CN85101697A - 二氢吡啶化合制剂及其制备方法 - Google Patents
二氢吡啶化合制剂及其制备方法 Download PDFInfo
- Publication number
- CN85101697A CN85101697A CN198585101697A CN85101697A CN85101697A CN 85101697 A CN85101697 A CN 85101697A CN 198585101697 A CN198585101697 A CN 198585101697A CN 85101697 A CN85101697 A CN 85101697A CN 85101697 A CN85101697 A CN 85101697A
- Authority
- CN
- China
- Prior art keywords
- dihydropyridine
- weight
- preparation
- combination preparations
- beta
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 239000002671 adjuvant Substances 0.000 claims abstract description 13
- 239000002876 beta blocker Substances 0.000 claims abstract description 9
- 229940097320 beta blocking agent Drugs 0.000 claims abstract description 9
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 8
- 230000003197 catalytic effect Effects 0.000 claims abstract description 5
- -1 atanolol Chemical compound 0.000 claims description 12
- 229920002678 cellulose Polymers 0.000 claims description 9
- 235000010980 cellulose Nutrition 0.000 claims description 9
- 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 8
- 229960005425 nitrendipine Drugs 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 8
- 239000001913 cellulose Substances 0.000 claims description 7
- 150000001875 compounds Chemical class 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- METKIMKYRPQLGS-GFCCVEGCSA-N (R)-atenolol Chemical compound CC(C)NC[C@@H](O)COC1=CC=C(CC(N)=O)C=C1 METKIMKYRPQLGS-GFCCVEGCSA-N 0.000 claims description 5
- 229960002122 acebutolol Drugs 0.000 claims description 5
- GOEMGAFJFRBGGG-UHFFFAOYSA-N acebutolol Chemical compound CCCC(=O)NC1=CC=C(OCC(O)CNC(C)C)C(C(C)=O)=C1 GOEMGAFJFRBGGG-UHFFFAOYSA-N 0.000 claims description 5
- 229960002274 atenolol Drugs 0.000 claims description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000000945 filler Substances 0.000 claims description 4
- 239000001095 magnesium carbonate Substances 0.000 claims description 4
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000000126 substance Substances 0.000 claims description 4
- 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 claims description 3
- 229920002472 Starch Polymers 0.000 claims description 3
- 239000008101 lactose Substances 0.000 claims description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 3
- 239000008107 starch Substances 0.000 claims description 3
- 235000019698 starch Nutrition 0.000 claims description 3
- 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 2
- 125000003545 alkoxy group Chemical group 0.000 claims description 2
- 125000004432 carbon atom Chemical group C* 0.000 claims description 2
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 2
- 125000003963 dichloro group Chemical group Cl* 0.000 claims description 2
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 claims description 2
- 235000014380 magnesium carbonate Nutrition 0.000 claims description 2
- 229960000715 nimodipine Drugs 0.000 claims description 2
- 229960002508 pindolol Drugs 0.000 claims description 2
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims 2
- AQHHHDLHHXJYJD-UHFFFAOYSA-N propranolol Chemical compound C1=CC=C2C(OCC(O)CNC(C)C)=CC=CC2=C1 AQHHHDLHHXJYJD-UHFFFAOYSA-N 0.000 claims 2
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims 1
- 229910052799 carbon Inorganic materials 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- VWPOSFSPZNDTMJ-UCWKZMIHSA-N nadolol Chemical compound C1[C@@H](O)[C@@H](O)CC2=C1C=CC=C2OCC(O)CNC(C)(C)C VWPOSFSPZNDTMJ-UCWKZMIHSA-N 0.000 claims 1
- 229960004255 nadolol Drugs 0.000 claims 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 claims 1
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims 1
- 229960003712 propranolol Drugs 0.000 claims 1
- 238000007363 ring formation reaction Methods 0.000 claims 1
- 239000000377 silicon dioxide Substances 0.000 claims 1
- 235000012239 silicon dioxide Nutrition 0.000 claims 1
- 239000000203 mixture Substances 0.000 abstract description 7
- 239000008279 sol Substances 0.000 abstract description 5
- 230000036772 blood pressure Effects 0.000 abstract description 2
- 238000009472 formulation Methods 0.000 abstract 1
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 6
- 229920002261 Corn starch Polymers 0.000 description 6
- 239000003814 drug Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 235000019359 magnesium stearate Nutrition 0.000 description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 5
- 238000006243 chemical reaction Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 229920000881 Modified starch Polymers 0.000 description 3
- 239000004368 Modified starch Substances 0.000 description 3
- 239000002253 acid Substances 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 description 3
- 239000008120 corn starch Substances 0.000 description 3
- 238000001035 drying Methods 0.000 description 3
- 235000019426 modified starch Nutrition 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000004094 surface-active agent Substances 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
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 description 2
- 241000195493 Cryptophyta Species 0.000 description 2
- 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 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical class [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 230000000052 comparative effect Effects 0.000 description 2
- 150000002148 esters Chemical class 0.000 description 2
- 239000000463 material Substances 0.000 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 description 2
- 238000002156 mixing Methods 0.000 description 2
- 229960000227 nisoldipine Drugs 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- TWBNMYSKRDRHAT-RCWTXCDDSA-N (S)-timolol hemihydrate Chemical compound O.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1.CC(C)(C)NC[C@H](O)COC1=NSN=C1N1CCOCC1 TWBNMYSKRDRHAT-RCWTXCDDSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 239000004215 Carbon black (E152) Substances 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 239000006096 absorbing agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 238000007605 air drying Methods 0.000 description 1
- 125000001931 aliphatic group Chemical group 0.000 description 1
- 150000001412 amines Chemical class 0.000 description 1
- 229910021529 ammonia Inorganic materials 0.000 description 1
- 239000002519 antifouling agent Substances 0.000 description 1
- 150000003934 aromatic aldehydes Chemical class 0.000 description 1
- 238000010533 azeotropic distillation Methods 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 230000017531 blood circulation Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000005253 cladding Methods 0.000 description 1
- 238000000975 co-precipitation Methods 0.000 description 1
- 230000015271 coagulation Effects 0.000 description 1
- 238000005345 coagulation Methods 0.000 description 1
- 238000010668 complexation reaction Methods 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 239000004744 fabric Substances 0.000 description 1
- 230000002349 favourable effect Effects 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- 150000002430 hydrocarbons Chemical class 0.000 description 1
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 1
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 238000005461 lubrication Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000012188 paraffin wax Substances 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- PHUTUTUABXHXLW-UHFFFAOYSA-N pindolol Chemical compound CC(C)NCC(O)COC1=CC=CC2=NC=C[C]12 PHUTUTUABXHXLW-UHFFFAOYSA-N 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- BITYAPCSNKJESK-UHFFFAOYSA-N potassiosodium Chemical compound [Na].[K] BITYAPCSNKJESK-UHFFFAOYSA-N 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- XMVJITFPVVRMHC-UHFFFAOYSA-N roxarsone Chemical group OC1=CC=C([As](O)(O)=O)C=C1[N+]([O-])=O XMVJITFPVVRMHC-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000007962 solid dispersion Substances 0.000 description 1
- 239000000243 solution Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 125000001424 substituent group Chemical group 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229960004605 timolol Drugs 0.000 description 1
- 230000001131 transforming effect Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
本发明是关于改进了生物利用率的新的固态化合制剂，该制剂含有一份重量微溶的通式为(I)的二氢吡啶，
其中，R1R2R3X，正如说明书和权利要求中所定义的；
和0.5到10份重量的β—阻滞剂，如果适合的话，添加通常的辅助剂和媒介剂。
该制剂特别用作冠状剂和血压剂。
Description
本发明是关于新的固体二氢吡啶化合制剂及其制备方法，该制剂改进了生物利用率，并含有微溶的二氢吡啶和P-阻滞剂（Blocker），以及作为药物使用，特别用作冠状剂和血压剂。
英国专利1358951已经透露了二氢吡啶物对血液循环有非常强力的影响。由于许多二氢吡啶物的溶介度极微，所以在药物制品的药剂制备中，产生一些困难，从大量的出版物和专利说明书中明显看到这些活性化合物的特殊配制，例如英国专利1456618指出的固体药用制剂同样要确保二氢吡啶有良好的生物利用率。德国专利2822822叙述了固体服药形式，由于活性组分的溶介度极微，想方设法通过使用某些增溶剂和表面活性剂来加以补偿。此外根据二氢吡啶物的被吸收性（欧洲供布的说明书1247）可使用聚乙烯醇和某些多孔载体得到改造。
文献中同样叙述了改进生物利用率的各种方法都直接与改造溶介度联系在一起的。除掉改变化学结构，例如通过改变相应的取代基来改进溶介度以外;同时也叙述了改变活性组分的物理性质有关的许多方法，例如减少活性组分粒子的大小，改变结晶结构，制备成盐的形式，加入润湿剂，与其它物质络合，利用生资载体，生产固体分散剂（共沉淀）或表面吸收剂的制备等。
采用特别措施补偿二氢吡啶差的溶介度，同时确保良好的生物利用率，到此为止各种企业都坚在一些缺点。使用表面活性物质，增溶剂，以及具有特殊表面例如多孔性的某些载体常常导致制剂使用形式不希望过大。为了便于咽下，通常把药片或胶囊形式转变成特殊形状，例如椭园形或长方形，但是在制剂的重量大于400毫克时，仍然不总是取得满意的结果。并非都是经常采取较小的制剂表示满意的解决。
关于药物配制这一点，辅助剂和媒介物加入的数月和量应尽可能少，当比较两个药物特制品时，总是优先考虑药物的制剂，该制剂含有除活性化合物以外，尽可能少的辅助剂和添加剂，基本上为了被免不希望的生物副作用。
本发明是关于新的固体化合制剂，并改进了生物利用率。该剂含有一分重量的微溶的二氢吡啶，其通式如下所示：
其中
R1表示C2-C3的烷氧基选择取代的C1-C4的烷基。
R2表示由C1-C3的烷氧基，三氟甲基或N-甲基-N-苯基氨基选择取代的C1-C10的烷基。
R3表示C1-C4烷基，氰基或羟基甲基和
X表示2-或3-硝基，2，3，二氯或2，3成环数，包括二N-O-N二。
和0.5到10份重量的β-阻滞剂，如果适合的话，添加通常使用的辅助剂和媒介剂。
特别注意的按本发明的化合制剂含有β-阻滞剂，该阻滞剂来自包于acebutolol，atenolol，nodolol，propranlol pindolol或timolol物质的基团。
Acebutolol和atenolol可能特别提到。
特别有趣的是按本发明的化合制剂含有1份重量通式为Ⅰ的二氢吡啶，其中R1和R2相互间始终不同，特别是nisoldipine，nimodipine或nitrendipine;和1到5份重量的-阻滞剂，Acebutolol和atenolol可以作为适宜的-阻滞剂。
由要造粒的二氢吡啶性化合物和β-阻滞剂活性化合物，与已知的辅助剂一起，采用湿的造粒工艺或干的压紧工艺制备本发明的化合制剂，如果适宜的话，至少有一种成片辅助剂，将粒子压制成片剂。
按照本发明使用的通式为Ⅰ的二氢吡啶物的制备，由通式为Ⅱ的ylidene化合物通式为Ⅲ的稀胺化合物，以低级脂肪作溶剂，反应温度40-100℃进行制备更为适宜。通式Ⅱ表示如下：
通式为Ⅲ的烯胺化合物如下所示：
其中R1，R2，R3和X所代表的含义与Ⅰ所表示的相同。
本反应的有利变换是使用小克分子过量的通式为Ⅲ的烯胺化合物，并同时除去反应生成的水，如果适宜在反应期间采用共沸蒸馏。
化学式为Ⅱ的YLidene化合物的制备，由克分子量的酮羧酸酯与芳醛，以低级醇，特别是，到4碳原子的醇作溶剂，在催化量的哌啶醋酸存在下，温度为20到70℃进行反应更为适宜。
通式Ⅲ的烯胺化合物的制备，由酮羧、酸、酯与氨，在低级醇中，特别以异丙醇为更宜，温度为0到50℃进行反应。
可以作为辅助剂的有锐变促进剂，例如沉粉，改良淀粉，纤维素，纤维素衍生物，交链聚乙烯（PVPP），藻脘酸钠和胶态氧化硅;粘结剂有明胶、黄胶、葡萄糖糖浆，淀粉糊、聚乙烯吡咯烷酮（PVP），纤维素衍生物，分子量为1000-5000（PEG）的聚乙二醇和藻脘酸盐;循滑剂有硬脂酸镁、硬脂酸钙、硬脂酸，石腊烃，滑石，动植物脂肪，油和腊，分子量为1000-5000的聚乙二醇和聚硅酮。
作为填料的有硫酸钙、碳酸钙、二元或三元混凝土酸钙，碳酸镁，羟基碳酸镁、氯化钠、钠钾的柠檬酸盐，酒石酸盐和丁二酸盐，淀粉，改良淀粉，纤维素、粉末纤维素，糖，例如乳糖、蔗糖和葡萄糖和糖醇，例如甘露醇或山梨糖醇。
特别感兴趣的是含有下列成份的辅助剂和填料，淀粉，改良淀粉，例如淀粉糊，纤维素，PVP，PVPP，胶态氧化硅、乳糖，碳酸镁，硬脂酸镁和硬脂酸钙。
从现有技术来看，奇怪的由二氢吡啶与上面提及的一种β-阻滞剂一起造粒而制成微溶的二氢吡啶制剂，能大大增加加放的可能性，因此，大大改进了生物利用率。按照有现有技术知识，释放速率的增加，并不决定于添加的辅助剂，例如络合剂、表面活性物质或可溶于水的聚合物的存在。
上述提到微溶的二氢吡啶的溶介度，在25℃时，每升水中不大于20毫克。
利用美国浆状搅槽方法在下列条件下进行释放试验：
4000毫升0.1N的氢氯酸
浆状搅槽的旋转速率为100rpm
采用本发明（实施例1的产品）的化合制剂，二小时以后，nitrendipine的释放速率大约达到80%。相应的传统nitrendipine片剂的配制中，所用的nitrendipine是同样的结晶组成，含有同样的辅助剂，但2小时后的释放速率仅约40%，释放的进展从表1看得很明显。
含有nitrendipine的片剂的vitro释放中（usp浆状搅槽方法）。
的累结释放为所用剂量百分数
释放时间（小时） 例1片剂 比较例的片剂
0.25 24 8
0.5 52 19
1 68 36
2 82 43
比较例：
将100g Nitrendipine、910g玉米淀粉、680克绕末纤维素和550克碳酸钙和10克月桂基硫酸钠在行星式混合器中混合5小时，用聚乙烯吡咯烷酮的水溶液造粒（0分钟（固体含量50g），将湿的组合物通过筛子，并在沸腾床干燥器中干燥，使最终水含量约4.5%。通过筛子（筛孔的大小为0.8mm目）均匀做成干燥粒子，再与50g硬脂酸镁激烈混合，然后将粒子压成片剂，其重量为235毫克。
实施例的具体化
例1
将100克Nitrendipine，500克Atenolol 660克玉米淀粉，430克粉状纤维素，550克碳酸钙，和10克月桂基硫酸钠，在行星式混合器中混合5分钟，用聚乙烯吡咯烷酮（固体含量50克）的水溶液造粒10分钟，将湿的组合物通过筛子，并在沸腾床干燥器中干燥，使最终水含量约为4.5%。使用筛子（筛孔的大小为0.8mm目）均匀做成干燥粒子，再与50克硬脂酸镁激烈混合，然后将粒子压成片剂，重235毫克。片剂也可用保护漆包复。
例2
50克nisoldipine，2216克acebntolol氯化氢，2244克玉米淀粉，250克玉米淀粉在处理之前已变成糊状物。750克粉状纤维素在混合造粒机中，与80Tween（含量15克）水溶液造粒，然后将湿的组合物通过一个锉磨（眼孔大小40mm），并在循环式空气干燥箱到残渣中水含量约为3.8%，通过筛子（筛孔的大小1.25mm目）做成均匀的干燥粒子，并与15克硬脂酸镁激烈混合，然后将粒子压制成片剂，其重量为277毫克。
片剂用轻质保护涂层复盖，因此粒子能装进胶囊。
Claims (10)
1、改进生物利用率的固态化合剂，含有一份重量微溶的，通式为Ⅰ的二氢吡啶
其中
R1代表由C2-C3烷氧选择取代的C1-C4烷基；
R2代表由C1-C3烷氧基、三氟甲基或N-甲基卞基氨基选择取代的C1-C3烷氧基；
R3代表C1-C4烷基、氰基、羟基甲基和；
X代表2-或3硝基、2，3二氯或2，3成环节数，包括
=N-O-N=
和0.5到10份重量的β阻滞剂，如果适合的话，还含有通常的辅助剂和媒介剂。
2、按照权利要求1的化合制剂，含有的β-阻滞剂来自acebutolol，atanolol，nadolol，propranolol，pindolol醇类的基团。
3、按照权利要求1和2的化合制剂，含有来自nisldipine，nimodipine和nitrendipine二品类基团
4、按照权利要求1到3的化合制剂，含有1份重量的微溶的化学式为Ⅰ的二氢吡啶，其中R1和R2相互间总是不同的;和1到5份重量的-阻滞剂。
5、含有acebutolol或atenolol作为-阻滞剂。
6、按照权利要求1到5的化合制剂的形式是粒子。
7、按照权利要求1的化合制备的制备方法，其特征是一份重要的微溶的二氢吡啶和0.5到10份重量的β-阻滞剂，与辅助剂和媒介剂一起造粒。
8、按照权利要求7的方法，其特征是1份重量的二氢吡啶，和1到5份重量的β-阻滞剂与辅助剂和填料一起，该填料来自淀粉、纤维素、PVP、二氧化硅、碳酸镁和/或乳糖的组分，在造粒机中进行水溶造粒，产生的粒子转变成通常的服用形式。
9、按照权利要求1的化合制剂用于轻型循环无序中
10、按照权利要求1到6的制剂的制备方法其特征是，通式为Ⅱ的Ylidene化合物，其中X和R1的含义如权利要求1所表示，与通式为Ⅲ的烯胺化合物，其中R2和R3的含义如权利要求，所表示，在1到4个碳原子的低级醇存在下，温度40到100℃之间进行反应，然后产生的二氢吡啶按照权利要求7的制造工艺进一步加工处理。
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19843419131 DE3419131A1 (de) | 1984-05-23 | 1984-05-23 | Dihydropyridinkombinationspraeparate und verfahren zu ihrer herstellung |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN85101697A true CN85101697A (zh) | 1987-01-24 |
Family
ID=6236599
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN198585101697A Pending CN85101697A (zh) | 1984-05-23 | 1985-04-01 | 二氢吡啶化合制剂及其制备方法 |
Country Status (8)
| Country | Link |
|---|---|
| EP (1) | EP0163984A3 (zh) |
| JP (1) | JPS60255725A (zh) |
| CN (1) | CN85101697A (zh) |
| AU (1) | AU576244B2 (zh) |
| DE (1) | DE3419131A1 (zh) |
| ES (1) | ES8607017A1 (zh) |
| GR (1) | GR851245B (zh) |
| ZA (1) | ZA853877B (zh) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3427402A1 (de) * | 1984-07-25 | 1986-01-30 | Bayer Ag, 5090 Leverkusen | Neues kombinationspraeparat, verfahren zu seiner herstellung und seine verwendung als arzneimittel |
| DE3447170A1 (de) * | 1984-12-22 | 1986-07-03 | Bayer Ag, 5090 Leverkusen | Mischung unterschiedlicher dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung in arzneimitteln |
| JPS6396126A (ja) * | 1986-10-13 | 1988-04-27 | Taisho Pharmaceut Co Ltd | 安定化組成物 |
| SE8703881D0 (sv) * | 1987-10-08 | 1987-10-08 | Haessle Ab | New pharmaceutical preparation |
| DE3829398A1 (de) * | 1988-08-30 | 1990-03-08 | Rentschler Arzneimittel | Fixe arzneimittelkombination mit verzoegerter freisetzung |
| GB8926715D0 (en) * | 1989-11-28 | 1990-01-17 | Haessle Ab | Improvements relating to the administration of pharmaceutical agents |
| JPH05221863A (ja) * | 1991-08-09 | 1993-08-31 | Taisho Pharmaceut Co Ltd | 安定化方法 |
| JP4334869B2 (ja) * | 2000-12-01 | 2009-09-30 | 協和発酵キリン株式会社 | 溶解性または経口吸収性の改善された組成物 |
| MX2007000911A (es) | 2004-07-30 | 2007-04-12 | Torrent Pharmaceuticals Ltd | Nevibolol y sus sales farmaceuticamente aceptables, proceso para su preparacion y composiciones farmaceuticas de nevibolol. |
Family Cites Families (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2117571C3 (de) * | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Unsymmetrische 1,4-Dihydropyridin-33-dicarbonsäureester, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel |
| DE2400819C2 (de) * | 1974-01-09 | 1982-04-22 | Bayer Ag, 5090 Leverkusen | Verfahren zur Herstellung fester Zubereitungen von schwerlöslichen Arzneimittelwirkstoffen in feinster Verteilung |
| GB1579818A (en) * | 1977-06-07 | 1980-11-26 | Yamanouchi Pharma Co Ltd | Nifedipine-containing solid preparation composition |
| EP0001247A1 (en) * | 1977-09-14 | 1979-04-04 | Kanebo, Ltd. | Pharmaceutical preparation containing nifedipine and a method for producing the same. |
| CH655658B (zh) * | 1980-09-18 | 1986-05-15 | ||
| GB2084017B (en) * | 1980-09-18 | 1984-08-22 | Sandoz Ltd | Pharmaceutical compositions effective against coronary heat disease and hypertension |
| DE3419128A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Dihydropyridinpraeparate und verfahren zu ihrer herstellung |
| DE3419129A1 (de) * | 1984-05-23 | 1985-11-28 | Bayer Ag, 5090 Leverkusen | Nifedipinpraeparate und verfahren zu ihrer herstellung |
-
1984
- 1984-05-23 DE DE19843419131 patent/DE3419131A1/de not_active Withdrawn
-
1985
- 1985-04-01 CN CN198585101697A patent/CN85101697A/zh active Pending
- 1985-05-11 EP EP85105799A patent/EP0163984A3/de not_active Withdrawn
- 1985-05-20 JP JP60106216A patent/JPS60255725A/ja active Pending
- 1985-05-21 GR GR851245A patent/GR851245B/el unknown
- 1985-05-21 ES ES543351A patent/ES8607017A1/es not_active Expired
- 1985-05-22 ZA ZA853877A patent/ZA853877B/xx unknown
- 1985-05-23 AU AU42810/85A patent/AU576244B2/en not_active Ceased
Also Published As
| Publication number | Publication date |
|---|---|
| ZA853877B (en) | 1986-01-29 |
| EP0163984A2 (de) | 1985-12-11 |
| ES8607017A1 (es) | 1986-06-01 |
| GR851245B (zh) | 1985-11-25 |
| DE3419131A1 (de) | 1985-11-28 |
| JPS60255725A (ja) | 1985-12-17 |
| ES543351A0 (es) | 1986-06-01 |
| AU576244B2 (en) | 1988-08-18 |
| AU4281085A (en) | 1985-11-28 |
| EP0163984A3 (de) | 1986-03-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| AU602931B2 (en) | Coating membrane and compositions prepared therefrom | |
| BE1000130A4 (fr) | Sels pharmaceutiques d'amlodipine ameliores et compositions pharmaceutiques les contenant. | |
| US5990152A (en) | Dosage forms containing thioctic acid or solid salts of thioctic acid with improved release and bioavailability | |
| CA2091370C (en) | Tablets, granulates and pellets with a high active substance content for highly concentrated, solid dosage forms | |
| CA1220718A (fr) | Composition pharmaceutique a base d'acide valproique et son procede de fabrication | |
| CN1156461C (zh) | 改良的水溶性药物制剂 | |
| FI92903B (fi) | Pitkävaikutteisen farmaseuttisen valmisteen valmistusmenetelmä | |
| EP0164959B1 (en) | Pharmaceutical composition in sustained release unit dose form and process for its preparation | |
| JP3944150B2 (ja) | ガバペンチン含有固形製剤の製造方法 | |
| US6168805B1 (en) | Aqueous process for manufacturing paroxetine solid dispersions | |
| FR2670488A1 (fr) | Composition pharmaceutique contenant une forme physique particuliere d'un amide heterocyclique et son procede de preparation. | |
| EP0188953A2 (fr) | Compositions pour l'enrobage des additifs alimentaires destinés aux ruminants et additifs alimentaires ainsi enrobés | |
| WO2010055260A1 (fr) | Nouvelle composition à base d'acide gamma-hydroxybutyrique | |
| FR2565104A1 (fr) | Nouvelles preparations solides de nifedipine, utiles notamment comme agents vasodilatateurs, et procede pour leur fabrication | |
| CN85101697A (zh) | 二氢吡啶化合制剂及其制备方法 | |
| FR2554717A1 (fr) | Comprimes pharmaceutiques a liberation etalee et procede pour les preparer | |
| CA2011943A1 (en) | Compositions for the preparation of dosage-form active vitamins d3 and process for preparing stable dosage-form active vitamins d3 by using the same | |
| KR920006908B1 (ko) | 디히드로피리딘을 함유하는 고상 약제의 제조 방법 | |
| CN85102334A (zh) | 制备二氢吡啶制剂的方法 | |
| JPH029007B2 (zh) | ||
| WO2008123798A1 (ru) | Твердая нанокомпозиция для доставки биологически активных веществ | |
| BE507692A (fr) | Perfectionnements apportés aux procedés de préparation de produits thérapeutiques | |
| FR2664814A1 (fr) | Compositions pharmaceutiques solides et leur procede de preparation. | |
| CN85101689A (zh) | 硝苯吡啶制剂及其制备方法 | |
| CN111643483A (zh) | 一种用于制备加兰他敏缓释微球的新方法 |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C01 | Deemed withdrawal of patent application (patent law 1993) | ||
| WD01 | Invention patent application deemed withdrawn after publication |