备复方依度沙班/甲酰四氢叶酸/维生素B6胶囊(1000粒量)
制备方法：取处方量甲酰四氢叶酸、维生素B6、依度沙班按照等量递增法混合均匀，备用；再与微晶纤维素、羧甲淀粉钠混合均匀后，过80目筛，加入5％聚维酮95％乙醇溶液适量，制软材，50℃干燥约6h过24目筛制颗粒，控制颗粒的含水量为2-3％，将干燥后的颗粒与处方量微粉硅胶、硬脂酸镁混合均匀，得到的颗粒中间体进行含量检测，检测合格后，装入空心胶囊即得。制备过程中注意避光，制成的胶囊需铝塑泡罩包装，避光保存。制成的胶囊中每粒含依度沙班15mg、甲酰四氢叶酸0.6mg、维生素B610mg。
实施例5.制备复方达比加群酯/5-MTHF+维生素B12双层片(1000片量)
达比加群酯颗粒的制备方法：将原料粉碎过80目筛，干燥备用。取75g达比加群酯、62.0g维晶纤维素和18.0g羧甲基淀粉钠，混合均匀，用5％聚维酮K29/30－95％乙醇溶液制成软材，20目筛制粒，50℃干燥约6h，20目筛整粒，控制颗粒的含水量为2-3％，得到达比加群酯层颗粒A；
维生素层颗粒的制备方法：取0.6g5-MTHF、0.2g维生素B12、50.0g微晶纤维素和25.0g低取代羟丙基纤维素，混合均匀，用5％聚维酮K29/30-95％乙醇溶液制成软 材，20目筛制粒，50℃干燥约6h，20目筛整粒，控制颗粒的含水量为2-3％，得到维生素层颗粒B；
双层片的制备方法：将干燥后的颗粒A、B分别与硬脂酸镁混合均匀，半成品分别进行检测，测定含量后，分别装入料斗中，用双层片压片机压片。制备过程中注意避光，制成的片剂需铝塑泡罩包装，避光保存。制成的复方片剂中每片含75mg达比加群酯、0.6mg的5-MTF、0.2mg维生素B12。
实施例6.达比加群酯/叶酸组合物对静脉栓塞家兔模型的抗凝、抗血栓作用
方法：健康、雄性新西兰兔18只，体重2.8～3.2kg/只，分为3组，每组6只，分别每日灌喂等容积生理盐水(空白对照组)、达比加群酯15mg/kg(阳性对照组)和达比加群酯15mg/kg+叶酸0.08mg/kg(实验组)，连续给药4周，于最后1次灌喂后2小时肌注麻醉，动物仰卧固定，分离左股静脉，插管以备采集血样及必要时补充麻醉。分离双侧颈静脉至颈外静脉与面静脉的分叉点，长度4cm，结扎小侧支。通过夹闭远、近端分离出一段颈静脉，套管排空血液，灌注0.5％聚多卡醇5分钟造成血管内皮损伤(诱导凝血)。抽干液体，生理盐水冲洗。然后，松散结扎远端使管腔直径狭窄至0.8毫米，恢复血流灌注25分钟，分离该静脉段，剥离血凝块，干燥、称重(每个动物血凝块重量取左、右两侧颈静脉内血块重量的平均值)，股静脉采血测定活化部分凝血活酶时间(APTT)。统计学检验方法采用t检验。
结果：见表1。阳性对照组及实验组APTT延长，显著大于空白对照组(均P<0.01)，表明达比加群酯显著抑制动物体内的凝血过程。阳性对照组及实验组血块重量也明显小于空白对照组(均P<0.01)，达比加群酯叶酸组合物对兔的抗凝作用优于达比加群酯单用(P<0.05)，提示叶酸有辅助抗凝或抗血栓形成作用。
表1达比加群酯叶酸组合物对兔静脉血栓形成的作用
注：与空白对照组比较，*P<0.01；与达比加群酯组比较，△P<0.05。
实施例7.利伐沙班/叶酸组合物对家兔的抗血栓作用
方法：健康、雄性新西兰兔18只，体重2.7～3.3kg/只，分为3组，每组6只，分别每日灌喂等容积生理盐水(空白对照组)、利伐沙班1mg/kg(阳性对照组)和利伐沙班1mg/kg+叶酸0.08mg/kg(实验组)，连续给药4周，于最后1次灌喂后2小时麻醉动物，仰卧固定，分离左股静脉，插管以备采集血样。分离双侧颈静脉至颈外静脉与面静脉的分叉点，长度4cm。通过夹闭远、近端分离出一段颈静脉，套管排空血液，灌注0.5％聚多卡醇5分钟造成血管内皮损伤。生理盐水冲洗。然后，松散结扎远端使管腔直径狭窄至0.8毫米，恢复血流灌注25分钟，分离该静脉段，剥离血凝块，干燥、称重(每个动物血凝块重量取左、右两侧颈静脉内血块重量的平均值)，股静脉采血测定APTT。统计学检验方法采用t检验。
结果：见表2。阳性对照组及实验组APTT延长，显著大于空白对照组(均P<0.01)，表明利伐沙班显著抑制动物体内的凝血过程。阳性对照组及实验组血块重量也明显小于空白对照组(均P<0.01)，利伐沙班叶酸组合物对兔的抗凝作用优于利伐沙班单用(P<0.05)，提示叶酸有辅助抗凝或抗血栓形成作用。
表2利伐沙班叶酸组合物对兔静脉血栓形成的作用
注：与空白对照组比较，*P<0.01；与达比加群酯组比较，△P<0.05。
实施例8.阿哌沙班/5-甲基四氢叶酸对大鼠血栓湿重的影响
方法：SD大鼠30只，雌雄各半，体重250～280g，随机分3组，每组10只。对照组(生理盐水)、阿哌沙班+5-甲基四氢叶酸组(0.5+0.09mg/kg)、阿哌沙班组(0.5mg/kg)，灌胃给药，每日一次，共7天。动物经上述给药方法给药后，禁食12小时不禁水，于次日给药2小时后，用戊巴比妥钠30-40mg/kg腹腔麻醉，仰卧位固定，分离右侧颈总动脉和左侧颈外静脉，在聚乙烯管中放一段长5cm的预先称重的4号丝线，并用肝素生理盐水充满聚乙烯管。当聚乙烯管的一端插入左颈外静脉后，在将聚乙烯管的另一端插入右颈总动脉。打开动脉夹，开放血流15分钟后中断血流，迅速取出丝线称重，总重量减去原丝线重量即为血栓湿重。
结果：见表3。实验结果表明，与对照组相比，阿哌沙班组和阿哌沙班+5-甲基四氢叶酸组血栓湿重均有明显减小，差异有统计意义。本实验还发现，合用阿哌沙班和5-甲基四氢叶酸对减小血栓大小也强于单独使用阿哌沙班(P<0.05)，提示5-甲基四氢叶酸在抑制血栓的形成中起一定作用(表3)。
表3阿哌沙班+5-甲基四氢叶酸对大鼠血栓湿重的影响(X±SD，n＝10)
注：与生理盐水组比较，*P<0.05，与阿哌沙班组比较，△P<0.05。
Claims (7)
1.一种用于房颤患者预防卒中的抗凝治疗的药物组合物，组成是：
（1）药用剂量的口服抗凝药或其盐类的一种；
（2）药用剂量的叶酸类化合物；
（3）药剂学上可接受的载体，
其中，所述口服抗凝药选自达比加群酯、利伐沙班、阿哌沙班、依度沙班、Betrixaban的一种，含量为1～220mg。
2.根据权利要求1所述的药物组合物，其特征在于：所述的达比加群酯的含量为75～175mg，利伐沙班的含量为5～15mg，阿哌沙班的含量为2.5～7.5mg，依度沙班的含量为15～30mg。
3.根据权利要求1所述的药物组合物，其特征在于：所述的叶酸类化合物选自叶酸、5-甲基四氢叶酸、甲酰四氢叶酸、亚叶酸、左亚叶酸钙、叶酸可药用盐的一种, 含量为 0.2～5mg。
4.根据权利要求3所述的药物组合物，其特征在于：所述的叶酸类化合物含量为0.4～1.6mg。
5.根据权利要求1～4中任一项所述的药物组合物，其特征在于该药物组合物的制药剂型为片剂、胶囊或颗粒剂。
6.权利要求1～5中任一项所述的药物组合物在制备用于房颤患者预防卒中的抗凝治疗药物的用途。
7.权利要求6所述的用途，其特征在于：所述的卒中是脑栓塞。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410257801.6A CN104013964B (zh) | 2014-06-11 | 2014-06-11 | 含有口服抗凝药和b族维生素的药物组合物及其用途 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410257801.6A CN104013964B (zh) | 2014-06-11 | 2014-06-11 | 含有口服抗凝药和b族维生素的药物组合物及其用途 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN104013964A CN104013964A (zh) | 2014-09-03 |
| CN104013964B true CN104013964B (zh) | 2016-08-17 |
Family
ID=51431142
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201410257801.6A Active CN104013964B (zh) | 2014-06-11 | 2014-06-11 | 含有口服抗凝药和b族维生素的药物组合物及其用途 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN104013964B (zh) |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058889A (zh) * | 2010-11-05 | 2011-05-18 | 王定豪 | 包含抗凝血类药物的分散片及其应用 |
Family Cites Families (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101897709A (zh) * | 2009-05-27 | 2010-12-01 | 北京奥萨医药研究中心有限公司 | 含有小剂量叶酸和阿司匹林的药物组合物及其用途 |
| US10391096B2 (en) * | 2011-10-13 | 2019-08-27 | Quercegen Pharmaceuticals Llc | Method for treating thrombotic disorders using quercetin-containing compositions |
-
2014
- 2014-06-11 CN CN201410257801.6A patent/CN104013964B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102058889A (zh) * | 2010-11-05 | 2011-05-18 | 王定豪 | 包含抗凝血类药物的分散片及其应用 |
Non-Patent Citations (1)
| Title |
|---|
| 维生素B6的抗血栓作用;孟宪珠;《新医学》;19830302;第10页右栏 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN104013964A (zh) | 2014-09-03 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| WO2011069326A1 (zh) | 包含阿替洛尔和氨氯地平的双层片剂 | |
| WO2010009618A1 (zh) | 用于治疗高血压和代谢综合症的药物组合物及其应用 | |
| PT1643999E (pt) | Piridoxamina para utilização no tratamento de nefropatia diabética na diabetes tipo ii | |
| EP2837380B1 (en) | Lercanidipine hydrochloride and losartan potassium compound preparation and preparation method thereof | |
| Lee et al. | A randomized, double-blind, candesartan-controlled, parallel group comparison clinical trial to evaluate the antihypertensive efficacy and safety of fimasartan in patients with mild to moderate essential hypertension | |
| CN104013964B (zh) | 含有口服抗凝药和b族维生素的药物组合物及其用途 | |
| CN106474480A (zh) | 含有葡萄糖激酶激动剂和b族维生素的药物组合物及其用途 | |
| CN106310278A (zh) | 一种含叶酸的多联降压药物组合物 | |
| Abdullah et al. | Valsartan: a brief current review | |
| CN103386130A (zh) | Ace抑制剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物及用途 | |
| TWI488658B (zh) | 溶出性之改善方法 | |
| CN101695496A (zh) | 一种含有三氟柳和氯吡格雷的药物组合物 | |
| CN112438976B (zh) | 一种具有肾脏保护作用的药物组合物 | |
| CN104224788A (zh) | 吲哒帕胺和叶酸的药物组合物及其用途 | |
| CN103800336A (zh) | 一种具有抗血栓活性药物的组合物 | |
| CN104001176B (zh) | 血小板adp受体拮抗剂和b族维生素的药物组合物 | |
| CN106310273A (zh) | 一种四联降压药物组合物 | |
| CN101897698A (zh) | 含有维格列汀和b族维生素的降糖药物组合物及其用途 | |
| CN104257668A (zh) | 阿司匹林、氯吡格雷与叶酸类化合物的药物组合物 | |
| CN103721259A (zh) | 血管紧张素ⅱ受体阻断剂/噻嗪类利尿剂/5-甲基四氢叶酸药物组合物 | |
| CN102755319B (zh) | 一种含有普拉格雷和卡维地洛的药物组合物及其用途 | |
| CN103272236B (zh) | 含有β-肾上腺素受体阻滞剂和B族维生素的药物组合物及其用途 | |
| CN112569356B (zh) | 一种含有利尿剂的药物组合物 | |
| US8470363B2 (en) | Antihypertensive pharmaceutical composition | |
| CN103599540B (zh) | 含有格列奈类药物和b族维生素的药物组合物及其用途 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20170703 Address after: 518057, Guangdong, Nanshan District, Shenzhen hi tech incubator, No. 16, No. three, building 3, building 3 Patentee after: SHENZHEN TAILEDE NUTRITION AND HEALTH Co.,Ltd. Address before: 518057, No. 16, No. 1, Nanshan District hi tech, Shenzhen, Guangdong Patentee before: SHENZHEN AUSA PHARMED Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder |
Address after: 518057, Guangdong, Nanshan District, Shenzhen hi tech incubator, No. 16, No. three, building 3, building 3 Patentee after: SHENZHEN KANGMUBAO NUTRITION AND HEALTH Co.,Ltd. Address before: 518057, Guangdong, Nanshan District, Shenzhen hi tech incubator, No. 16, No. three, building 3, building 3 Patentee before: SHENZHEN TAILEDE NUTRITION AND HEALTH Co.,Ltd. |
|
| CP01 | Change in the name or title of a patent holder | ||
| CP03 | Change of name, title or address |
Address after: 518057 3rd Floor, No. 16 Biological Incubator Phase III Building, High-tech Middle Road, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. Address before: 518057 3rd floor of No. 16 Biological Incubator Phase III Building, Nanshan High-tech Middle Road, Shenzhen City, Guangdong Province Patentee before: SHENZHEN KANGMUBAO NUTRITION AND HEALTH Co.,Ltd. |
|
| CP03 | Change of name, title or address | ||
| TR01 | Transfer of patent right | ||
| TR01 | Transfer of patent right |
Effective date of registration: 20230907 Address after: 518057 the 1st and 2nd floors of No.2 building, phase III of biological incubator, No.16, Gaoxin Zhongyi Road, central high tech Zone, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd. Patentee after: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Address before: 518057 3rd Floor, No. 16 Biological Incubator Phase III Building, High-tech Middle Road, Nanshan District, Shenzhen City, Guangdong Province Patentee before: SHENZHEN FULAITE NUTRITION & HEALTH Co.,Ltd. |