WO2024055984A1 - 奈必洛尔与氨氯地平组合物、其制备方法及应用 - Google Patents
奈必洛尔与氨氯地平组合物、其制备方法及应用 Download PDFInfo
- Publication number
- WO2024055984A1 WO2024055984A1 PCT/CN2023/118513 CN2023118513W WO2024055984A1 WO 2024055984 A1 WO2024055984 A1 WO 2024055984A1 CN 2023118513 W CN2023118513 W CN 2023118513W WO 2024055984 A1 WO2024055984 A1 WO 2024055984A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- nebivolol
- amlodipine
- microcrystalline cellulose
- percentage
- sodium
- Prior art date
Links
- 229960000619 nebivolol Drugs 0.000 title claims abstract description 101
- 229960000528 amlodipine Drugs 0.000 title claims abstract description 100
- KOHIRBRYDXPAMZ-YHBROIRLSA-N (S,R,R,R)-nebivolol Chemical compound C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)CNC[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 KOHIRBRYDXPAMZ-YHBROIRLSA-N 0.000 title claims abstract description 97
- 239000000203 mixture Substances 0.000 title claims abstract description 79
- 238000002360 preparation method Methods 0.000 title claims abstract description 40
- 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 title abstract 7
- 239000003814 drug Substances 0.000 claims abstract description 15
- 150000003839 salts Chemical class 0.000 claims abstract description 14
- 229940079593 drug Drugs 0.000 claims abstract description 13
- -1 amlodipine compound Chemical class 0.000 claims abstract description 12
- 206010020772 Hypertension Diseases 0.000 claims abstract description 10
- 239000012453 solvate Substances 0.000 claims abstract description 8
- ZPBWCRDSRKPIDG-UHFFFAOYSA-N amlodipine benzenesulfonate Chemical compound OS(=O)(=O)C1=CC=CC=C1.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl ZPBWCRDSRKPIDG-UHFFFAOYSA-N 0.000 claims description 117
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 58
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 41
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 41
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 41
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 41
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 32
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 32
- JWEXHQAEWHKGCW-VCVZPGOSSA-N (S,R,R,R)-nebivolol hydrochloride Chemical compound [Cl-].C1CC2=CC(F)=CC=C2O[C@H]1[C@H](O)C[NH2+]C[C@@H](O)[C@H]1OC2=CC=C(F)C=C2CC1 JWEXHQAEWHKGCW-VCVZPGOSSA-N 0.000 claims description 31
- 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 31
- 229940068174 nebivolol hydrochloride Drugs 0.000 claims description 31
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 30
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 29
- 235000019359 magnesium stearate Nutrition 0.000 claims description 29
- 229960004005 amlodipine besylate Drugs 0.000 claims description 27
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 26
- 229960001021 lactose monohydrate Drugs 0.000 claims description 26
- 239000008119 colloidal silica Substances 0.000 claims description 25
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 19
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 19
- 229940068968 polysorbate 80 Drugs 0.000 claims description 19
- 229920000053 polysorbate 80 Polymers 0.000 claims description 19
- 229920000881 Modified starch Polymers 0.000 claims description 18
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 18
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 18
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 17
- 229960003943 hypromellose Drugs 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 16
- 239000011230 binding agent Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 15
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical group [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 14
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 14
- 238000005469 granulation Methods 0.000 claims description 13
- 230000003179 granulation Effects 0.000 claims description 13
- 239000011734 sodium Substances 0.000 claims description 11
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 10
- 229910052708 sodium Inorganic materials 0.000 claims description 10
- 208000024172 Cardiovascular disease Diseases 0.000 claims description 9
- 229920002472 Starch Polymers 0.000 claims description 9
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 9
- 239000000945 filler Substances 0.000 claims description 9
- 239000008107 starch Substances 0.000 claims description 9
- 229940032147 starch Drugs 0.000 claims description 9
- 235000019698 starch Nutrition 0.000 claims description 9
- 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 8
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical group [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 claims description 8
- 229930195725 Mannitol Natural products 0.000 claims description 8
- 239000004480 active ingredient Substances 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 239000000314 lubricant Substances 0.000 claims description 8
- 239000000594 mannitol Substances 0.000 claims description 8
- 235000010355 mannitol Nutrition 0.000 claims description 8
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 8
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 7
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 7
- 239000000126 substance Substances 0.000 claims description 7
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 235000021355 Stearic acid Nutrition 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 6
- 229920000136 polysorbate Polymers 0.000 claims description 6
- 229950008882 polysorbate Drugs 0.000 claims description 6
- 239000008117 stearic acid Substances 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- 150000001875 compounds Chemical class 0.000 claims description 5
- 238000007908 dry granulation Methods 0.000 claims description 5
- 239000007888 film coating Substances 0.000 claims description 5
- 238000009501 film coating Methods 0.000 claims description 5
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 239000004094 surface-active agent Substances 0.000 claims description 5
- 206010002383 Angina Pectoris Diseases 0.000 claims description 4
- 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 claims description 4
- 239000002775 capsule Substances 0.000 claims description 4
- 239000003086 colorant Substances 0.000 claims description 4
- 229960001855 mannitol Drugs 0.000 claims description 4
- 239000008183 oral pharmaceutical preparation Substances 0.000 claims description 4
- 239000008188 pellet Substances 0.000 claims description 4
- 239000000843 powder Substances 0.000 claims description 4
- 239000000741 silica gel Substances 0.000 claims description 4
- 229940080313 sodium starch Drugs 0.000 claims description 4
- 206010019280 Heart failures Diseases 0.000 claims description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 150000007942 carboxylates Chemical class 0.000 claims description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 claims description 3
- 208000029078 coronary artery disease Diseases 0.000 claims description 3
- 150000002148 esters Chemical class 0.000 claims description 3
- 229910052751 metal Inorganic materials 0.000 claims description 3
- 239000002184 metal Substances 0.000 claims description 3
- 208000010125 myocardial infarction Diseases 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- TZNOWAJJWCGILX-BTJKTKAUSA-N (z)-but-2-enedioic acid;3-o-ethyl 5-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound OC(=O)\C=C/C(O)=O.CCOC(=O)C1=C(COCCN)NC(C)=C(C(=O)OC)C1C1=CC=CC=C1Cl TZNOWAJJWCGILX-BTJKTKAUSA-N 0.000 claims description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 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 claims description 2
- 208000002330 Congenital Heart Defects Diseases 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 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 claims description 2
- 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 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 2
- 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 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- MHQJUHSHQGQVTM-HNENSFHCSA-N Octadecyl fumarate Chemical compound CCCCCCCCCCCCCCCCCCOC(=O)\C=C/C(O)=O MHQJUHSHQGQVTM-HNENSFHCSA-N 0.000 claims description 2
- 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 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 206010003119 arrhythmia Diseases 0.000 claims description 2
- 230000006793 arrhythmia Effects 0.000 claims description 2
- 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 claims description 2
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 claims description 2
- 208000028831 congenital heart disease Diseases 0.000 claims description 2
- 229920001531 copovidone Polymers 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 239000002552 dosage form Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- 238000001125 extrusion Methods 0.000 claims description 2
- FBPFZTCFMRRESA-GUCUJZIJSA-N galactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-GUCUJZIJSA-N 0.000 claims description 2
- 239000008103 glucose Substances 0.000 claims description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 229910002055 micronized silica Inorganic materials 0.000 claims description 2
- 229940069328 povidone Drugs 0.000 claims description 2
- 229910002027 silica gel Inorganic materials 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 238000005563 spheronization Methods 0.000 claims description 2
- 229940071138 stearyl fumarate Drugs 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 239000003826 tablet Substances 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 239000000454 talc Substances 0.000 claims 2
- 229910052623 talc Inorganic materials 0.000 claims 2
- 241001474374 Blennius Species 0.000 claims 1
- 239000004375 Dextrin Substances 0.000 claims 1
- 229920001353 Dextrin Polymers 0.000 claims 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims 1
- 208000002564 X-linked cardiac valvular dysplasia Diseases 0.000 claims 1
- 239000001506 calcium phosphate Substances 0.000 claims 1
- 229960000913 crospovidone Drugs 0.000 claims 1
- 235000019425 dextrin Nutrition 0.000 claims 1
- 229940038472 dicalcium phosphate Drugs 0.000 claims 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims 1
- 238000007907 direct compression Methods 0.000 claims 1
- LQZZUXJYWNFBMV-UHFFFAOYSA-N dodecan-1-ol Chemical compound CCCCCCCCCCCCO LQZZUXJYWNFBMV-UHFFFAOYSA-N 0.000 claims 1
- 229960001031 glucose Drugs 0.000 claims 1
- 239000003292 glue Substances 0.000 claims 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims 1
- 229960002160 maltose Drugs 0.000 claims 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims 1
- 229960004793 sucrose Drugs 0.000 claims 1
- 235000000346 sugar Nutrition 0.000 claims 1
- 150000008163 sugars Chemical class 0.000 claims 1
- 230000000694 effects Effects 0.000 abstract description 8
- 230000009286 beneficial effect Effects 0.000 abstract description 4
- 230000036772 blood pressure Effects 0.000 abstract description 3
- 206010061818 Disease progression Diseases 0.000 abstract description 2
- 206010061819 Disease recurrence Diseases 0.000 abstract description 2
- 230000003211 malignant effect Effects 0.000 abstract description 2
- 208000019505 Deglutition disease Diseases 0.000 abstract 1
- 238000001727 in vivo Methods 0.000 abstract 1
- 230000036470 plasma concentration Effects 0.000 abstract 1
- 239000008187 granular material Substances 0.000 description 42
- 239000002245 particle Substances 0.000 description 18
- 239000000853 adhesive Substances 0.000 description 13
- 230000001070 adhesive effect Effects 0.000 description 13
- 239000007864 aqueous solution Substances 0.000 description 13
- 238000002156 mixing Methods 0.000 description 12
- 238000003756 stirring Methods 0.000 description 10
- 239000008213 purified water Substances 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 238000000889 atomisation Methods 0.000 description 6
- 230000002572 peristaltic effect Effects 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- 239000000243 solution Substances 0.000 description 4
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 description 3
- 201000001068 Prinzmetal angina Diseases 0.000 description 3
- 229910001424 calcium ion Inorganic materials 0.000 description 3
- 238000005516 engineering process Methods 0.000 description 3
- 206010067484 Adverse reaction Diseases 0.000 description 2
- 208000007530 Essential hypertension Diseases 0.000 description 2
- QUSNBJAOOMFDIB-UHFFFAOYSA-N Ethylamine Chemical compound CCN QUSNBJAOOMFDIB-UHFFFAOYSA-N 0.000 description 2
- 230000006838 adverse reaction Effects 0.000 description 2
- 230000003276 anti-hypertensive effect Effects 0.000 description 2
- 210000002565 arteriole Anatomy 0.000 description 2
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- 238000005520 cutting process Methods 0.000 description 2
- 230000010339 dilation Effects 0.000 description 2
- FPAFDBFIGPHWGO-UHFFFAOYSA-N dioxosilane;oxomagnesium;hydrate Chemical compound O.[Mg]=O.[Mg]=O.[Mg]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O.O=[Si]=O FPAFDBFIGPHWGO-UHFFFAOYSA-N 0.000 description 2
- 238000001035 drying Methods 0.000 description 2
- 230000004941 influx Effects 0.000 description 2
- 230000000302 ischemic effect Effects 0.000 description 2
- 229910052749 magnesium Inorganic materials 0.000 description 2
- 239000011777 magnesium Substances 0.000 description 2
- 230000007246 mechanism Effects 0.000 description 2
- 210000002464 muscle smooth vascular Anatomy 0.000 description 2
- 210000004165 myocardium Anatomy 0.000 description 2
- 239000001301 oxygen Substances 0.000 description 2
- 229910052760 oxygen Inorganic materials 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 230000000304 vasodilatating effect Effects 0.000 description 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 description 1
- HAIDNNYCHKHYHX-UHFFFAOYSA-N (6-fluoro-3,4-dihydro-2h-chromen-2-yl)methanol Chemical compound FC1=CC=C2OC(CO)CCC2=C1 HAIDNNYCHKHYHX-UHFFFAOYSA-N 0.000 description 1
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- MTMRFXOURLMMJJ-UHFFFAOYSA-N 5-o-ethyl 3-o-methyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate Chemical group CCOC(=O)C1=C(C)NC(COCCN)=C(C(=O)OC)C1C1=CC=CC=C1Cl MTMRFXOURLMMJJ-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 206010003211 Arteriosclerosis coronary artery Diseases 0.000 description 1
- 206010003225 Arteriospasm coronary Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 208000009079 Bronchial Spasm Diseases 0.000 description 1
- 208000014181 Bronchial disease Diseases 0.000 description 1
- 206010006482 Bronchospasm Diseases 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 206010007558 Cardiac failure chronic Diseases 0.000 description 1
- 206010007559 Cardiac failure congestive Diseases 0.000 description 1
- 108091006146 Channels Proteins 0.000 description 1
- 208000003890 Coronary Vasospasm Diseases 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 206010019233 Headaches Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 206010020880 Hypertrophy Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 241000124008 Mammalia Species 0.000 description 1
- 208000001089 Multiple system atrophy Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 206010031127 Orthostatic hypotension Diseases 0.000 description 1
- 229920001213 Polysorbate 20 Polymers 0.000 description 1
- 229920003081 Povidone K 30 Polymers 0.000 description 1
- 208000007718 Stable Angina Diseases 0.000 description 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 description 1
- 208000009325 Variant Angina Pectoris Diseases 0.000 description 1
- JAWMENYCRQKKJY-UHFFFAOYSA-N [3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-ylmethyl)-1-oxa-2,8-diazaspiro[4.5]dec-2-en-8-yl]-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]methanone Chemical compound N1N=NC=2CN(CCC=21)CC1=NOC2(C1)CCN(CC2)C(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F JAWMENYCRQKKJY-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000008351 acetate buffer Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 description 1
- 230000008485 antagonism Effects 0.000 description 1
- 239000005557 antagonist Substances 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 229940127088 antihypertensive drug Drugs 0.000 description 1
- 239000002876 beta blocker Substances 0.000 description 1
- 229940097320 beta blocking agent Drugs 0.000 description 1
- 102000016967 beta-1 Adrenergic Receptors Human genes 0.000 description 1
- 108010014494 beta-1 Adrenergic Receptors Proteins 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 230000004531 blood pressure lowering effect Effects 0.000 description 1
- 208000006218 bradycardia Diseases 0.000 description 1
- 230000036471 bradycardia Effects 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 230000007012 clinical effect Effects 0.000 description 1
- 238000004040 coloring Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 201000011634 coronary artery vasospasm Diseases 0.000 description 1
- 208000026758 coronary atherosclerosis Diseases 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000003745 diagnosis Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- GGWBHVILAJZWKJ-UHFFFAOYSA-N dimethyl-[[5-[2-[[1-(methylamino)-2-nitroethenyl]amino]ethylsulfanylmethyl]furan-2-yl]methyl]azanium;chloride Chemical compound Cl.[O-][N+](=O)C=C(NC)NCCSCC1=CC=C(CN(C)C)O1 GGWBHVILAJZWKJ-UHFFFAOYSA-N 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- MOTZDAYCYVMXPC-UHFFFAOYSA-N dodecyl hydrogen sulfate Chemical compound CCCCCCCCCCCCOS(O)(=O)=O MOTZDAYCYVMXPC-UHFFFAOYSA-N 0.000 description 1
- 229940043264 dodecyl sulfate Drugs 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940075529 glyceryl stearate Drugs 0.000 description 1
- 231100000869 headache Toxicity 0.000 description 1
- 230000004217 heart function Effects 0.000 description 1
- 208000018578 heart valve disease Diseases 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000001050 lubricating effect Effects 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- 239000002609 medium Substances 0.000 description 1
- 125000000325 methylidene group Chemical group [H]C([H])=* 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000036581 peripheral resistance Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 235000010486 polyoxyethylene sorbitan monolaurate Nutrition 0.000 description 1
- 239000000256 polyoxyethylene sorbitan monolaurate Substances 0.000 description 1
- 229940068977 polysorbate 20 Drugs 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 230000036316 preload Effects 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000003087 receptor blocking agent Substances 0.000 description 1
- 230000002040 relaxant effect Effects 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 235000002639 sodium chloride Nutrition 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 239000007779 soft material Substances 0.000 description 1
- 239000011343 solid material Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 230000002861 ventricular 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
- A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
-
- 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
- A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
-
- 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
-
- 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
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61P9/12—Antihypertensives
Definitions
- the present invention relates to a composition of nebivolol and amlodipine, its preparation method and application.
- Hypertension is one of the most common cardiovascular diseases, with a prevalence rate of 25% to 30% among adults. If hypertension is not effectively controlled for a long time, it will increase coronary atherosclerosis, left ventricular Risk of hypertrophy, atherosclerosis, and kidney disease. At present, the diagnosis and treatment of hypertension are mostly based on drug intervention, which has significant clinical effects and can effectively suppress the disease and alleviate the clinical symptoms of patients. Therefore, the development of pharmaceutical preparations to treat hypertension and cardiovascular diseases and reduce toxic and side effects is of positive significance for clinical use.
- Naibiluoer 2,2'-[iminobis(methylene)]bis[6-fluoro-3,4-dihydro-2H-1-benzopyran-2- Methanol]bis[2-hydroxy-2-(6fluoro-3,4-dihydro-2H-1-benzopyran-2-)]ethylamine, molecular formula C 22 H 25 F 2 NO 4 , molecular weight 405.43 , its structural formula is as follows:
- Nebivolol as a potent, highly selective (cardioselective) adrenergic ⁇ 1 receptor blocker with vasodilatory activity, has no ⁇ -adrenergic antagonism, and has a vasodilatory effect on It has a certain protective effect on cardiac function and can reduce cardiac preload. It is mainly used to treat essential hypertension and chronic heart failure. Its indications include cardiovascular diseases such as hypertension, angina pectoris, myocardial infarction and congestive heart failure; naphtha hydrochloride Birol tablets have the advantages of significant efficacy, convenient administration, and few adverse reactions. It is a new and promising antihypertensive drug. It was first approved for marketing in Germany in 1997 for the treatment of essential hypertension. However, common adverse reactions of beta-blockers include headache, nausea, bradycardia, orthostatic hypotension, and bronchospasm.
- amlodipine 6-methyl-2-(2-aminoethoxy)methyl-4-(2-chlorophenyl)-1,4-dihydro-3,5-pyridinedicarboxylic acid Methyl ethyl ester, molecular formula C 20 H 25 CIN 2 O 5 , molecular weight 408.88, its structural formula is as follows:
- Amlodipine is a dihydropyridine calcium ion influx inhibitor (slow channel blocker or calcium ion antagonist) that inhibits the transmembrane influx of calcium ions into cardiac and vascular smooth muscle.
- the antihypertensive mechanism of amlodipine is its direct relaxing effect on vascular smooth muscle. The exact mechanism by which amlodipine relieves angina has not been fully determined, but amlodipine reduces the overall ischemic load through the following two effects: 1. Amlodipine can dilate peripheral arterioles, thereby reducing the total peripheral resistance (afterload) when the heart is working ). This offloading of the heart reduces the energy expenditure and oxygen demand of the myocardium as the heart rate remains stable. 2.
- amlodipine may also involve dilation of the main coronary arteries and coronary arterioles in normal and ischemic areas. This dilation increases myocardial oxygen delivery in patients with coronary artery spasm (Prinzmetal's or variant angina).
- Amlodipine is a long-acting calcium channel blocker used to treat hypertension, chronic stable angina, and vasospastic angina.
- the technical problem solved by the present invention is to provide a composition of nebivolol and amlodipine that is different from the existing technology, its preparation method and application.
- the invention provides a nebivolol and amlodipine composition, which contains the active ingredient nebivolol and the active ingredient amlodipine; the active ingredient nebivolol includes nebivolol, its pharmaceutical One or more of acceptable salts and solvates are provided; the active ingredient amlodipine is provided by one or more of amlodipine, its pharmaceutically acceptable salts and solvates. .
- the pharmaceutically acceptable salt of nebivolol may be nebivolol hydrochloride.
- the pharmaceutically acceptable salt of amlodipine may be amlodipine besylate and/or amlodipine maleate.
- the composition of nebivolol and amlodipine may be a composition of nebivolol hydrochloride and amlodipine besylate.
- the nebivolol and amlodipine composition further includes surfactants, fillers, binders, disintegrants, lubricants, glidants, colorants and coating films one or more of them.
- the surfactant may be sodium lauryl sulfate and/or polysorbate; for example, the polysorbate may be selected from polysorbate 80 and/or polysorbate 20 .
- the filler refers to a solid material that can be added to the material to improve the performance of the material, or can solubilize, increase the weight, and reduce the cost of the material, and is selected from microcrystalline cellulose (such as microcrystalline cellulose 101 or microcrystalline cellulose 102), calcium hydrogen phosphate, mannitol, sucrose, glucose, maltose, lactose (such as lactose monohydrate), sorbitol, xylitol, maltitol, galactitol, erythritol, paste One or more types of alcohol and trehalose.
- microcrystalline cellulose such as microcrystalline cellulose 101 or microcrystalline cellulose 102
- calcium hydrogen phosphate such as microcrystalline cellulose 101 or microcrystalline cellulose 102
- mannitol such as microcrystalline cellulose 101 or microcrystalline cellulose 102
- calcium hydrogen phosphate such as microcrystalline cellulose 101 or microcrystalline cellulose 102
- mannitol such as microcrystalline cellulose 101 or microcrystalline cellulose 102
- the adhesive can be a conventional additive in the art that can increase the viscosity of the dispersion medium to reduce the settling speed of the particles or increase the hydrophilicity of the particles, and is selected from the group consisting of polyoxyethylene, hydroxyl Propylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, ethylcellulose, copovidone, povidone (e.g. povidone K30), pregelatinized starch, gum arabic, polyvinylpyrrolidone and One or more types of sodium alginate.
- the disintegrant refers to a substance that can cause the preparation (such as tablets or granules) prepared by the composition to disintegrate during dissolution, and is selected from one or more of cross-linked polyvinylpyrrolidone, cross-linked sodium carboxymethyl cellulose, sodium carboxymethyl starch and corn starch.
- the lubricant can be a conventional substance with lubricating effect in the art, selected from one or more of stearic acid metal salts, stearic acid, talcum powder, stearic acid esters, stearyl fumarate and micro-powder silica gel.
- the stearic acid metal salt is preferably one or more of magnesium stearate, calcium stearate and sodium stearyl fumarate.
- the stearic acid ester is preferably glyceryl stearate.
- the glidant can be a conventional auxiliary material in the art that can reduce the friction between particles and improve the fluidity of powder or particles, and is selected from the group consisting of talc powder, micronized silica gel and colloidal dioxide. One or more types of silicon.
- the colorant may be a substance conventional in the art that can achieve coloring purposes, and may be selected from iron oxide red and/or iron oxide yellow.
- the components of the nebivolol and amlodipine composition except the coating film together form a tablet core.
- the mass percentage of nebivolol, its pharmaceutically acceptable salt or solvate in the tablet core is 1 to 10%, such as 1.5 to 7%, and an example is 1.60%. , 1.82%, 2.00%, 2.18%, 2.27%, 2.50%, 2.73%, 3.00%, 3.50%, 4.00%, 5.00%, 5.45%, 6.00%.
- the mass percentage of amlodipine, its pharmaceutically acceptable salt or solvate in the tablet core is 1 to 20%, such as 1.5 to 15%, and an example is 2.00%, 2.31%, 2.77%, 2.89%, 3.00%, 4.00%, 5.00%, 5.45%, 6.00%, 6.93%, 8.00%, 10.00%, 12.00%, 13.86%, 14.00%.
- the mass percentage of the surfactant in the tablet core is 0.05 to 10%, for example 0.1 to 5%, examples are 0.19%, 0.25%, 0.38%, 0.50%, 1.20%, 2.00%, and 3.00%.
- the mass percentage of the filler in the tablet core is 40 to 95%, such as 60 to 90%, exemplarily 68.25%, 79.70%, 88.07%, 78.77%, 79.14%, 81.05 %, 66.06%, 66.00%, 65.81%.
- the mass percentage of the adhesive in the tablet core is 1 to 30%, such as 5 to 25%, and examples are 5.00%, 6.67%, 8.00%, 10.00%, and 18.00%. ,20.80%.
- the mass percentage of the disintegrant in the tablet core is 1 to 10%, such as 2 to 8%, and examples are 4.00%, 5.00%, 6.00%, 6.60%, and 7.00%. .
- the mass percentage of the lubricant in the tablet core is 0.1 to 5%, such as 0.5 to 3%, and examples are 1.00%, 1.50%, and 2.00%.
- the mass percentage of the glidant in the tablet core is 0.1 to 5%, such as 0.2 to 3%, and examples are 0.25%, 0.30%, 0.40%, 0.50%, and 1.00%. ,2.00%.
- the coating film of the present invention can select a film-packed premix (gastric soluble type).
- the tablet core may have any of the following formulas:
- amlodipine besylate 1.82% nebivolol hydrochloride, 39.70% mannitol, 20.00% lactose monohydrate, 6.67% hypromellose, 6.00% croscarmellose sodium, 2.00% ten Sodium dialkyl sulfate, 10.00% microcrystalline cellulose 102, 10.00% anhydrous calcium hydrogen phosphate, 0.50% colloidal silica, 1.00% magnesium stearate, the percentages mentioned refer to the mass of each component in the tablet Percentage of total core mass;
- Amlodipine layer 6.93% amlodipine besylate, 60.00% microcrystalline cellulose 102, 28.07% lactose monohydrate, 4.00% sodium starch carboxylate and 1.00% magnesium stearate, the percentages refer to each group The weight of the fraction accounts for the percentage of the total mass of the amlodipine layer;
- Nebivolol layer 2.73% nebivolol hydrochloride, 63.77% microcrystalline cellulose 101, 15.00% lactose monohydrate, 6.00% croscarmellose sodium, 8.00% pregelatinized starch, 3.00% polysorbate Ester 80, 0.50% colloidal silica and 1.00% magnesium stearate, the percentages mentioned refer to the weight of each component as a percentage of the total mass of the nebivolol layer;
- Amlodipine layer 13.86% amlodipine besylate, 54.14% microcrystalline cellulose 102, 25.00% anhydrous calcium hydrogen phosphate, 6.00% sodium carboxymethyl starch and 1.00% magnesium stearate, the percentages refer to The weight of each component accounts for the percentage of the total mass of the amlodipine layer;
- Nebivolol layer 5.45% nebivolol hydrochloride, 56.05% microcrystalline cellulose 101, 25.00% mannitol, 5.00% croscarmellose sodium, 5.00% hydroxypropyl cellulose, 2.00% polysorbate Ester 80, 0.50% colloidal silica and 1.00% magnesium stearate, the percentages mentioned refer to the weight of each component as a percentage of the total mass of the nebivolol layer;
- the nebivolol and amlodipine composition may contain nebivolol at a dosage of 2.5 mg to 20.0 mg, such as 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg or 20.0mg.
- the nebivolol and amlodipine composition may contain amlodipine at a dosage of 2.5 mg to 20.0 mg, such as 2.5 mg, 5.0 mg, 7.5 mg, 10.0 mg, 15.0 mg or 20.0 mg.
- the dissolution amounts of nebivolol and amlodipine in the composition of nebivolol and amlodipine within 30 minutes are both more than 70%, for example, both are more than 75%, preferably both are. is more than 80%.
- the present invention also provides the use of the composition of nebivolol and amlodipine in the preparation of medicines for the treatment and/or prevention of cardiovascular diseases. Applications in medicine.
- the cardiovascular diseases include hypertension, heart failure, coronary heart disease, angina pectoris, arrhythmia, myocardial infarction, congenital heart disease, valvular heart disease, etc.
- the present invention also provides a method for treating and/or preventing cardiovascular disease, which is to administer a therapeutically effective amount of the nebivolol and amlodipine composition, the drug to a mammal in need (such as a human) or the following pharmaceutical preparations.
- the invention also provides the use of the composition of nebivolol and amlodipine in the preparation of pharmaceutical preparations.
- the pharmaceutical preparation may be an oral pharmaceutical preparation; for example, the dosage forms of the oral pharmaceutical preparation include but are not limited to compound tablets, double-layer tablets, capsules, pellets, microtablets, etc.
- the present invention also provides a pharmaceutical preparation prepared from the above composition of nebivolol and amlodipine.
- the pharmaceutical formulation has the definitions as described above.
- the invention also provides a method for preparing the composition of nebivolol and amlodipine, including but not limited to direct powder tableting method, wet granulation method, dry granulation method, fluidized granulation method, extrusion method Spheronization or pellet coating.
- the wet granulation method or fluidized granulation method may include the following steps:
- Step 1 Mix nebivolol hydrochloride, filler, binder and disintegrant, then mix with the binder aqueous solution for wet granulation, wet granulation, drying and dry granulation to obtain dry nebivolol particles; particles
- Step 2 Mix the nebivolol dry granules obtained in step 1 with amlodipine and filler, then mix with a lubricant and glidant, and compress into tablets to obtain nebivolol amlodipine tablets;
- Step 3 Coat the nebivolol amlodipine tablets obtained in step 2 with the aqueous solution of the film coating premix to obtain nebivolol amlodipine tablets.
- the dry granulation method may include the following steps:
- Step 1 Mix nebivolol hydrochloride, filler, binder and disintegrant, then granulate with the binder aqueous solution, wet granulate, dry and dry granule to obtain nebivolol dry granules; then The obtained nebivolol dry particles are then mixed with a lubricant and a glidant to obtain nebivolol total mixed particles;
- Step 2 Mix amlodipine, filler and disintegrant evenly; then use a dry granulator to granulate and mix evenly with lubricant to obtain amlodipine total mixed granules;
- Step 3 Compress the nebivolol mixed granules obtained in step A and the amlodipine mixed granules obtained in step B into tablets to obtain nebivolol amlodipine tablets; then perform film coating to obtain nebivolol. Amlodipine tablets.
- the reagents and raw materials used in the present invention are all commercially available.
- the invention provides a compound preparation of nebivolol and amlodipine, which is used to treat and/or prevent cardiovascular diseases.
- Preparation of adhesive Use purified water to prepare hypromellose into adhesive (solid content 5%), then add polysorbate 80, stir evenly and set aside;
- Step 1 Place nebivolol hydrochloride, microcrystalline cellulose 101, lactose monohydrate, pregelatinized starch, and sodium carboxymethyl starch in a wet granulation pot, turn on the stirring speed and cutting speed, and mix for 5 minutes; then add The binder aqueous solution is wet-granulated, and the granulated material is wet-granulated using a 16-mesh screen. The granulated material is placed in an oven and dried until the moisture content is less than 3.0%; the dried particles are passed through a 20-mesh sieve. Use a net to perform dry granulation to obtain nebivolol hydrochloride dry granules;
- Step 2 Add the nebivolol hydrochloride dry particles, amlodipine besylate and microcrystalline cellulose 102 obtained in step 1 into the mixing pot, mix for 20 minutes, then add colloidal silica and magnesium stearate and mix. 5 minutes; then use a rotary tablet press to compress tablets to obtain nebivolol amlodipine tablets;
- Step 3 Coat the nebivolol amlodipine tablets obtained in step 2 with the aqueous solution of the film coating premix (solid content 12%, the percentage refers to the mass of the coating premix to the coating premix percentage of the total mass of the aqueous solution) to obtain nebivolol amlodipine tablets.
- Preparation of adhesive Use purified water to prepare hypromellose into an adhesive (solid content 5%), then add sodium lauryl sulfate, stir and dissolve, and set aside;
- Step 1 Add nebivolol hydrochloride, mannitol, lactose monohydrate, and croscarmellose sodium into the mixing pot and mix for 20 minutes, then place the mixed material in the fluidized bed, set the air inlet volume, and Wind temperature, atomization temperature, feeding speed parameters, use a peristaltic pump to add the binder aqueous solution for fluidized granulation; use a 30-mesh sieve to sieve the granulated material to obtain nebivolol dry granules;
- Step 2 Add the nebivolol dry particles obtained in step 1, amlodipine besylate, microcrystalline cellulose 102, anhydrous calcium hydrogen phosphate and colloidal silica into the mixing pot, mix for 15 minutes and then add hard Magnesium fatty acid, mix for 10 minutes; then use a rotary tablet press to press tablets to obtain nebivolol amlodipine tablets;
- Step 3 Coat the nebivolol amlodipine tablets obtained in step 2 with the aqueous solution of the film coating premix (solid content 12%, the percentage refers to the mass of the coating premix to the coating premix percentage of the total mass of the aqueous solution) to obtain nebivolol amlodipine tablets.
- Step A Preparation of nebivolol layer total mixture materials:
- nebivolol hydrochloride microcrystalline cellulose 101, lactose monohydrate, and croscarmellose sodium into the wet granulator, turn on stirring and cutting, and mix for 10 minutes; add aqueous binder solution for slurrying and Granulate, use a 16-mesh sieve to wet and granulate the soft material after granulation; then put the wet granules into a constant temperature drying oven to dry to moisture ⁇ 3.0%, and use a 20-mesh sieve to dry and granulate; then nebivolol Add dry particles, colloidal silica, and magnesium stearate into a three-dimensional mixer and mix for 5 minutes to obtain nebivolol total mixed particles;
- Step B Preparation of amlodipine layer total mixture materials:
- Step C Compress the nebivolol mixed granules obtained in step A and the amlodipine mixed granules obtained in step B using a double-layer tablet press to obtain nebivolol amlodipine tablets; and then proceed Film-coated nebivolol and amlodipine tablets.
- nebivolol hydrochloride, microcrystalline cellulose 101, mannitol, and croscarmellose sodium into the three-dimensional mixer and mix for 10 minutes; then place the mixed material in the fluidized bed and set the air inlet volume, Inlet air temperature, atomization temperature, feeding speed parameters, use a peristaltic pump to add the binder aqueous solution for fluidized granulation; use a 30-mesh screen to sieve the granulated material to obtain nebivolol dry granules; then add Magnesium stearate and colloidal silica were mixed for 5 minutes to obtain nebivolol total mixed particles.
- amlodipine total mixture material and nebivolol total mixture granules are compressed using a double-layer tablet press to obtain nebivolol amlodipine tablets, and then film-coated to obtain nebivolol amlodipine tablets. .
- Preparation of adhesive Use purified water to prepare hypromellose into adhesive, then add polysorbate 80 and sodium lauryl sulfate, stir evenly and set aside;
- Step 1 Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (internally added) to the mixing pot and mix for 20 minutes, then place the mixture in the fluidized bed , set the inlet air volume, inlet air temperature, atomization temperature, and feed speed parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation; the granulated materials are dry granulated using a granulator. Lor dry granules;
- Step 2 Add the nebivolol dry particles obtained in step 1, amlodipine besylate, croscarmellose sodium (additional), colloidal silica, and microcrystalline cellulose 101 into the mixing pot, and mix After 10 minutes, use a granulator to grind the granules. After the granulation is complete, continue mixing for 10 minutes. Add magnesium stearate and mix for 5 minutes. Then use a rotary tablet press to press the tablets.
- Preparation of adhesive Use purified water to prepare hypromellose into adhesive, then add polysorbate 80, stir evenly and set aside;
- Step 1 Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (internally added) to the mixing pot and mix for 20 minutes, then place the mixture in the fluidized bed , set the inlet air volume, inlet air temperature, atomization temperature, and feed speed parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation; the granulated material is granulated using a 20-mesh screen, and Nebirol is obtained. Ergan particles;
- Step 2 Combine the nebivolol dry particles obtained in step 1, amlodipine besylate, croscarmellose sodium (additional), colloidal silica, microcrystalline cellulose 101, and dodecyl sulfate Add sodium into the mixing pot, mix for 10 minutes, add magnesium stearate, mix for 5 minutes, and then use a rotary tablet press to press tablets.
- Preparation of adhesive Use purified water to prepare hypromellose into adhesive, then add polysorbate 80 and sodium lauryl sulfate, stir evenly and set aside;
- Step 1 Add nebivolol hydrochloride, lactose monohydrate, pregelatinized starch, and croscarmellose sodium (internally added) to the mixing pot and mix for 20 minutes, then place the mixture in the fluidized bed , set the inlet air volume, inlet air temperature, atomization temperature, and feed speed parameters, and use a peristaltic pump to add the binder aqueous solution for fluidized granulation; the granulated materials are dry granulated using a granulator. Lor dry granules;
- Step 2 Add the nebivolol dry particles obtained in step 1, amlodipine besylate, croscarmellose sodium (additional), colloidal silica, and microcrystalline cellulose 101 into the mixing pot, and mix After 10 minutes, use a granulator to grind the granules. After the granulation is complete, continue mixing for 10 minutes. Add magnesium stearate and mix for 5 minutes. Then use a rotary tablet press to press the tablets.
- amlodipine besylate, microcrystalline cellulose (internally added), and anhydrous calcium hydrogen phosphate into a mixer and mix for 20 minutes; use a dry granulator to adjust the roller pressure and feeding parameters for compression, and then use 24 The granules were sieved to obtain amlodipine granules.
- nebivolol hydrochloride, lactose monohydrate, and pregelatinized starch into the three-dimensional mixer and mix for 10 minutes; then place the mixed materials in the fluidized bed and set the air inlet volume, air inlet temperature, and atomization temperature.
- a peristaltic pump is used to add the aqueous binder solution for fluidized granulation; the granulated material is sieved using a 30-mesh screen to obtain nebivolol granules.
- Example 1-8 The dissolution test of the amlodipine-nebivolol compound preparation was carried out in a pH 4.5 acetate buffer with a volume of 900 ml, using USP Method 2 with a rotation speed of 50 rpm.
- the specification of the amlodipine-nebivolol compound preparation in Example 4 is 10 mg (calculated as amlodipine)/10 mg (calculated as nebivolol).
- amlodipine The specification of nebivolol compound preparation is 5mg (calculated as amlodipine)/5mg (calculated as nebivolol). The dissolution results are shown in Table 1.
- the compound preparation of nebivolol and amlodipine provided by the invention has good synergy, is beneficial to improving the antihypertensive effect, improving safety tolerance, and reducing side effects.
- the advantages of combined use of nebivolol and amlodipine are: (1) reducing the number of medications and improving patient compliance; (2) for the elderly or people with difficulty swallowing, it is beneficial to improve their medication intake Compliance; (3) Maintain stable blood drug concentrations in the body, maintain long-term blood pressure stability in patients with hypertension, and reduce the side effects of respective drugs. use; (4) Avoid patients from arbitrarily interrupting medication and prevent disease recurrence and progression of malignant complications.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Cardiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Hospice & Palliative Care (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
一种奈必洛尔与氨氯地平组合物，其包含奈必洛尔和氨氯地平；所述的奈必洛尔包括奈必洛尔、其药学上可接受的盐和溶剂合物中的一种或多种；所述的氨氯地平包括氨氯地平、其药学上可接受的盐和溶剂合物中的一种或多种。奈必洛尔与氨氯地平复方制剂，有利于提高降压效果，提高安全耐受性，降低副作用。与其单药相比，奈必洛尔与氨氯地平联合用药的优势在于：减少了服药数量，提高患者的顺应性；对于老人或吞咽困难的人群，有利于提高其服药依从性；维持体内血药浓度平稳，维持高血压患者血压长期稳定，降低各自药物的副作用；避免患者随意中断用药，预防疾病复发和恶性并发症进展。
Description
本申请要求申请人于2022年9月14日向中国国家知识产权局提交的专利申请号为202211112943.4，发明名称为“奈必洛尔与氨氯地平组合物、其制备方法及应用”的在先申请的优先权。所述在先申请的全文通过引用的方式结合于本申请中。
本发明涉及奈必洛尔与氨氯地平组合物、其制备方法及应用。
高血压(Hypertension)是最常见的心血管疾病之一，在成年人中的患病率到25％～30％，高血压如果长期得不到有效控制，会增加冠脉粥样硬化、左心室肥厚、劲动脉粥样硬化、肾脏疾病的发病风险。目前高血压的诊疗多以药物干预为主，临床效果显著，可有效抑制疾病，减缓患者的临床症状。因此，开发治疗高血压及心血管疾病、降低毒副作用的药物制剂对于临床用药具有积极意义。
奈必洛尔(Naibiluoer)的化学名为2,2’-[亚氨基二(亚甲基)]双[6-氟-3,4-二氢-2H-1-苯并吡喃-2-甲醇]二[2-羟基-2-(6氟-3,4-二氢-2H-1-苯并吡喃-2-)]乙基胺，分子式C22H25F2NO4，分子量405.43，其结构式如下：
奈必洛尔作为一种具有血管扩张活性的、强效和高选择性(心脏选择性)的肾上腺素β1受体阻滞剂，没有α肾上腺素能拮抗作用，且兼有血管扩张作用，对心功能有一定的保护作用，可降低心脏前负荷，主要用于治疗原发性高血压和慢性心力衰竭，适应症有高血压、心绞痛、心肌梗死和充血性心力衰竭等心血管疾病；盐酸奈必洛尔片具有疗效显著、服药方便、不良反应少等优点，是一个新的有前途的降压药物，1997年首次在德国获准上市用于治疗原发性高血压。但β受体阻滞剂常见的不良反应包括头痛、恶心、心动过缓、***性低血压和支气管痉挛等。
氨氯地平的化学名为6-甲基-2-(2-氨基乙氧基)甲基-4-(2-氯苯基)-1,4-二氢-3,5-吡啶二甲酸
甲乙酯，分子式C20H25CIN2O5，分子量408.88，其结构式如下：
氨氯地平是一种二氢吡啶类钙离子内流抑制剂(缓通道阻滞剂或钙离子拮抗剂)，可抑制钙离子跨膜内流进入心脏和血管平滑肌。氨氯地平的降压作用机制是其对血管平滑肌的直接弛缓作用。氨氯地平缓解心绞痛的确切机制尚未完全确定，但氨氯地平通过以下两种作用降低整个缺血负荷：1.氨氯地平可扩张外周小动脉，从而降低心脏工作时的总外周阻力(后负荷)。由于心率保持稳定，心脏的这种卸载减少了心肌的能量消耗和氧气需求。2.氨氯地平的作用机制也可能涉及正常和缺血区域的冠状动脉主干和冠状动脉小动脉的扩张。这种扩张增加了冠状动脉痉挛(Prinzmetal's或变异型心绞痛)患者的心肌氧输送。氨氯地平是一种长效的钙通道阻滞剂，用于治疗高血压、慢性稳定型心绞痛和血管痉挛型心绞痛。
然而现有技术为单方制剂，因此，急需开发一种协同作用好、稳定性好、副作用小、降血压药效好、患者顺应性好的新型复方制剂。
发明内容
本发明解决的技术问题是提供一种与现有技术不同的奈必洛尔与氨氯地平组合物、其制备方法及应用。
本发明提供了一种奈必洛尔与氨氯地平组合物，包含活性成分奈必洛尔和活性成分氨氯地平；所述的活性成分奈必洛尔由包括奈必洛尔、其药学上可接受的盐和溶剂合物中的一种或多种提供；所述的活性成分氨氯地平由包括氨氯地平、其药学上可接受的盐和溶剂合物中的一种或多种提供。
根据本发明的实施方案，所述的奈必洛尔药学上可接受的盐可以为盐酸奈必洛尔。
根据本发明的实施方案，所述的氨氯地平药学上可接受的盐可以为苯磺酸氨氯地平和/或马来酸氨氯地平。
根据本发明的实施方案，所述的奈必洛尔与氨氯地平组合物，可以为盐酸奈必洛尔与苯磺酸氨氯地平组合物。
根据本发明的实施方案，所述的奈必洛尔与氨氯地平组合物进一步包含表面活性剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、着色剂和包衣膜中的一种或多种。
根据本发明的实施方案，所述的表面活性剂可以为十二烷基硫酸钠和/或聚山梨酯；例如，所述的聚山梨酯可选自聚山梨酯80和/或聚山梨酯20。
根据本发明的实施方案，所述的填充剂是指加入物料中可以改善物料性能，或能增溶、增重，降低物料的成本的固体物质，选自微晶纤维素(例如微晶纤维素101或微晶纤维素102)、磷酸氢钙、甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖(例如一水乳糖)、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种。
根据本发明的实施方案，所述的粘合剂可以为本领域中常规的能够增加分散介质的黏度，以降低微粒的沉降速度或增加微粒亲水性的附加剂，选自聚氧乙烯、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、聚维酮(例如聚维酮K30)、预胶化淀粉、***胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种。
根据本发明的实施方案，所述的崩解剂是指能使组合物制备的制剂(例如片剂或颗粒)在溶解中崩散的物质，选自交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠和玉米淀粉中的一种或多种。
根据本发明的实施方案，所述的润滑剂可以为本领域中常规的具有润滑作用的物质，选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种。所述的硬脂酸金属盐优选硬脂酸镁、硬脂酸钙和硬酯富马酸钠中的一种或多种。所述的硬脂酸酯优选为硬脂酸甘油酯。
根据本发明的实施方案，所述的助流剂可以为本领域中常规的能够降低粒子间的摩擦力而能改善粉末或颗粒流动性的辅料，选自滑石粉、微粉硅胶和胶态二氧化硅中的一种或多种。
根据本发明的实施方案，所述的着色剂可以为本领域中常规的能够达到着色目的的物质，选自氧化铁红和/或氧化铁黄。
根据本发明的实施方案，所述的奈必洛尔与氨氯地平组合物中除了包衣膜之外的组分共同组成片芯。
根据本发明的实施方案，所述奈必洛尔、其药学上可接受的盐或溶剂合物占所述片芯的质量百分比为1～10％，例如1.5～7％，示例性为1.60％、1.82％、2.00％、2.18％、2.27％、2.50％、2.73％、3.00％、3.50％、4.00％、5.00％、5.45％、6.00％。
根据本发明的实施方案，所述氨氯地平、其药学上可接受的盐或溶剂合物占所述片芯的质量百分比为1～20％，例如1.5～15％，示例性为2.00％、2.31％、2.77％、2.89％、3.00％、4.00％、5.00％、5.45％、6.00％、6.93％、8.00％、10.00％、12.00％、13.86％、14.00％。
根据本发明的实施方案，所述表面活性剂占所述片芯的质量百分比为0.05～10％，例如
0.1～5％，示例性为0.19％、0.25％、0.38％、0.50％、1.20％、2.00％、3.00％。
根据本发明的实施方案，所述填充剂占所述片芯的质量百分比为40～95％，例如60～90％，示例性为68.25％、79.70％、88.07％、78.77％、79.14％、81.05％、66.06％、66.00％、65.81％。
根据本发明的实施方案，所述的粘合剂占所述片芯的质量百分比为1～30％，例如5～25％，示例性为5.00％、6.67％、8.00％、10.00％、18.00％、20.80％。
根据本发明的实施方案，所述的崩解剂占所述片芯的质量百分比为1～10％，例如2～8％，示例性为4.00％、5.00％、6.00％、6.60％、7.00％。
根据本发明的实施方案，所述的润滑剂占所述片芯的质量百分比为0.1～5％，例如0.5～3％，示例性为1.00％、1.50％、2.00％。
根据本发明的实施方案，所述的助流剂占所述片芯的质量百分比为0.1～5％，例如0.2～3％，示例性为0.25％、0.30％、0.40％、0.50％、1.00％、2.00％。
根据本发明的实施方案，本发明的包衣膜可以选择薄膜包预混剂(胃溶型)。
根据本发明的实施方案，所述的片芯可以为以下任一处方：
处方1：2.77％苯磺酸氨氯地平、2.18％盐酸奈必洛尔、44.25％微晶纤维素101、16.00％一水乳糖、12.00％预胶化淀粉、6.00％羧甲淀粉钠、6.00％羟丙纤维素、1.20％聚山梨酯80、8.00％微晶纤维素102、0.60％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；
处方2：
2.31％苯磺酸氨氯地平、1.82％盐酸奈必洛尔、39.70％甘露醇、20.00％一水乳糖、6.67％羟丙甲纤维素、6.00％交联羧甲基纤维素钠、2.00％十二烷基硫酸钠、10.00％微晶纤维素102、10.00％无水磷酸氢钙、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；
处方3：
氨氯地平层：6.93％苯磺酸氨氯地平、60.00％微晶纤维素102、28.07％一水乳糖、4.00％羧甲淀粉钠和1.00％硬脂酸镁，所述的百分比是指各组分的重量占氨氯地平层总质量的百分比；
奈必洛尔层：2.73％盐酸奈必洛尔、63.77％微晶纤维素101、15.00％一水乳糖、6.00％交联羧甲基纤维素钠、8.00％预胶化淀粉、3.00％聚山梨酯80、0.50％胶态二氧化硅和1.00％硬脂酸镁，所述的百分比是指各组分的重量占奈必洛尔层总质量的百分比；
处方4：
氨氯地平层：13.86％苯磺酸氨氯地平、54.14％微晶纤维素102、25.00％无水磷酸氢钙、6.00％羧甲淀粉钠和1.00％硬脂酸镁，所述的百分比是指各组分的重量占氨氯地平层总质量的百分比；
奈必洛尔层：5.45％盐酸奈必洛尔、56.05％微晶纤维素101、25.00％甘露醇、5.00％交联羧甲基纤维素钠、5.00％羟丙基纤维素、2.00％聚山梨酯80、0.50％胶态二氧化硅和1.00％硬脂酸镁，所述的百分比是指各组分的重量占奈必洛尔层总质量的百分比；
处方5：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.41％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.38％聚山梨酯80、0.25％十二烷基硫酸钠、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；
处方6：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.35％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.19％聚山梨酯80、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％十二烷基硫酸钠、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；
处方7：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.16％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.38％聚山梨酯80、0.50％十二烷基硫酸钠、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；
处方8：1.56％盐酸奈必洛尔、1.98％苯磺酸氨氯地平、22.85％微晶纤维素(内加)、11.43％无水磷酸氢钙、38.25％乳糖一水合物、11.43％预胶化淀粉、1.29％羟丙甲纤维素、0.26％聚山梨酯80、0.17％十二烷基硫酸钠、4.28％微晶纤维素(外加)、5.00％交联羧甲纤维素钠(外加)、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比。
根据本发明的实施方案，所述奈必洛尔与氨氯地平组合物包含奈必洛尔的剂量可以为2.5mg至20.0mg，例如2.5mg、5.0mg、7.5mg、10.0mg、15.0mg或20.0mg。
根据本发明的实施方案，所述奈必洛尔与氨氯地平组合物包含氨氯地平的剂量可以为2.5mg至20.0mg，例如2.5mg、5.0mg、7.5mg、10.0mg、15.0mg或20.0mg。
根据本发明的实施方案，所述奈必洛尔与氨氯地平组合物本在30分钟内奈必洛尔和氨氯地平的溶出量均为70％以上，例如均为75％以上，优选均为80％以上。
本发明还提供了所述的奈必洛尔与氨氯地平组合物在制备治疗和/或预防心血管疾病的
药物中的应用。
根据本发明的实施方案，所述的心血管疾病包括高血压、心力衰竭、冠心病、心绞痛、心律失常、心肌梗死、先天性心脏病和心瓣膜病等。
本发明还提供了治疗和/或预防心血管疾病的方法，其为给有需要的哺乳动物(例如人)施用治疗有效量的所述的奈必洛尔与氨氯地平组合物、所述药物或下述药物制剂。
本发明还提供了所述的奈必洛尔与氨氯地平组合物在制备药物制剂中的应用。
根据本发明的实施方案，所述的药物制剂可以为口服药物制剂；例如，所述的口服药物制剂的剂型包括但不限于复方片、双层片、胶囊、微丸和微片等。
本发明还提供一种药物制剂，由上述奈必洛尔与氨氯地平组合物制备得到。优选地，所述药物制剂具有如上文所述的限定。
本发明还提供了所述的奈必洛尔与氨氯地平组合物的制备方法，包括但不限于粉末直接压片法、湿法制粒法、干法制粒法、流化制粒法、挤出滚圆法或微丸包衣法。
根据本发明的实施方案，所述湿法制粒法或流化制粒法可以包括以下步骤：
步骤1：将盐酸奈必洛尔、填充剂、粘合剂和崩解剂混合，然后再与粘合剂水溶液混合湿法制粒、湿整粒、干燥、干整粒，得到奈必洛尔干颗粒；
步骤2：将步骤1得到的奈必洛尔干颗粒与氨氯地平、填充剂混合，然后再与润滑剂和助流剂混合、压片，得到奈必洛尔氨氯地平素片；
步骤3：将步骤2得到的奈必洛尔氨氯地平素片用薄膜包衣预混剂的水溶液进行包衣，得到奈必洛尔氨氯地平片。
根据本发明的实施方案，所述干法制粒法可以包括以下步骤：
步骤①：将盐酸奈必洛尔、填充剂、粘合剂和崩解剂混合、再与粘合剂水溶液制粒、湿整粒、干燥、干整粒，得到奈必洛尔干颗粒；然后将得到的奈必洛尔干颗粒再与润滑剂和助流剂混合，得到奈必洛尔总混颗粒；
步骤②：将氨氯地平、填充剂、崩解剂混合均匀；然后再使用干法制粒机制粒，与润滑剂混合均匀，得氨氯地平总混颗粒；
步骤③：将步骤A得到的奈必洛尔总混颗粒和步骤B得到的氨氯地平总混颗粒压片，得奈必洛尔氨氯地平素片；然后再进行薄膜包衣得奈必洛尔氨氯地平片。
上述步骤①和②可以改变顺序。
本发明所用试剂和原料均市售可得。
本发明提供了奈必洛尔与氨氯地平的复方制剂，该制剂用于治疗和/或预防心血管疾病。
下文将结合具体实施例对本发明的技术方案做更进一步的详细说明。应当理解，下列实施例仅为示例性地说明和解释本发明，而不应被解释为对本发明保护范围的限制。凡基于本发明上述内容所实现的技术均涵盖在本发明旨在保护的范围内。
除非另有说明，以下实施例中使用的原料和试剂均为市售商品，或者可以通过已知方法制备。
实施例1
1)处方组成
2)制备方法
粘合剂配制：将羟丙甲纤维素用纯化水配制成粘合剂(固含量5％)，再加入聚山梨酯80，搅拌均匀备用；
步骤1：将盐酸奈必洛尔、微晶纤维素101、一水乳糖、预胶化淀粉、羧甲淀粉钠置于湿法制粒锅中，开启搅拌速度和切割速度，混合5分钟；再加入粘合剂水溶液进行湿法制粒，将制粒后的物料用16目筛网进行湿整粒，将整粒后的物料放入烘箱干燥至水分小于3.0％；将干燥后的颗粒过20目筛网进行干整粒，得到盐酸奈必洛尔干颗粒；
步骤2：将步骤1得到的盐酸奈必洛尔干颗粒、苯磺酸氨氯地平、微晶纤维素102加入混合锅中，混合20分钟，再加入胶态二氧化硅、硬脂酸镁混合5分钟；再使用旋转压片机进行压片，得到奈必洛尔氨氯地平素片；
步骤3：将步骤2得到的奈必洛尔氨氯地平素片用薄膜包衣预混剂的水溶液进行包衣(固含量12％，百分比是指包衣预混剂的质量占包衣预混剂水溶液总质量的百分比)，得到奈必洛尔氨氯地平片。
实施例2
1)处方组成
2)制备方法
粘合剂配制：将羟丙甲纤维素用纯化水配制成粘合剂(固含量5％)，再加入十二烷基硫酸钠，搅拌溶解备用；
步骤1：将盐酸奈必洛尔、甘露醇、一水乳糖、交联羧甲基纤维素钠加入混合锅中混合20分钟，再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用30目筛网过筛，得奈必洛尔干颗粒；
步骤2：将步骤1得到的奈必洛尔干颗粒、苯磺酸氨氯地平、微晶纤维素102、无水磷酸氢钙、胶态二氧化硅加入混合锅中，混合15分钟后加入硬脂酸镁，混合10分钟；再使用旋转压片机压片，得到奈必洛尔氨氯地平素片；
步骤3：将步骤2得到的奈必洛尔氨氯地平素片用薄膜包衣预混剂的水溶液进行包衣(固含量12％，百分比是指包衣预混剂的质量占包衣预混剂水溶液总质量的百分比)，得到奈必洛尔氨氯地平片。
实施例3
1)处方组成
2)制备方法
步骤A奈必洛尔层总混物料制备：
将预胶化淀粉缓慢加入搅拌的纯化水中溶解，再加入聚山梨酯80搅拌均匀备用；
将盐酸奈必洛尔、微晶纤维素101、一水乳糖、交联羧甲基纤维素钠加入湿法制粒机中，开启搅拌和切割，混合10分钟；加入粘合剂水溶液进行加浆和制粒，制粒后的软材用16目筛网湿整粒；再将湿颗粒放入恒温干燥箱中干燥至水分≤3.0％，用20目筛网干整粒；接着将奈必洛尔干颗粒、胶态二氧化硅、硬脂酸镁加入三维混合机中，混合5分钟，得奈必洛尔总混颗粒；
步骤B氨氯地平层总混物料制备：
将苯磺酸氨氯地平、微晶纤维素102、一水乳糖、羧甲纤维素钠置于三维混合机中，混合20分钟；使用干法制粒机，调节辊压压力、辊压速度、进料速度进行干法制粒，用24目筛网干整粒；再加入硬脂酸镁，混合5分钟；得到氨氯地平总混颗粒。
步骤C：将步骤A得到的奈必洛尔总混颗粒与步骤B得到的氨氯地平总混颗粒使用双层压片机进行压片，得奈必洛尔氨氯地平素片；然后再进行薄膜包衣得奈必洛尔氨氯地平片。
实施例4
1)处方组成
2)制备方法
氨氯地平层总混物料制备：
将苯磺酸氨氯地平、微晶纤维素102、一水乳糖、微晶纤维素102、羧甲淀粉钠置于三维混合机中，混合20分钟；再加入硬脂酸镁，混合5分钟。
奈必洛尔层总混物料制备：
将羟丙甲纤维素缓慢加入搅拌的纯化水中溶解，再加入聚山梨酯80搅拌均匀备用；
将盐酸奈必洛尔、微晶纤维素101、甘露醇、交联羧甲基纤维素钠加入三维混合机中，混合10分钟；再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用30目筛网过筛，得奈必洛尔干颗粒；再加入硬脂酸镁和胶态二氧化硅混合5分钟，得到奈必洛尔总混颗粒。
将氨氯地平总混物料和奈必洛尔总混颗粒使用双层压片机进行压片，得奈必洛尔氨氯地平素片，再进行薄膜包衣得奈必洛尔氨氯地平片。
实施例5
1)处方组成
2)制备方法
粘合剂配制：将羟丙甲纤维素用纯化水配制成粘合剂，再加入聚山梨酯80和十二烷基硫酸钠，搅拌均匀备用；
步骤1：将盐酸奈必洛尔、乳糖一水合物、预胶化淀粉、交联羧甲基纤维素钠(内加)加入混合锅中混合20分钟，再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用整粒机进行干整粒，得奈必洛尔干颗粒；
步骤2：将步骤1得到的奈必洛尔干颗粒、苯磺酸氨氯地平、交联羧甲纤维素钠(外加)、胶态二氧化硅、微晶纤维素101加入混合锅中，混合10分钟后，使用整粒机整粒，整粒完成后继续混合10分钟，加入硬脂酸镁，混合5分钟；再使用旋转压片机压片即得。
实施例6
1)处方组成
2)制备方法
粘合剂配制：将羟丙甲纤维素用纯化水配制成粘合剂，再加入聚山梨酯80，搅拌均匀备用；
步骤1：将盐酸奈必洛尔、乳糖一水合物、预胶化淀粉、交联羧甲基纤维素钠(内加)加入混合锅中混合20分钟，再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用20目筛网整粒，得奈必洛尔干颗粒；
步骤2：将步骤1得到的奈必洛尔干颗粒、苯磺酸氨氯地平、交联羧甲纤维素钠(外加)、胶态二氧化硅、微晶纤维素101、十二烷基硫酸钠加入混合锅中，混合10分钟后，加入硬脂酸镁，混合5分钟；再使用旋转压片机压片即得。
实施例7
1)处方组成
2)制备方法
粘合剂配制：将羟丙甲纤维素用纯化水配制成粘合剂，再加入聚山梨酯80和十二烷基硫酸钠，搅拌均匀备用；
步骤1：将盐酸奈必洛尔、乳糖一水合物、预胶化淀粉、交联羧甲基纤维素钠(内加)加入混合锅中混合20分钟，再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用整粒机进行干整粒，得奈必洛尔干颗粒；
步骤2：将步骤1得到的奈必洛尔干颗粒、苯磺酸氨氯地平、交联羧甲纤维素钠(外加)、胶态二氧化硅、微晶纤维素101加入混合锅中，混合10分钟后，使用整粒机整粒，整粒完成后继续混合10分钟，加入硬脂酸镁，混合5分钟；再使用旋转压片机压片即得。
实施例8
1)处方组成
2)制备方法
氨氯地平颗粒制备：
将苯磺酸氨氯地平、微晶纤维素(内加)、无水磷酸氢钙置于混合机中，混合20分钟；使用干法制粒机调节辊压和进料参数进行压制，再用24目筛网整粒，得到氨氯地平颗粒。
奈必洛尔颗粒制备：
粘合剂溶液配制：将羟丙甲纤维素缓慢加入搅拌的纯化水中溶解，再加入十二烷基硫酸钠和聚山梨酯80搅拌溶解备用；
将盐酸奈必洛尔、乳糖一水合物、预胶化淀粉加入三维混合机中，混合10分钟；再将混合物料置于流化床中，设置进风风量、进风温度、雾化温度，进料速度参数，使用蠕动泵加入粘合剂水溶液进行流化制粒；制粒后的物料使用30目筛网过筛，得到奈必洛尔颗粒。
将氨氯地平颗粒、奈必洛尔颗粒、微晶纤维素(外加)、交联羧甲纤维素钠(外加)、胶态二氧化硅加入混合锅中，混合10分钟，再加入硬脂酸镁混合5分钟，得到奈必洛尔氨氯地平总混颗粒，再将总混颗粒灌装胶囊，得到奈必洛尔氨氯地平胶囊。
实例1-8氨氯地平奈必洛尔复方制剂在在体积为900ml的pH4.5醋酸盐缓冲液中，采用USP第二法转速50rpm进行溶出实验。实施例4中氨氯地平奈必洛尔复方制剂的规格为10mg(以氨氯地平计)/10mg(以奈必洛尔计)，实施例1-3和实施例5-8中氨氯地平奈必洛尔复方制剂的规格为5mg(以氨氯地平计)/5mg(以奈必洛尔计)，溶出结果见表1。
表1-氨氯地平奈必洛尔复方制剂在pH4.5介质中的溶出结果
本发明提供的奈必洛尔与氨氯地平的复方制剂，协同作用好，有利于提高降压效果，提高安全耐受性，降低副作用。与其单药相比，奈必洛尔与氨氯地平联合用药的优势在于：(1)减少了服药数量，提高患者的顺应性；(2)对于老人或吞咽困难的人群，有利于提高其服药依从性；(3)维持体内血药浓度平稳，维持高血压患者血压长期稳定，降低各自药物的副作
用；(4)避免患者随意中断用药，预防疾病复发和恶性并发症进展。
以上，对本发明的实施方式进行了说明。但是，本发明不限定于上述实施方式。凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
Claims (10)
- 一种奈必洛尔与氨氯地平组合物，其特征在于，所述奈必洛尔与氨氯地平组合物包含活性成分奈必洛尔和活性成分氨氯地平；所述的活性成分奈必洛尔包括奈必洛尔、其药学上可接受的盐和溶剂合物中的一种或多种；所述的活性成分氨氯地平包括氨氯地平、其药学上可接受的盐和溶剂合物中的一种或多种。
- 如权利要求1所述的奈必洛尔与氨氯地平组合物，其特征在于：所述的奈必洛尔药学上可接受的盐为盐酸奈必洛尔；和/或，所述的氨氯地平药学上可接受的盐为苯磺酸氨氯地平和/或马来酸氨氯地平。
- 如权利要求1所述的奈必洛尔与氨氯地平组合物，其特征在于：所述的奈必洛尔与氨氯地平组合物进一步包括表面活性剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、着色剂和包衣膜中的一种或多种。
- 如权利要求3所述的奈必洛尔与氨氯地平组合物，其特征在于：所述的表面活性剂选自十二烷基硫酸钠和/或聚山梨酯；和/或，所述的填充剂选自微晶纤维素、磷酸氢钙、甘露醇、蔗糖、葡萄糖、麦芽糖、乳糖、山梨醇、木糖醇、麦芽糖醇、半乳糖醇、赤藓糖醇、糊精和海藻糖中的一种或多种；和/或，所述的粘合剂选自聚氧乙烯、羟丙甲基纤维素、羟丙基纤维素、羟乙基纤维素、乙基纤维素、共聚维酮、聚维酮、预胶化淀粉、***胶、聚乙烯吡咯烷酮和海藻酸钠中的一种或多种；和/或，所述的崩解剂选自交联聚维酮、交联羧甲基纤维素钠、羧甲淀粉钠和玉米淀粉中的一种或多种；和/或，所述的润滑剂选自硬脂酸金属盐、硬脂酸、滑石粉、硬脂酸酯、硬酯酰富马酸盐和微粉硅胶中的一种或多种；和/或，所述的助流剂选自滑石粉、微粉硅胶和胶态二氧化硅中的一种或多种；和/或，所述的着色剂选自氧化铁红和/或氧化铁黄；和/或，所述的包衣膜为薄膜包衣预混剂。
- 如权利要求1-4任一项所述的奈必洛尔与氨氯地平组合物，其特征在于：所述的奈必洛尔与氨氯地平组合物中除了包衣膜之外的组分共同组成片芯；所述的片芯选自以下任一处方：处方1：2.77％苯磺酸氨氯地平、2.18％盐酸奈必洛尔、44.25％微晶纤维素101、16.00％一水乳糖、12.00％预胶化淀粉、6.00％羧甲淀粉钠、6.00％羟丙纤维素、1.20％聚山梨酯80、8.00％微晶纤维素102、0.60％胶态二氧化硅、1.00％硬脂酸镁和包衣材料，所述的百分比是指各组分的质量占片芯总质量的百分比；处方2：2.31％苯磺酸氨氯地平、1.82％盐酸奈必洛尔、39.70％甘露醇、20.00％一水乳糖、6.67％羟丙甲纤维素、6.00％交联羧甲基纤维素钠、2.00％十二烷基硫酸钠、10.00％微晶纤维素102、10.00％无水磷酸氢钙、0.50％胶态二氧化硅、1.00％硬脂酸镁和包衣材料，所述的百分比是指各组分的质量占片芯总质量的百分比；处方3：氨氯地平层：6.93％苯磺酸氨氯地平、60.00％微晶纤维素102、28.07％一水乳糖、4.00％羧甲淀粉钠和1.00％硬脂酸镁，所述的百分比是指各组分的重量占氨氯地平层总质量的百分比；奈必洛尔层：2.73％盐酸奈必洛尔、63.77％微晶纤维素101、15.00％一水乳糖、6.00％交联羧甲基纤维素钠、8.00％预胶化淀粉、3.00％聚山梨酯80、0.50％胶态二氧化硅和1.00％硬脂酸镁，所述的百分比是指各组分的重量占奈必洛尔层总质量的百分比；处方4：氨氯地平层：13.86％苯磺酸氨氯地平、54.14％微晶纤维素102、25.00％无水磷酸氢钙、6.00％羧甲淀粉钠和1.00％硬脂酸镁，所述的百分比是指各组分的重量占氨氯地平层总质量的百分比；奈必洛尔层：5.45％盐酸奈必洛尔、56.05％微晶纤维素101、25.00％甘露醇、5.00％交联 羧甲基纤维素钠、5.00％羟丙基纤维素、2.00％聚山梨酯80、0.50％胶态二氧化硅和1.00％硬脂酸镁，所述的百分比是指各组分的重量占奈必洛尔层总质量的百分比；处方5：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.41％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.38％聚山梨酯80、和0.25％十二烷基硫酸钠、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；处方6：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.35％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.19％聚山梨酯80、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％十二烷基硫酸钠、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；处方7：2.27％盐酸奈必洛尔、2.89％苯磺酸氨氯地平、59.16％乳糖一水合物、19.16％预胶化淀粉、2.87％交联羧甲纤维素钠(内加)、1.63％羟丙甲纤维素、0.38％聚山梨酯80、0.50％十二烷基硫酸钠、3.74％交联羧甲纤维素钠(外加)、0.25％胶态二氧化硅、6.65％微晶纤维素101、0.50％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比；处方8：1.56％盐酸奈必洛尔、1.98％苯磺酸氨氯地平、22.85％微晶纤维素(内加)、11.43％无水磷酸氢钙、38.25％乳糖一水合物、11.43％预胶化淀粉、1.29％羟丙甲纤维素、0.26％聚山梨酯80、0.17％十二烷基硫酸钠、4.28％微晶纤维素(外加)、5.00％交联羧甲纤维素钠(外加)、0.50％胶态二氧化硅、1.00％硬脂酸镁，所述的百分比是指各组分的质量占片芯总质量的百分比。
- 如权利要求1～5任一项所述的奈必洛尔与氨氯地平组合物在制备治疗和/或预防心血管疾病的药物中的应用。
- 如权利要求6所述的应用，其特征在于：所述的心血管疾病包括高血压、心力衰竭、冠心病、心绞痛、心律失常、心肌梗死、先天性心脏病和心瓣膜病。
- 如权利要求1～5任一项所述的奈必洛尔与氨氯地平组合物在制备药物制剂中的应用；所述的药物制剂优选口服药物制剂。
- 如权利要求8所述的应用，其特征在于：所述的口服药物制剂的剂型包括但不限于复方片、双层片、胶囊、微丸和微片。
- 如权利要求1～5任一项所述的奈必洛尔与氨氯地平组合物的制备方法，其特征在于，所述制备方法包括但不限于粉末直接压片法、湿法制粒法、干法制粒法、流化制粒法、挤出 滚圆法和微丸包衣法。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202380012674.0A CN118043047A (zh) | 2022-09-14 | 2023-09-13 | 奈必洛尔与氨氯地平组合物、其制备方法及应用 |
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202211112943 | 2022-09-14 | ||
| CN202211112943.4 | 2022-09-14 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024055984A1 true WO2024055984A1 (zh) | 2024-03-21 |
Family
ID=90274280
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/CN2023/118513 WO2024055984A1 (zh) | 2022-09-14 | 2023-09-13 | 奈必洛尔与氨氯地平组合物、其制备方法及应用 |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN118043047A (zh) |
| WO (1) | WO2024055984A1 (zh) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766611A (zh) * | 2010-02-09 | 2010-07-07 | 施慧达药业集团(吉林)有限公司 | 一种左旋氨氯地平或其可药用盐和β受体阻滞剂的药物组合物及其应用 |
| CN103566372A (zh) * | 2012-08-09 | 2014-02-12 | 江苏柯菲平医药有限公司 | 一种降血压药物组合物 |
| CN108463250A (zh) * | 2016-01-08 | 2018-08-28 | 艾力森制药公司 | 包含具有改善溶解率的奈比洛尔的药物组合物 |
-
2023
- 2023-09-13 WO PCT/CN2023/118513 patent/WO2024055984A1/zh unknown
- 2023-09-13 CN CN202380012674.0A patent/CN118043047A/zh active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101766611A (zh) * | 2010-02-09 | 2010-07-07 | 施慧达药业集团(吉林)有限公司 | 一种左旋氨氯地平或其可药用盐和β受体阻滞剂的药物组合物及其应用 |
| CN103566372A (zh) * | 2012-08-09 | 2014-02-12 | 江苏柯菲平医药有限公司 | 一种降血压药物组合物 |
| CN108463250A (zh) * | 2016-01-08 | 2018-08-28 | 艾力森制药公司 | 包含具有改善溶解率的奈比洛尔的药物组合物 |
Non-Patent Citations (4)
| Title |
|---|
| JALANDER DONAPATI, SANDEEP KOSIKA, PARAMESHWAR KONDAPURAM, RAMAKRISHNA B., SURESH CHINDAM: "A Comparative clinical study on the Combination Therapy of Nebivolol/Amlodipine with Atenolol/Amlodipin in the management of hypertension", ASIAN JOURNAL OF PHARMACY AND PHARMACOLOGY, vol. 4, no. 1, 1 February 2018 (2018-02-01), pages 38 - 44, XP093147974, ISSN: 2455-2674, DOI: 10.31024/ajpp.2018.4.1.7 * |
| SHAIKH, S. A. ET AL.: "Formulation and Evaluation of S-(-)-Amlodipine Besylate and Nebivolol Hydrochloride Tablets", J. ADV. PHARM. TECH. RES., vol. 1, no. 2, 30 June 2010 (2010-06-30), pages 199 - 206, XP009160106 * |
| SULTAN EL-ZAHRAA M., RABEA HODA, ELBERRY AHMED A., MAHMOUD HESHAM B.: "Effect of Amlodipine/Nebivolol combination therapy on central BP and PWV compared to Amlodipine/Valsartan combination therapy", THE EGYPTIAN HEART JOURNAL, vol. 74, no. 1, 1 December 2022 (2022-12-01), XP093147971, ISSN: 2090-911X, DOI: 10.1186/s43044-022-00254-0 * |
| SUN YING-XIAN: "Research progress of new drugs for the treatment of hypertension", CHINESE JOURNAL OF PRACTICAL INTERNAL MEDICINE, vol. 35, no. 4, 1 April 2015 (2015-04-01), pages 290 - 294, XP093147969, ISSN: 1005-2194, DOI: 10.7504/nk2015030303 * |
Also Published As
| Publication number | Publication date |
|---|---|
| CN118043047A (zh) | 2024-05-14 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| TWI706947B (zh) | 含有葡萄糖激酶啟動劑和k-atp通道阻斷劑的藥物組合及其製備方法和用途 | |
| US8628799B2 (en) | Coated tablet formulation and method | |
| US20060088594A1 (en) | Highly compressible controlled delivery compositions of metformin | |
| WO2009034541A9 (en) | Controlled release pharmaceutical dosage forms of trimetazidine | |
| JP2001511184A (ja) | デスカルボエトキシロラタディンのラクトースを含まず非吸湿性かつ無水の薬剤組成物 | |
| WO2018108157A1 (zh) | 一种瑞卡帕布口服缓控释药物组合物及其用途 | |
| TW201545745A (zh) | 阿利沙坦酯固體分散體及藥物組合物 | |
| EP2468268A1 (en) | Combination composition of vildagliptin and gliclazide | |
| TWI784575B (zh) | 一種複合物的藥物組合物及其製備方法 | |
| US20090088424A1 (en) | Methods and compositions for controlling the bioavailability of poorly soluble drugs | |
| EP2638898A1 (en) | Metformin and Pioglitazone Formulation with Different Release Profiles | |
| EP3025707A1 (en) | A multilayer tablet comprising metformin and pioglitazone | |
| WO2021197376A1 (zh) | 一种非布司他片 | |
| WO2024055984A1 (zh) | 奈必洛尔与氨氯地平组合物、其制备方法及应用 | |
| CA3047325A1 (en) | Solid pharmaceutical formulations of asimadoline | |
| EP2392318A1 (en) | A pharmaceutical controlled release composition of losartan | |
| CN112618505A (zh) | 一种宠物用含有贝那普利和匹莫苯丹的复方药物组合物及其制备方法 | |
| CN114306263B (zh) | 一种复方降压药物组合物及其制备方法 | |
| TWI415604B (zh) | 調控釋放卡菲蒂羅劑型 | |
| CN114224859B (zh) | 一种复方降压药物组合物及其制备方法 | |
| EP2682109B1 (en) | Combined immediate release formulations of flurbiprofen and famotidine | |
| KR20090107960A (ko) | 심혈관계 질환 치료용 약제학적 제제 | |
| WO2024109927A1 (zh) | 包含美阿沙坦钾与钙通道阻滞剂的药物组合物，及其制备方法及应用 | |
| RU2772875C1 (ru) | Фармацевтическая комбинация, композиция и комбинированный состав, содержащий активатор глюкокиназы и блокатор к-атф-каналов, способ их приготовления и их применение | |
| NZ562286A (en) | Bi-layered modified release tablets for sustained release of guaifenesin combination drugs |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 23864716 Country of ref document: EP Kind code of ref document: A1 |