CN105232488A - 一种含有利伐沙班的固体药物组合物 - Google Patents
一种含有利伐沙班的固体药物组合物 Download PDFInfo
- Publication number
- CN105232488A CN105232488A CN201510670400.8A CN201510670400A CN105232488A CN 105232488 A CN105232488 A CN 105232488A CN 201510670400 A CN201510670400 A CN 201510670400A CN 105232488 A CN105232488 A CN 105232488A
- Authority
- CN
- China
- Prior art keywords
- razaxaban
- solid composite
- composite medicament
- obtains
- tablet
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 239000007787 solid Substances 0.000 title claims abstract description 34
- 239000008194 pharmaceutical composition Substances 0.000 title abstract description 12
- 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 title abstract description 10
- 229960001148 rivaroxaban Drugs 0.000 title abstract description 8
- 239000000203 mixture Substances 0.000 claims abstract description 30
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims abstract description 26
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims abstract description 25
- 238000004090 dissolution Methods 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 description 120
- 229950010535 razaxaban Drugs 0.000 claims description 120
- 239000003814 drug Substances 0.000 claims description 98
- 229940079593 drug Drugs 0.000 claims description 56
- AMQJEAYHLZJPGS-UHFFFAOYSA-N N-Pentanol Chemical group CCCCCO AMQJEAYHLZJPGS-UHFFFAOYSA-N 0.000 claims description 38
- 239000013078 crystal Substances 0.000 claims description 34
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 24
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 24
- 229950005770 hyprolose Drugs 0.000 claims description 24
- 239000000463 material Substances 0.000 claims description 24
- 230000015572 biosynthetic process Effects 0.000 claims description 23
- 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 claims description 20
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 20
- 239000002131 composite material Substances 0.000 claims description 20
- 238000004132 cross linking Methods 0.000 claims description 20
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 20
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 20
- 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 claims description 18
- 229930195725 Mannitol Natural products 0.000 claims description 18
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 18
- 239000011248 coating agent Substances 0.000 claims description 18
- 238000000576 coating method Methods 0.000 claims description 18
- 239000000594 mannitol Substances 0.000 claims description 18
- 235000010355 mannitol Nutrition 0.000 claims description 18
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 18
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 18
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 18
- 238000009835 boiling Methods 0.000 claims description 16
- 239000007921 spray Substances 0.000 claims description 16
- 239000003795 chemical substances by application Substances 0.000 claims description 15
- 239000007888 film coating Substances 0.000 claims description 14
- 238000009501 film coating Methods 0.000 claims description 14
- 239000008187 granular material Substances 0.000 claims description 13
- 238000002425 crystallisation Methods 0.000 claims description 12
- 230000008025 crystallization Effects 0.000 claims description 12
- 239000003112 inhibitor Substances 0.000 claims description 12
- 239000012528 membrane Substances 0.000 claims description 12
- 238000009472 formulation Methods 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 11
- 239000002245 particle Substances 0.000 claims description 10
- 230000009471 action Effects 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 8
- 239000012530 fluid Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- 238000004519 manufacturing process Methods 0.000 claims description 6
- 229920001328 Polyvinylidene chloride Polymers 0.000 claims description 4
- 239000005030 aluminium foil Substances 0.000 claims description 4
- 239000005033 polyvinylidene chloride Substances 0.000 claims description 4
- 239000005434 MCC/mannitol excipient Substances 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 abstract description 41
- 238000005516 engineering process Methods 0.000 abstract description 13
- 239000012535 impurity Substances 0.000 abstract description 11
- 239000004094 surface-active agent Substances 0.000 abstract description 7
- 238000003860 storage Methods 0.000 abstract description 4
- 230000008901 benefit Effects 0.000 abstract description 2
- 230000007774 longterm Effects 0.000 abstract description 2
- 239000007941 film coated tablet Substances 0.000 abstract 2
- 239000003826 tablet Substances 0.000 abstract 2
- 238000000034 method Methods 0.000 description 22
- 239000002671 adjuvant Substances 0.000 description 11
- 238000002474 experimental method Methods 0.000 description 10
- 239000000523 sample Substances 0.000 description 9
- 230000008569 process Effects 0.000 description 8
- 238000012360 testing method Methods 0.000 description 8
- 238000001228 spectrum Methods 0.000 description 7
- 239000000725 suspension Substances 0.000 description 6
- 101100087414 Arabidopsis thaliana RH20 gene Proteins 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 238000005550 wet granulation Methods 0.000 description 4
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical class OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 229920003081 Povidone K 30 Polymers 0.000 description 3
- 208000007536 Thrombosis Diseases 0.000 description 3
- 206010047249 Venous thrombosis Diseases 0.000 description 3
- 239000003146 anticoagulant agent Substances 0.000 description 3
- 230000010100 anticoagulation Effects 0.000 description 3
- 238000002386 leaching Methods 0.000 description 3
- 230000002265 prevention Effects 0.000 description 3
- 208000004043 venous thromboembolism Diseases 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
- 229960005080 warfarin Drugs 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 2
- 206010051055 Deep vein thrombosis Diseases 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 206010014522 Embolism venous Diseases 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 208000032843 Hemorrhage Diseases 0.000 description 2
- 208000006193 Pulmonary infarction Diseases 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 101000712605 Theromyzon tessulatum Theromin Proteins 0.000 description 2
- 229940122388 Thrombin inhibitor Drugs 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 230000001133 acceleration Effects 0.000 description 2
- 230000001154 acute effect Effects 0.000 description 2
- 229940127219 anticoagulant drug Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 230000006399 behavior Effects 0.000 description 2
- 230000009286 beneficial effect Effects 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 230000008859 change Effects 0.000 description 2
- 238000006243 chemical reaction Methods 0.000 description 2
- 230000015271 coagulation Effects 0.000 description 2
- 238000005345 coagulation Methods 0.000 description 2
- 235000013409 condiments Nutrition 0.000 description 2
- 230000007547 defect Effects 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000010977 jade Substances 0.000 description 2
- 150000002576 ketones Chemical group 0.000 description 2
- 238000013150 knee replacement Methods 0.000 description 2
- 239000006101 laboratory sample Substances 0.000 description 2
- 150000003951 lactams Chemical group 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000000465 moulding Methods 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 230000007575 pulmonary infarction Effects 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 238000005070 sampling Methods 0.000 description 2
- 238000001356 surgical procedure Methods 0.000 description 2
- 239000003868 thrombin inhibitor Substances 0.000 description 2
- 230000001732 thrombotic effect Effects 0.000 description 2
- 238000011541 total hip replacement Methods 0.000 description 2
- 229940055725 xarelto Drugs 0.000 description 2
- OVBICQMTCPFEBS-SATRDZAXSA-N (2s)-1-[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2s)-2-[[(2s)-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-acetamido-3-naphthalen-2-ylpropanoyl]amino]-3-(4-chlorophenyl)propanoyl]amino]-3-pyridin-3-ylpropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-6-[bi Chemical compound CC(O)=O.CC(O)=O.C([C@@H](C(=O)N[C@H](CCCCN=C(NCC)NCC)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCCCN=C(NCC)NCC)C(=O)N1[C@@H](CCC1)C(=O)N[C@H](C)C(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](CC=1C=NC=CC=1)NC(=O)[C@@H](CC=1C=CC(Cl)=CC=1)NC(=O)[C@@H](CC=1C=C2C=CC=CC2=CC=1)NC(C)=O)C1=CC=C(O)C=C1 OVBICQMTCPFEBS-SATRDZAXSA-N 0.000 description 1
- 206010008190 Cerebrovascular accident Diseases 0.000 description 1
- 108010074860 Factor Xa Proteins 0.000 description 1
- 206010019851 Hepatotoxicity Diseases 0.000 description 1
- 108010007267 Hirudins Proteins 0.000 description 1
- 102000007625 Hirudins Human genes 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- 208000006011 Stroke Diseases 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 201000007023 Thrombotic Thrombocytopenic Purpura Diseases 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 229930003448 Vitamin K Natural products 0.000 description 1
- 230000003213 activating effect Effects 0.000 description 1
- 206010000891 acute myocardial infarction Diseases 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229940127218 antiplatelet drug Drugs 0.000 description 1
- 229940127217 antithrombotic drug Drugs 0.000 description 1
- KXNPVXPOPUZYGB-XYVMCAHJSA-N argatroban Chemical compound OC(=O)[C@H]1C[C@H](C)CCN1C(=O)[C@H](CCCN=C(N)N)NS(=O)(=O)C1=CC=CC2=C1NC[C@H](C)C2 KXNPVXPOPUZYGB-XYVMCAHJSA-N 0.000 description 1
- 229960003856 argatroban Drugs 0.000 description 1
- OIRCOABEOLEUMC-GEJPAHFPSA-N bivalirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(N)=O)NC(=O)CNC(=O)CNC(=O)CNC(=O)CNC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 OIRCOABEOLEUMC-GEJPAHFPSA-N 0.000 description 1
- 229960001500 bivalirudin Drugs 0.000 description 1
- 108010055460 bivalirudin Proteins 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
- 230000023555 blood coagulation Effects 0.000 description 1
- 210000004204 blood vessel Anatomy 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 238000013172 carotid endarterectomy Methods 0.000 description 1
- 230000006652 catabolic pathway Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 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 description 1
- 229960003850 dabigatran Drugs 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000000857 drug effect Effects 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002708 enhancing effect Effects 0.000 description 1
- 229960000610 enoxaparin Drugs 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000003527 fibrinolytic agent Substances 0.000 description 1
- 229960003661 fondaparinux sodium Drugs 0.000 description 1
- XEKSTYNIJLDDAZ-JASSWCPGSA-F fondaparinux sodium Chemical compound [Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].[Na+].O[C@@H]1[C@@H](NS([O-])(=O)=O)[C@@H](OC)O[C@H](COS([O-])(=O)=O)[C@H]1O[C@H]1[C@H](OS([O-])(=O)=O)[C@@H](O)[C@H](O[C@@H]2[C@@H]([C@@H](OS([O-])(=O)=O)[C@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O[C@@H]4[C@@H]([C@@H](O)[C@H](O)[C@@H](COS([O-])(=O)=O)O4)NS([O-])(=O)=O)[C@H](O3)C(O)=O)O)[C@@H](COS([O-])(=O)=O)O2)NS([O-])(=O)=O)[C@H](C(O)=O)O1 XEKSTYNIJLDDAZ-JASSWCPGSA-F 0.000 description 1
- 108700032141 ganirelix Proteins 0.000 description 1
- 230000036397 gastrointestinal physiology Effects 0.000 description 1
- 238000000227 grinding Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000007686 hepatotoxicity Effects 0.000 description 1
- 231100000304 hepatotoxicity Toxicity 0.000 description 1
- 238000011540 hip replacement Methods 0.000 description 1
- 229940006607 hirudin Drugs 0.000 description 1
- WQPDUTSPKFMPDP-OUMQNGNKSA-N hirudin Chemical compound C([C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(OS(O)(=O)=O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC=1NC=NC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H]1N(CCC1)C(=O)[C@H](CCCCN)NC(=O)[C@H]1N(CCC1)C(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@H]1NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CCC(O)=O)NC(=O)CNC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)CNC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)CC)NC(=O)[C@@H]2CSSC[C@@H](C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@H](C(NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N2)=O)CSSC1)C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]1NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CO)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@@H](NC(=O)[C@H](CC=2C=CC(O)=CC=2)NC(=O)[C@@H](NC(=O)[C@@H](N)C(C)C)C(C)C)[C@@H](C)O)CSSC1)C(C)C)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 WQPDUTSPKFMPDP-OUMQNGNKSA-N 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 238000005286 illumination Methods 0.000 description 1
- 230000008676 import Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 210000000629 knee joint Anatomy 0.000 description 1
- 229960004408 lepirudin Drugs 0.000 description 1
- OTQCKZUSUGYWBD-BRHMIFOHSA-N lepirudin Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CS)C(=O)N[C@H](C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CO)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@H](C(=O)N[C@@H](CS)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)NCC(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CS)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CS)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC=1NC=NC=1)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC(O)=O)C(=O)NCC(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(N)=O)C(O)=O)C(C)C)[C@@H](C)O)[C@@H](C)O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC(C)C)[C@@H](C)O)C1=CC=C(O)C=C1 OTQCKZUSUGYWBD-BRHMIFOHSA-N 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 238000009115 maintenance therapy Methods 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004531 microgranule Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 210000005259 peripheral blood Anatomy 0.000 description 1
- 239000011886 peripheral blood Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- SHUZOJHMOBOZST-UHFFFAOYSA-N phylloquinone Natural products CC(C)CCCCC(C)CCC(C)CCCC(=CCC1=C(C)C(=O)c2ccccc2C1=O)C SHUZOJHMOBOZST-UHFFFAOYSA-N 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 238000012805 post-processing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- 239000013558 reference substance Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000008247 solid mixture Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- DENPQNAWGQXKCU-UHFFFAOYSA-N thiophene-2-carboxamide Chemical class NC(=O)C1=CC=CS1 DENPQNAWGQXKCU-UHFFFAOYSA-N 0.000 description 1
- 229940043263 traditional drug Drugs 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019168 vitamin K Nutrition 0.000 description 1
- 239000011712 vitamin K Substances 0.000 description 1
- 150000003721 vitamin K derivatives Chemical class 0.000 description 1
- 229940046010 vitamin k Drugs 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
原辅料 | 单位制剂含量 |
利伐沙班 | 10mg-20mg |
正戊醇 | 适量 |
羟丙纤维素 | 10mg-20mg |
微晶纤维素 | 49mg-35mg |
甘露醇 | 25mg-18mg |
交联羧甲基纤维素钠 | 5mg |
硬脂酰富马酸钠 | 1mg-2mg |
素片片重 | 100mg |
欧巴代(R)II | 增重3%-5% |
原辅料 | 规格1 | 规格2 | 规格3 |
利伐沙班 | 10g | 15g | 20g |
正戊醇 | 适量 | 适量 | 适量 |
羟丙纤维素 | 10g | 15g | 20g |
微晶纤维素 | 49g | 42g | 35g |
甘露醇 | 25g | 21g | 18g |
交联羧甲基纤维素钠 | 5g | 5g | 5g |
硬脂酰富马酸钠 | 1g | 2g | 2g |
共制成 | 1000片 | 1000片 | 1000片 |
欧巴代(R)II | 增重3%-5% | 增重3%-5% | 增重3%-5% |
原辅料 | 利伐沙班 | 羟丙纤维素 | 微晶纤维素 | 甘露醇 | 交联羧甲基纤维素钠 | 硬脂酰富马酸钠 | 正戊醇 | 欧巴代(R)II |
处方一 | 10.0g | 5.0g | 53.0g | 26.0g | 5.0g | 1.0g | 适量 | 增重3-5% |
处方二 | 10.0g | 10.0g | 49.0g | 25.0g | 5.0g | 1.0g | 适量 | 增重3-5% |
处方三 | 10.0g | 20.0g | 43.0g | 21.0g | 5.0g | 1.0g | 适量 | 增重3-5% |
处方四 | 15.0g | 7.5g | 48.0g | 24.0g | 5.0g | 1.0g | 适量 | 增重3-5% |
处方五 | 15.0g | 15.0g | 42.0g | 21.0g | 5.0g | 2.0g | 适量 | 增重3-5% |
处方六 | 15.0g | 30.0g | 32.0g | 16.0g | 5.0g | 2.0g | 适量 | 增重3-5% |
处方七 | 20.0g | 1.0g | 48.0g | 24.0g | 5.0g | 2.0g | 适量 | 增重3-5% |
处方八 | 20.0g | 20.0g | 35.0g | 18.0g | 5.0g | 2.0g | 适量 | 增重3-5% |
处方九 | 20.0g | 40.0g | 22.0g | 11.0g | 5.0g | 2.0g | 适量 | 增重3-5% |
样品 | 10min | 15min | 20min | 30min | 45min |
A(处方二) | 55.76 | 75.18 | 86.86 | 94.67 | 96.97 |
B(拜瑞妥10mg) | 52.89 | 71.76 | 83.35 | 91.22 | 93.50 |
C(处方五) | 54.09 | 74.23 | 86.42 | 94.08 | 96.86 |
D(拜瑞妥15mg) | 51.01 | 72.25 | 82.78 | 89.48 | 95.01 |
E(处方八) | 55.73 | 75.52 | 86.84 | 93.31 | 96.46 |
F(拜瑞妥20mg) | 50.69 | 72.12 | 82.52 | 91.06 | 93.60 |
原辅料 | 用量 |
利伐沙班 | 10g |
正戊醇 | 适量 |
羟丙纤维素 | 10g |
微晶纤维素 | 49g |
甘露醇 | 25g |
交联羧甲基纤维素钠 | 5g |
硬脂酰富马酸钠 | 1g |
共制成 | 1000片 |
欧巴代(R)II | 增重3%-5% |
原辅料 | 用量 |
利伐沙班 | 15g |
正戊醇 | 适量 |
羟丙纤维素 | 15g |
微晶纤维素 | 42g |
甘露醇 | 21g |
交联羧甲基纤维素钠 | 5g |
硬脂酰富马酸钠 | 2g |
共制成 | 1000片 |
欧巴代(R)II | 增重3%-5% |
原辅料 | 用量 |
利伐沙班 | 20g |
正戊醇 | 适量 |
羟丙纤维素 | 20g |
微晶纤维素 | 35g |
甘露醇 | 18g |
交联羧甲基纤维素钠 | 5g |
硬脂酰富马酸钠 | 2g |
共制成 | 1000片 |
欧巴代(R)II | 增重3%-5% |
Claims (8)
Priority Applications (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110032235.9A CN112656772B (zh) | 2015-10-15 | 2015-10-15 | 利伐沙班药物组合物 |
CN201510670400.8A CN105232488B (zh) | 2015-10-15 | 2015-10-15 | 一种含有利伐沙班的固体药物组合物 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN201510670400.8A CN105232488B (zh) | 2015-10-15 | 2015-10-15 | 一种含有利伐沙班的固体药物组合物 |
Related Child Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110032235.9A Division CN112656772B (zh) | 2015-10-15 | 2015-10-15 | 利伐沙班药物组合物 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN105232488A true CN105232488A (zh) | 2016-01-13 |
CN105232488B CN105232488B (zh) | 2021-05-04 |
Family
ID=55030492
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN201510670400.8A Active CN105232488B (zh) | 2015-10-15 | 2015-10-15 | 一种含有利伐沙班的固体药物组合物 |
CN202110032235.9A Active CN112656772B (zh) | 2015-10-15 | 2015-10-15 | 利伐沙班药物组合物 |
Family Applications After (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202110032235.9A Active CN112656772B (zh) | 2015-10-15 | 2015-10-15 | 利伐沙班药物组合物 |
Country Status (1)
Country | Link |
---|---|
CN (2) | CN105232488B (zh) |
Cited By (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN105726499A (zh) * | 2016-02-01 | 2016-07-06 | 深圳信立泰药业股份有限公司 | 一种利伐沙班药物组合物及其制备方法 |
CN108836947A (zh) * | 2018-07-12 | 2018-11-20 | 天津双硕医药科技有限公司 | 一种维奈妥拉纳米晶体口服固体药物组合物 |
CN109157516A (zh) * | 2018-11-05 | 2019-01-08 | 天津双硕医药科技有限公司 | 一种西洛他唑口服固体药物组合物 |
US10723700B2 (en) | 2015-08-12 | 2020-07-28 | Incyte Corporation | Salts of an LSD1 inhibitor |
US10800779B2 (en) | 2015-04-03 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US10968200B2 (en) | 2018-08-31 | 2021-04-06 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
US10968221B2 (en) | 2014-07-10 | 2021-04-06 | Incyte Corporation | Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US11155532B2 (en) | 2014-02-13 | 2021-10-26 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US11247992B2 (en) | 2014-02-13 | 2022-02-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN114533899B (zh) * | 2022-03-08 | 2023-01-31 | 山东新时代药业有限公司 | 一种利伐沙班制剂及其制备方法 |
Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101282968A (zh) * | 2005-10-04 | 2008-10-08 | 拜耳医药保健股份公司 | 新型多晶态形式和非晶态形式的5-氯-n-({(5s)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1,3-唑烷-5-基}-甲基)-2-噻吩羧酰胺 |
WO2010017948A2 (en) * | 2008-08-11 | 2010-02-18 | Ratiopharm Gmbh | Pharmaceutical compositions with modified release properties comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl)-methyl)-2-thiophencarboxamid |
CN103550165A (zh) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | 一种含有利伐沙班的药物组合物及其制备方法 |
CN103705520A (zh) * | 2013-12-27 | 2014-04-09 | 华润赛科药业有限责任公司 | 一种利伐沙班固体组合物的制备方法 |
EP2808011A1 (en) * | 2013-05-29 | 2014-12-03 | Sandoz Ag | Process for the preparation of a pharmaceutical composition comprising Rivaroxaban |
CN104666262A (zh) * | 2015-02-03 | 2015-06-03 | 山东新时代药业有限公司 | 一种利伐沙班片 |
EP2907507A1 (en) * | 2014-02-17 | 2015-08-19 | Sandoz Ag | Pharmaceutical composition comprising apixaban |
CN104887633A (zh) * | 2014-03-04 | 2015-09-09 | 山东新时代药业有限公司 | 一种利伐沙班片剂及其制备方法 |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP2554159A1 (en) * | 2011-08-04 | 2013-02-06 | ratiopharm GmbH | Dosage forms comprising apixaban and content uniformity enhancer |
CN104173313B (zh) * | 2014-08-25 | 2017-05-17 | 杭州朱养心药业有限公司 | 利伐沙班片剂药物组合物 |
-
2015
- 2015-10-15 CN CN201510670400.8A patent/CN105232488B/zh active Active
- 2015-10-15 CN CN202110032235.9A patent/CN112656772B/zh active Active
Patent Citations (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101282968A (zh) * | 2005-10-04 | 2008-10-08 | 拜耳医药保健股份公司 | 新型多晶态形式和非晶态形式的5-氯-n-({(5s)-2-氧-3-[4-(3-氧-4-吗啉基)-苯基]-1,3-唑烷-5-基}-甲基)-2-噻吩羧酰胺 |
WO2010017948A2 (en) * | 2008-08-11 | 2010-02-18 | Ratiopharm Gmbh | Pharmaceutical compositions with modified release properties comprising 5-chloro-n-({(5s)-2-oxo-3-[4-(3-oxo-4-morpholinyl)-phenyl]-1,3-oxazolidin-5-yl)-methyl)-2-thiophencarboxamid |
EP2808011A1 (en) * | 2013-05-29 | 2014-12-03 | Sandoz Ag | Process for the preparation of a pharmaceutical composition comprising Rivaroxaban |
CN103550165A (zh) * | 2013-10-19 | 2014-02-05 | 浙江华海药业股份有限公司 | 一种含有利伐沙班的药物组合物及其制备方法 |
CN103705520A (zh) * | 2013-12-27 | 2014-04-09 | 华润赛科药业有限责任公司 | 一种利伐沙班固体组合物的制备方法 |
EP2907507A1 (en) * | 2014-02-17 | 2015-08-19 | Sandoz Ag | Pharmaceutical composition comprising apixaban |
CN104887633A (zh) * | 2014-03-04 | 2015-09-09 | 山东新时代药业有限公司 | 一种利伐沙班片剂及其制备方法 |
CN104666262A (zh) * | 2015-02-03 | 2015-06-03 | 山东新时代药业有限公司 | 一种利伐沙班片 |
Non-Patent Citations (3)
Title |
---|
AGRAWAL ET AL.: "Apixaban:A New Player in the Anticoagulant Class", 《CURRENT DRUG TARGETS》 * |
杜艺伟等: "利伐沙班片处方与工艺的优化", 《中国当代医药》 * |
钟益玮等: "利伐沙班片的制备及处方优化", 《安徽医药》 * |
Cited By (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US11155532B2 (en) | 2014-02-13 | 2021-10-26 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US11247992B2 (en) | 2014-02-13 | 2022-02-15 | Incyte Corporation | Cyclopropylamines as LSD1 inhibitors |
US10968221B2 (en) | 2014-07-10 | 2021-04-06 | Incyte Corporation | Substituted [1,2,4]triazolo[1,5-a]pyrazines as LSD1 inhibitors |
US10800779B2 (en) | 2015-04-03 | 2020-10-13 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US11401272B2 (en) | 2015-04-03 | 2022-08-02 | Incyte Corporation | Heterocyclic compounds as LSD1 inhibitors |
US10723700B2 (en) | 2015-08-12 | 2020-07-28 | Incyte Corporation | Salts of an LSD1 inhibitor |
US11498900B2 (en) | 2015-08-12 | 2022-11-15 | Incyte Corporation | Salts of an LSD1 inhibitor |
CN105726499A (zh) * | 2016-02-01 | 2016-07-06 | 深圳信立泰药业股份有限公司 | 一种利伐沙班药物组合物及其制备方法 |
CN108836947A (zh) * | 2018-07-12 | 2018-11-20 | 天津双硕医药科技有限公司 | 一种维奈妥拉纳米晶体口服固体药物组合物 |
US10968200B2 (en) | 2018-08-31 | 2021-04-06 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
US11512064B2 (en) | 2018-08-31 | 2022-11-29 | Incyte Corporation | Salts of an LSD1 inhibitor and processes for preparing the same |
CN109157516A (zh) * | 2018-11-05 | 2019-01-08 | 天津双硕医药科技有限公司 | 一种西洛他唑口服固体药物组合物 |
Also Published As
Publication number | Publication date |
---|---|
CN112656772B (zh) | 2022-05-20 |
CN112656772A (zh) | 2021-04-16 |
CN105232488B (zh) | 2021-05-04 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN105232488A (zh) | 一种含有利伐沙班的固体药物组合物 | |
CN104173313B (zh) | 利伐沙班片剂药物组合物 | |
US20070026065A1 (en) | Solid, modified-release pharmaceutical dosage forms which can be administered orally | |
CN105555258A (zh) | 包含无定形达格列净的制剂 | |
CN106102716A (zh) | 雄激素受体拮抗剂的固体药物组合物 | |
CA2601955A1 (en) | Pharmaceutical composition comprising an omega-carboxyaryl substituted diphenyl urea for the treatment of cancer | |
CN105078915A (zh) | 一种利伐沙班片及其制备方法 | |
CN104434805A (zh) | 一种替格瑞洛固体分散体及其制备方法 | |
CN102764264A (zh) | 一种具高溶出度的塞来昔布固体组合物、制备方法及应用 | |
CN104644577A (zh) | 一种利伐沙班口腔崩解片及其制备方法 | |
CA2764172A1 (en) | A thrombin receptor antagonist and clopidogrel fixed dose tablet | |
CN111297822A (zh) | 一种利伐沙班微丸胶囊及其制备方法 | |
CN105395504A (zh) | 一种盐酸氟桂利嗪骨架缓释片及其制备方法 | |
CN103006594A (zh) | 一种格列美脲组合物及其制备方法 | |
CN102008469B (zh) | 一种替米沙坦氨氯地平片的制备方法 | |
CN102379855A (zh) | 格列美脲分散片及其制备方法 | |
CN103505460B (zh) | 一种制备氯沙坦钾氢氯噻嗪组合物的方法 | |
CN105395506A (zh) | 一种盐酸可乐定缓释片 | |
CN105030717A (zh) | 一种盐酸莫西沙星薄膜衣片及其制备方法 | |
CN103800336A (zh) | 一种具有抗血栓活性药物的组合物 | |
CN108721238A (zh) | 一种碳酸锂缓释片 | |
CN101744780A (zh) | 氯吡格雷分散片及其制备方法 | |
CN101601660A (zh) | 一种含氯吡格雷的可溶片剂 | |
KR101910707B1 (ko) | 복용순응도가 향상된 메트포르민 서방성 정제 및 이의 제조방법 | |
CN104650058A (zh) | 利伐沙班一水合物化合物 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20210414 Address after: Room 201, No.5, Lane 3399, Kangxin Road, Pudong New Area, Shanghai Applicant after: SHANGHAI LINKCHEM TECHNOLOGY Co.,Ltd. Address before: Room 8-703, No.1 Swan Lake, south of Guangyuan Road, Wuqing Development Zone, Wuqing District, Tianjin Applicant before: Yang Yuting |
|
GR01 | Patent grant | ||
GR01 | Patent grant | ||
CP03 | Change of name, title or address |
Address after: Room 201, No. 5, Lane 3399, Kangxin Road, Pudong New Area, Shanghai, 201318 Patentee after: Shanghai Lingkai Technology Co.,Ltd. Country or region after: China Address before: Room 201, No.5, Lane 3399, Kangxin Road, Pudong New Area, Shanghai Patentee before: SHANGHAI LINKCHEM TECHNOLOGY Co.,Ltd. Country or region before: China |