WO1996034607A1 - Kombinationspräparate mit vaskulärer wirkung, welche dihydropyridine, acetylsalicylsäure-nitroester und vitamine enthalten - Google Patents
Kombinationspräparate mit vaskulärer wirkung, welche dihydropyridine, acetylsalicylsäure-nitroester und vitamine enthalten Download PDFInfo
- Publication number
- WO1996034607A1 WO1996034607A1 PCT/EP1996/001631 EP9601631W WO9634607A1 WO 1996034607 A1 WO1996034607 A1 WO 1996034607A1 EP 9601631 W EP9601631 W EP 9601631W WO 9634607 A1 WO9634607 A1 WO 9634607A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- radical
- nimodipine
- acetylsalicylic acid
- vitamins
- dihydropyridines
- Prior art date
Links
- 125000004925 dihydropyridyl group Chemical group N1(CC=CC=C1)* 0.000 title claims abstract description 11
- 229940088594 vitamin Drugs 0.000 title claims abstract description 9
- 229930003231 vitamin Natural products 0.000 title claims abstract description 9
- 235000013343 vitamin Nutrition 0.000 title claims abstract description 9
- 239000011782 vitamin Substances 0.000 title claims abstract description 9
- MABOJVBZGLJSDS-UHFFFAOYSA-N nitro 2-acetyloxybenzoate Chemical class CC(=O)OC1=CC=CC=C1C(=O)O[N+]([O-])=O MABOJVBZGLJSDS-UHFFFAOYSA-N 0.000 title claims abstract description 5
- 238000002360 preparation method Methods 0.000 title claims description 9
- 230000002792 vascular Effects 0.000 title abstract description 4
- 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 40
- 229960000715 nimodipine Drugs 0.000 claims description 40
- 244000194101 Ginkgo biloba Species 0.000 claims description 38
- 239000000284 extract Substances 0.000 claims description 29
- BSYNRYMUTXBXSQ-UHFFFAOYSA-N Aspirin Chemical compound CC(=O)OC1=CC=CC=C1C(O)=O BSYNRYMUTXBXSQ-UHFFFAOYSA-N 0.000 claims description 23
- 125000004432 carbon atom Chemical group C* 0.000 claims description 14
- 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 9
- 229960001597 nifedipine Drugs 0.000 claims description 9
- 229960000528 amlodipine Drugs 0.000 claims description 7
- 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 7
- 229960001138 acetylsalicylic acid Drugs 0.000 claims description 5
- 239000004480 active ingredient Substances 0.000 claims description 5
- 235000019155 vitamin A Nutrition 0.000 claims description 5
- 239000011719 vitamin A Substances 0.000 claims description 5
- 125000000217 alkyl group Chemical group 0.000 claims description 4
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical group [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 4
- OENHQHLEOONYIE-UKMVMLAPSA-N beta-Carotene Chemical compound CC=1CCCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C OENHQHLEOONYIE-UKMVMLAPSA-N 0.000 claims description 4
- 239000001301 oxygen Substances 0.000 claims description 4
- 229910052760 oxygen Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 3
- 235000019156 vitamin B Nutrition 0.000 claims description 3
- 239000011720 vitamin B Substances 0.000 claims description 3
- 235000019154 vitamin C Nutrition 0.000 claims description 3
- 239000011718 vitamin C Substances 0.000 claims description 3
- 235000019165 vitamin E Nutrition 0.000 claims description 3
- 239000011709 vitamin E Substances 0.000 claims description 3
- 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 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims description 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000002947 alkylene group Chemical group 0.000 claims description 2
- 235000013734 beta-carotene Nutrition 0.000 claims description 2
- 239000011648 beta-carotene Substances 0.000 claims description 2
- TUPZEYHYWIEDIH-WAIFQNFQSA-N beta-carotene Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CCCC1(C)C)C=CC=C(/C)C=CC2=CCCCC2(C)C TUPZEYHYWIEDIH-WAIFQNFQSA-N 0.000 claims description 2
- 229960002747 betacarotene Drugs 0.000 claims description 2
- 239000000460 chlorine Substances 0.000 claims description 2
- 229910052801 chlorine Inorganic materials 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 239000001257 hydrogen Substances 0.000 claims description 2
- 229910052739 hydrogen Inorganic materials 0.000 claims description 2
- 125000004435 hydrogen atom Chemical class [H]* 0.000 claims description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 2
- 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 2
- 229960000227 nisoldipine Drugs 0.000 claims description 2
- 229960005425 nitrendipine Drugs 0.000 claims description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- 235000019166 vitamin D Nutrition 0.000 claims description 2
- 239000011710 vitamin D Substances 0.000 claims description 2
- 150000003722 vitamin derivatives Chemical class 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 claims 2
- 239000000654 additive Substances 0.000 claims 1
- 238000011282 treatment Methods 0.000 abstract description 7
- 239000013543 active substance Substances 0.000 abstract description 4
- 230000002526 effect on cardiovascular system Effects 0.000 abstract description 3
- 208000024172 Cardiovascular disease Diseases 0.000 abstract description 2
- 230000002265 prevention Effects 0.000 abstract description 2
- 208000026106 cerebrovascular disease Diseases 0.000 abstract 1
- 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 description 38
- 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 38
- DFPAKSUCGFBDDF-UHFFFAOYSA-N Nicotinamide Chemical compound NC(=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-UHFFFAOYSA-N 0.000 description 36
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 33
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 32
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 20
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 20
- -1 dihydropyridines acetylsalicylic acid nitroesters Chemical class 0.000 description 20
- 229930182470 glycoside Natural products 0.000 description 20
- 235000019171 pyridoxine hydrochloride Nutrition 0.000 description 20
- 239000011764 pyridoxine hydrochloride Substances 0.000 description 20
- 235000007586 terpenes Nutrition 0.000 description 20
- 229940011671 vitamin b6 Drugs 0.000 description 20
- 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 description 19
- ZAKOWWREFLAJOT-CEFNRUSXSA-N D-alpha-tocopherylacetate Chemical compound CC(=O)OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C ZAKOWWREFLAJOT-CEFNRUSXSA-N 0.000 description 19
- FPIPGXGPPPQFEQ-OVSJKPMPSA-N all-trans-retinol Chemical compound OC\C=C(/C)\C=C\C=C(/C)\C=C\C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-OVSJKPMPSA-N 0.000 description 19
- 229960002104 cyanocobalamin Drugs 0.000 description 19
- 235000000639 cyanocobalamin Nutrition 0.000 description 19
- 239000011666 cyanocobalamin Substances 0.000 description 19
- ZUFQODAHGAHPFQ-UHFFFAOYSA-N pyridoxine hydrochloride Chemical compound Cl.CC1=NC=C(CO)C(CO)=C1O ZUFQODAHGAHPFQ-UHFFFAOYSA-N 0.000 description 19
- 229960002477 riboflavin Drugs 0.000 description 19
- 235000019192 riboflavin Nutrition 0.000 description 19
- 239000002151 riboflavin Substances 0.000 description 19
- 229940042585 tocopherol acetate Drugs 0.000 description 19
- 229960003966 nicotinamide Drugs 0.000 description 18
- 235000005152 nicotinamide Nutrition 0.000 description 18
- 239000011570 nicotinamide Substances 0.000 description 18
- UIERGBJEBXXIGO-UHFFFAOYSA-N thiamine mononitrate Chemical compound [O-][N+]([O-])=O.CC1=C(CCO)SC=[N+]1CC1=CN=C(C)N=C1N UIERGBJEBXXIGO-UHFFFAOYSA-N 0.000 description 18
- 239000003826 tablet Substances 0.000 description 17
- 235000019359 magnesium stearate Nutrition 0.000 description 16
- 229940086704 ascorbic acid 200 mg Drugs 0.000 description 14
- 150000002338 glycosides Chemical class 0.000 description 12
- 229960004106 citric acid Drugs 0.000 description 11
- 239000007938 effervescent tablet Substances 0.000 description 11
- 239000001509 sodium citrate Substances 0.000 description 11
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 11
- 239000000843 powder Substances 0.000 description 10
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 10
- 235000017557 sodium bicarbonate Nutrition 0.000 description 10
- 229910000029 sodium carbonate Inorganic materials 0.000 description 10
- 150000002596 lactones Chemical class 0.000 description 9
- 238000004519 manufacturing process Methods 0.000 description 9
- 239000000203 mixture Substances 0.000 description 9
- 150000003505 terpenes Chemical class 0.000 description 9
- 229920002261 Corn starch Polymers 0.000 description 8
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 8
- 239000008120 corn starch Substances 0.000 description 8
- 229940099112 cornstarch Drugs 0.000 description 8
- 229930003944 flavone Natural products 0.000 description 8
- 235000011949 flavones Nutrition 0.000 description 8
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 6
- 239000008187 granular material Substances 0.000 description 6
- 239000007939 sustained release tablet Substances 0.000 description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 5
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000011777 magnesium Substances 0.000 description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 4
- 208000019553 vascular disease Diseases 0.000 description 4
- 229940085398 ascorbic acid 50 mg Drugs 0.000 description 3
- MWUXSHHQAYIFBG-UHFFFAOYSA-N nitrogen oxide Inorganic materials O=[N] MWUXSHHQAYIFBG-UHFFFAOYSA-N 0.000 description 3
- FPIPGXGPPPQFEQ-UHFFFAOYSA-N 13-cis retinol Natural products OCC=C(C)C=CC=C(C)C=CC1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-UHFFFAOYSA-N 0.000 description 2
- BSYNRYMUTXBXSQ-FOQJRBATSA-N 59096-14-9 Chemical compound CC(=O)OC1=CC=CC=C1[14C](O)=O BSYNRYMUTXBXSQ-FOQJRBATSA-N 0.000 description 2
- 208000007814 Unstable Angina Diseases 0.000 description 2
- FPIPGXGPPPQFEQ-BOOMUCAASA-N Vitamin A Natural products OC/C=C(/C)\C=C\C=C(\C)/C=C/C1=C(C)CCCC1(C)C FPIPGXGPPPQFEQ-BOOMUCAASA-N 0.000 description 2
- VRAIHTAYLFXSJJ-UHFFFAOYSA-N alumane Chemical compound [AlH3].[AlH3] VRAIHTAYLFXSJJ-UHFFFAOYSA-N 0.000 description 2
- 230000003288 anthiarrhythmic effect Effects 0.000 description 2
- 235000010323 ascorbic acid Nutrition 0.000 description 2
- 229960005070 ascorbic acid Drugs 0.000 description 2
- 239000011668 ascorbic acid Substances 0.000 description 2
- 230000002213 calciumantagonistic effect Effects 0.000 description 2
- 230000002490 cerebral effect Effects 0.000 description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 238000001727 in vivo Methods 0.000 description 2
- 229940095440 nifedipine 30 mg Drugs 0.000 description 2
- 229940016070 nifedipine 90 mg Drugs 0.000 description 2
- 230000008092 positive effect Effects 0.000 description 2
- 238000011321 prophylaxis Methods 0.000 description 2
- 230000002195 synergetic effect Effects 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 229940045997 vitamin a Drugs 0.000 description 2
- AEDORKVKMIVLBW-BLDDREHASA-N 3-oxo-3-[[(2r,3s,4s,5r,6r)-3,4,5-trihydroxy-6-[[5-hydroxy-4-(hydroxymethyl)-6-methylpyridin-3-yl]methoxy]oxan-2-yl]methoxy]propanoic acid Chemical compound OCC1=C(O)C(C)=NC=C1CO[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](COC(=O)CC(O)=O)O1 AEDORKVKMIVLBW-BLDDREHASA-N 0.000 description 1
- 0 CC(NC(*)=C1*)=C(*)C1/C1=C/C=C/*(*)/C=*(\*)/C1 Chemical compound CC(NC(*)=C1*)=C(*)C1/C1=C/C=C/*(*)/C=*(\*)/C1 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- JRWZLRBJNMZMFE-UHFFFAOYSA-N Dobutamine Chemical compound C=1C=C(O)C(O)=CC=1CCNC(C)CCC1=CC=C(O)C=C1 JRWZLRBJNMZMFE-UHFFFAOYSA-N 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound 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 1
- 206010020772 Hypertension Diseases 0.000 description 1
- 206010061216 Infarction Diseases 0.000 description 1
- SNIOPGDIGTZGOP-UHFFFAOYSA-N Nitroglycerin Chemical compound [O-][N+](=O)OCC(O[N+]([O-])=O)CO[N+]([O-])=O SNIOPGDIGTZGOP-UHFFFAOYSA-N 0.000 description 1
- 239000000006 Nitroglycerin Substances 0.000 description 1
- DFPAKSUCGFBDDF-ZQBYOMGUSA-N [14c]-nicotinamide Chemical compound N[14C](=O)C1=CC=CN=C1 DFPAKSUCGFBDDF-ZQBYOMGUSA-N 0.000 description 1
- 229940066481 amlodipine 10 mg Drugs 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 230000007211 cardiovascular event Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 238000007887 coronary angioplasty Methods 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229960001089 dobutamine Drugs 0.000 description 1
- 239000008298 dragée Substances 0.000 description 1
- 239000006196 drop Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229960003711 glyceryl trinitrate Drugs 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- 230000001631 hypertensive effect Effects 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 229960000201 isosorbide dinitrate Drugs 0.000 description 1
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 238000012153 long-term therapy Methods 0.000 description 1
- 229940079467 nifedipine 10 mg Drugs 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000006187 pill Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000009257 reactivity Effects 0.000 description 1
- 239000013557 residual solvent Substances 0.000 description 1
- 208000037803 restenosis Diseases 0.000 description 1
- 229960001790 sodium citrate Drugs 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009424 thromboembolic effect Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/60—Salicylic acid; Derivatives thereof
- A61K31/618—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate
- A61K31/621—Salicylic acid; Derivatives thereof having the carboxyl group in position 1 esterified, e.g. salsalate having the hydroxy group in position 2 esterified, e.g. benorylate
Definitions
- the invention relates to new combination preparations for the prevention and treatment of vascular diseases, in particular cardiovascular and cerebral vascular diseases, containing calcium antagonistically active dihydropyridines, acetylsalicylic acid nitro esters and vitamins and, if appropriate, further auxiliaries or active substances.
- the individual elements of the combination according to the invention and their therapeutic effects on the vascular system are largely known. This applies in particular to the calcium-antagonistic active ingredients and to acetylsalicylic acid, hereinafter referred to as ASS, and some of its derivatives. It is also known that e.g. ASA or calcium-antagonistic dihydropyridines such as nifedipine and also combinations of these active substances have a positive synergistic effect on thrombogenesis (see E. Dong et al., Effects of the combination of
- Combinations of parenterally administered nitroglycerin with nifedipine, isosorbide dinitrate, heparin and ASA show a clearly antiarrhythmic effect with unstable angina pectoris at the end of the first week of treatment, which also persists with further treatment with a lower dose (cf. TE Dobrotvorskaya et al., Antiarrhythmic effect of Cordaron in patients with unstable angina pectoris and myocard infarction, Klin. Med. (Mosk.) 67 (II) (1993)).
- ASA is used for the prophylaxis of thromboembolic and cardiovascular events. ASA derivatives that are split into ASA and nitrogen oxides in vivo are also known and, with the same potency as ASA, are said to have fewer gastrointestinal side effects (cf. WO 92/01668, 6.2.1992).
- the invention relates to new combinations of dihydropyridines of the general formula (I)
- R 1 is cyano or alkyl having 1 to 4 carbon atoms, which is optionally substituted by hydroxy or represents the radical OCH 2 CH 2 NH 2 ,
- R 2 and R 3 are the same or different and each represent alkyl having 1 to 4 carbon atoms, which is optionally substituted by alkoxy having 1 to 4 carbon atoms or by an N-methylbenzyl radical,
- R 4 and R 5 are the same or different and each represent hydrogen, nitro, trifluoromethyl, chlorine or the radical OCHF 2 or together with
- A represents oxygen or NH
- B represents a straight-chain or branched alkylene radical having 2 to 7 C atoms, a cycloalkylene radical having 3 to 7 C atoms or an aralkylene radical having 7 to 12 C atoms and
- n a number from 1 to 5, preferably 1 to 3,
- nifedipine nifedipine, amlodipine, nimodipine, nitrendipine and nisoldipine.
- Combination therapy with nimodipine is particularly recommended for the treatment of cerebral vascular diseases.
- Combinations containing nifedipine or amlodipine are of particular interest for the treatment of cardiovascular diseases.
- ASA derivatives are particularly well tolerated and are therefore suitable for the prophylaxis and long-term therapy of corresponding vascular diseases.
- the combination according to the invention can be used in conventional application forms for oral administration. Preferred are: tablets, pills, dragees, capsules, solutions, drops and sprays.
- Sodium citrate, citric acid, ascorbic acid, nifedipine and nicotinamide are granulated with water in the fluidized bed and then dried.
- the grain size of the granules is preferably 90% between 125 and 400 ⁇ m.
- the remaining constituents are mixed into these granules (acetylsalicylic acid, vitamin A, riboflavin, pyridoxine-HCl, cyanocobalamin, D- ⁇ -tocopherol acetate, dry extract from gingkobiloba leaves) and this mixture on suitable tablet presses to form effervescent tablets with a Diameter of 20 mm pressed.
- the tablets are then packed, for example, in aluminum-aluminum blisters.
- the granules are then mixed with magnesium stearate and pressed into oblong tablets.
- the tablets are then packed, for example, in aluminum-aluminum blisters.
- Examples 8 to 10 are prepared analogously.
- Metholose 60 SH 50 400 mg
- a coprecipitate is used due to the low solubility of the nimodipine. This coprecipitate releases nimodipine rapidly and oversaturated in vitro, so that the active ingredient quickly becomes bioavailable in vivo.
- composition of the coprecipitate is composition of the coprecipitate:
- Nimodipine and PVP are dissolved in a sufficient amount of acetone or ethanol.
- the solvent is then stripped off with heating and reduced pressure and the nimodipine-PVP coprecipitate formed is dried at elevated temperature (> 90 ° C.) until the residual solvent content is less than 200 ppm.
- the nimodipine coprecipitate produced in this way is X-ray amorphous and releases nimodipine quickly and supersaturated.
- the coprecipitate is ground and classified on suitable equipment.
- the ratio between nimodipine and PVP can vary between 1: 1 and 1: 5.
- NO-ASS 100 mg nimodipine coprecipitate 40 mg (10 mg
- Corn starch, Avicel, polyplasdone, ascorbic acid, nicotinamide, riboflavin and thiamine nitrate, pyridoxine HCl are granulated with water in the fluidized bed and then dried.
- the grain size of the granules is preferably 90% between 125 and 400 ⁇ m.
- NO-ASS, the nimodipine coprecipitate, vitamin A, pyridoxine HCl, cyanocobalamin, D- ⁇ -tocopherol acetate, the dry extract from gingko-biloba leaves and magnesium stearate are mixed with these granules and the mixture is compressed into suitable tablet presses on suitable tablet presses.
- the NO-ASS and the magnesium stearate are moistened with a suitable amount of water in a conventional mixer.
- This mixture is compressed under suitable conditions in an extruder and extruded, for example, through a 1 mm sieve plate. If necessary, the extrudate strands obtained in this way are rounded off in a spheronizer and then dried.
- the dried extrudate is mixed with the nimodipine coprecipitate, NO-ASS and magnesium stearate and compressed on suitable tablet machines (11 mm in diameter).
- the Gingko dry extract is moistened with cornstarch, Avicel and Polyplasdone with a sufficient amount of water in a conventional mixer. This mixture is compressed under suitable conditions in an extruder and extruded, for example, through a 1 mm sieve plate. The extrudate thus obtained If necessary, strands are rounded off in a spheronizer and then dried.
- the dried extrudate is mixed with the nimodipine coprecipitate, NO-ASS and magnesium stearate and compressed on suitable tablet machines (9 mm in diameter).
- the Gingko dry extract is moistened with corn starch, Avicel and Polyplasdone with a sufficient amount of water in a conventional mixer. This mixture is compressed under suitable conditions in an extruder and extruded, for example, through a 1 mm sieve plate. The extrudate strands obtained in this way are rounded off in a spheronizer if necessary and then dried.
- Example 19 sustained release tablet
- nimodipine coprecipitate For prolonged-release tablets, a special nimodipine coprecipitate must be prepared which allows supersaturated release over several hours.
- This sustained-release coprecipitate is produced analogously to the method in exemplary embodiment 11.
- the Gingko dry extract is moistened with cornstarch, Avicel and Polyplasdone with a sufficient amount of water in a conventional mixer. This mixture is compressed under suitable conditions in an extruder and extruded, for example, through a 1 mm sieve plate. The extrudate strands obtained in this way are rounded off * if necessary * in a spheronizer and then dried. - 26 -
- the dried extrudate is mixed with the nimodipine coprecipitate, NO-ASS and magnesium stearate and compressed on suitable tablet machines (11 mm in diameter).
- D- ⁇ -tocopherol acetate 15 mg dry extract from gingko biloba leaves (50: 1), 40 mg standardized to 960 mg gingkoflavone glycosides and 240 mg terpene lactones
- the NO-ASS and the magnesium stearate are moistened with a suitable amount of water in a conventional mixer.
- This mixture is compressed under suitable conditions in an extruder and extruded, for example, through a 1 mm sieve plate.
- the extrudate strands obtained in this way are rounded off in a spheronizer if necessary and then dried.
- the dried extrudate is mixed with the nimodipine coprecipitate, NO-ASS and magnesium stearate and compressed on suitable tablet machines (11 mm in diameter).
Abstract
Description
Claims
Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
AU56470/96A AU5647096A (en) | 1995-05-02 | 1996-04-19 | Combined preparations with vascular effect containing dihydr opyridines, acetylsalicylic acid nitroesters and vitamins |
EP96913513A EP0825866A1 (de) | 1995-05-02 | 1996-04-19 | Kombinationspräparate mit vaskulärer wirkung, welche dihydropyridine, acetylsalicylsäure-nitroester und vitamine enthalten |
US08/945,516 US5998448A (en) | 1995-05-02 | 1996-04-19 | Combined preparations with vascular effect containing dihydropyridines acetylsalicylic acid nitroesters and vitamins |
JP8532964A JPH11504907A (ja) | 1995-05-02 | 1996-04-19 | ジヒドロピリジン、アセチルサリチル酸ニトロエステル及びビタミンを含有する血管性効果を有する組み合わせ調剤 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19515971.3 | 1995-05-02 | ||
DE19515971A DE19515971A1 (de) | 1995-05-02 | 1995-05-02 | Kombinationspräparate mit vaskulärer Wirkung |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1996034607A1 true WO1996034607A1 (de) | 1996-11-07 |
Family
ID=7760804
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/EP1996/001631 WO1996034607A1 (de) | 1995-05-02 | 1996-04-19 | Kombinationspräparate mit vaskulärer wirkung, welche dihydropyridine, acetylsalicylsäure-nitroester und vitamine enthalten |
Country Status (6)
Country | Link |
---|---|
US (1) | US5998448A (de) |
EP (1) | EP0825866A1 (de) |
JP (1) | JPH11504907A (de) |
AU (1) | AU5647096A (de) |
DE (1) | DE19515971A1 (de) |
WO (1) | WO1996034607A1 (de) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999043331A1 (de) * | 1998-02-24 | 1999-09-02 | Ernst Albrecht Bender | Acetylsalicylsäure und folsäure zum dekoagulieren von blutplättchen |
Families Citing this family (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
AU2001262252A1 (en) * | 2000-05-15 | 2001-11-26 | Bayer Aktiengesellschaft | Means for treating attacks of auto-immune diseases |
US7569236B2 (en) * | 2003-10-10 | 2009-08-04 | Ethypharm | Sustained-release microgranules containing gingko biloba extract and the process for manufacturing these |
JP5519906B2 (ja) * | 2004-04-22 | 2014-06-11 | ハワード ジェイ. スミス アンド アソシエイツ ピーティーワイ エルティーディー | 肝臓疾患の支持療法 |
US8197871B2 (en) * | 2009-05-13 | 2012-06-12 | L Europa Gary A | Composition for headache treatment |
US8889157B1 (en) | 2010-08-31 | 2014-11-18 | Gary L'Europa | Composition for cardiovascular treatment |
PL3876912T3 (pl) | 2018-11-07 | 2023-08-07 | Dsm Ip Assets B.V. | Leki zawierające ryboflawinę wykazujące lepsze płynięcie |
-
1995
- 1995-05-02 DE DE19515971A patent/DE19515971A1/de not_active Withdrawn
-
1996
- 1996-04-19 EP EP96913513A patent/EP0825866A1/de not_active Withdrawn
- 1996-04-19 JP JP8532964A patent/JPH11504907A/ja active Pending
- 1996-04-19 US US08/945,516 patent/US5998448A/en not_active Expired - Fee Related
- 1996-04-19 WO PCT/EP1996/001631 patent/WO1996034607A1/de not_active Application Discontinuation
- 1996-04-19 AU AU56470/96A patent/AU5647096A/en not_active Abandoned
Non-Patent Citations (4)
Title |
---|
FETKOVSKA N. ET AL: "Treatment of hypertension with calcium antagonists and aspirin. Effects on 24-h platelet activity", AM. J. HYPERTENS., 1993, 6/3 II SUPPL. (98S-101S), USA, XP000602309 * |
FOLTS, JOHN D. ET AL: "Potentiation of the antiplatelet effect of aspirin by the calcium channel antagonist amlodipine", MED. SCI. SYMP. SER. (1993), 3(CALCIUM ANTAGONISTS), 165-71 CODEN: MSSYEI;ISSN: 0928-9550, 1993, XP000602310 * |
TISON P ET AL: "Effects of dihydropyridines and their combination with aspirin on blood pressure and circadian platelet activity in patients with essential hypertension", AMERICAN JOURNAL OF HYPERTENSION, 7 (7 PART 2). 1994. 46S-49S., XP000601397 * |
TISON P. ET AL: "Treatment of hypertension with dihydropyridine calcium antagonists and aspirin", BLOOD PRESS. SUPPL., 1994, 3/1 (57-60), NORWAY, XP000601396 * |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1999043331A1 (de) * | 1998-02-24 | 1999-09-02 | Ernst Albrecht Bender | Acetylsalicylsäure und folsäure zum dekoagulieren von blutplättchen |
Also Published As
Publication number | Publication date |
---|---|
JPH11504907A (ja) | 1999-05-11 |
EP0825866A1 (de) | 1998-03-04 |
DE19515971A1 (de) | 1996-11-07 |
AU5647096A (en) | 1996-11-21 |
US5998448A (en) | 1999-12-07 |
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