WO2006134604A1 - Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor - Google Patents
Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor Download PDFInfo
- Publication number
- WO2006134604A1 WO2006134604A1 PCT/IN2005/000196 IN2005000196W WO2006134604A1 WO 2006134604 A1 WO2006134604 A1 WO 2006134604A1 IN 2005000196 W IN2005000196 W IN 2005000196W WO 2006134604 A1 WO2006134604 A1 WO 2006134604A1
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- WIPO (PCT)
- Prior art keywords
- weight
- range
- formulation
- ezetimibe
- tablet
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims description 69
- CABVTRNMFUVUDM-VRHQGPGLSA-N (3S)-3-hydroxy-3-methylglutaryl-CoA Chemical compound O[C@@H]1[C@H](OP(O)(O)=O)[C@@H](COP(O)(=O)OP(O)(=O)OCC(C)(C)[C@@H](O)C(=O)NCCC(=O)NCCSC(=O)C[C@@](O)(CC(O)=O)C)O[C@H]1N1C2=NC=NC(N)=C2N=C1 CABVTRNMFUVUDM-VRHQGPGLSA-N 0.000 title description 5
- 229940123934 Reductase inhibitor Drugs 0.000 title description 4
- 229940122502 Cholesterol absorption inhibitor Drugs 0.000 title description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 120
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims abstract description 115
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims abstract description 110
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims abstract description 108
- OLNTVTPDXPETLC-XPWALMASSA-N ezetimibe Chemical compound N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 OLNTVTPDXPETLC-XPWALMASSA-N 0.000 claims abstract description 95
- 229960000815 ezetimibe Drugs 0.000 claims abstract description 94
- 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 abstract description 69
- 229920002785 Croscarmellose sodium Polymers 0.000 claims abstract description 68
- 229960001681 croscarmellose sodium Drugs 0.000 claims abstract description 67
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims abstract description 67
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims abstract description 60
- 229960000913 crospovidone Drugs 0.000 claims abstract description 60
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims abstract description 60
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims abstract description 60
- 239000000377 silicon dioxide Substances 0.000 claims abstract description 60
- 235000019359 magnesium stearate Nutrition 0.000 claims abstract description 58
- 239000004408 titanium dioxide Substances 0.000 claims abstract description 55
- 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 claims abstract description 54
- 239000001087 glyceryl triacetate Substances 0.000 claims abstract description 54
- 235000013773 glyceryl triacetate Nutrition 0.000 claims abstract description 54
- 229960002622 triacetin Drugs 0.000 claims abstract description 54
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 claims abstract description 42
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 claims abstract description 41
- 229960002855 simvastatin Drugs 0.000 claims abstract description 41
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 25
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 24
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 24
- 239000004255 Butylated hydroxyanisole Substances 0.000 claims abstract description 23
- 235000019282 butylated hydroxyanisole Nutrition 0.000 claims abstract description 23
- 229940043253 butylated hydroxyanisole Drugs 0.000 claims abstract description 23
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 claims abstract description 23
- SGHZXLIDFTYFHQ-UHFFFAOYSA-L Brilliant Blue Chemical compound [Na+].[Na+].C=1C=C(C(=C2C=CC(C=C2)=[N+](CC)CC=2C=C(C=CC=2)S([O-])(=O)=O)C=2C(=CC=CC=2)S([O-])(=O)=O)C=CC=1N(CC)CC1=CC=CC(S([O-])(=O)=O)=C1 SGHZXLIDFTYFHQ-UHFFFAOYSA-L 0.000 claims abstract description 22
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- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 10
- 239000007787 solid Substances 0.000 claims abstract description 10
- 229940121710 HMGCoA reductase inhibitor Drugs 0.000 claims abstract description 9
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 claims abstract description 9
- 239000007884 disintegrant Substances 0.000 claims abstract description 6
- -1 starlac Chemical compound 0.000 claims abstract description 6
- 229960004756 ethanol Drugs 0.000 claims abstract description 3
- 235000019441 ethanol Nutrition 0.000 claims abstract description 3
- 229940071676 hydroxypropylcellulose Drugs 0.000 claims abstract description 3
- 229940057948 magnesium stearate Drugs 0.000 claims abstract description 3
- 239000003826 tablet Substances 0.000 claims description 88
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 70
- XUKUURHRXDUEBC-KAYWLYCHSA-N Atorvastatin Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-KAYWLYCHSA-N 0.000 claims description 55
- XUKUURHRXDUEBC-UHFFFAOYSA-N Atorvastatin Natural products C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CCC(O)CC(O)CC(O)=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 XUKUURHRXDUEBC-UHFFFAOYSA-N 0.000 claims description 55
- 229960005370 atorvastatin Drugs 0.000 claims description 55
- 238000009472 formulation Methods 0.000 claims description 52
- 229920002472 Starch Polymers 0.000 claims description 44
- 229960000672 rosuvastatin Drugs 0.000 claims description 44
- BPRHUIZQVSMCRT-VEUZHWNKSA-N rosuvastatin Chemical compound CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC(O)=O BPRHUIZQVSMCRT-VEUZHWNKSA-N 0.000 claims description 44
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- 229940032147 starch Drugs 0.000 claims description 44
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- 239000011248 coating agent Substances 0.000 claims description 38
- 238000000576 coating method Methods 0.000 claims description 38
- 239000000463 material Substances 0.000 claims description 36
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 35
- 150000003839 salts Chemical class 0.000 claims description 35
- 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 32
- 239000008101 lactose Substances 0.000 claims description 32
- 229920006316 polyvinylpyrrolidine Polymers 0.000 claims description 18
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 12
- 239000011230 binding agent Substances 0.000 claims description 6
- 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 5
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose 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-DCSYEGIMSA-N 0.000 claims description 5
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 5
- 239000000945 filler Substances 0.000 claims description 4
- 239000000391 magnesium silicate Substances 0.000 claims description 4
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 4
- 239000000454 talc Substances 0.000 claims description 4
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- 235000012222 talc Nutrition 0.000 claims description 4
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 229960003563 calcium carbonate Drugs 0.000 claims description 3
- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 3
- 229960001375 lactose Drugs 0.000 claims description 3
- 239000000314 lubricant Substances 0.000 claims description 3
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 3
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- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-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
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 2
- 239000007894 caplet Substances 0.000 claims description 2
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- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 2
- 239000003085 diluting agent Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 239000000395 magnesium oxide Substances 0.000 claims description 2
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
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- 235000019793 magnesium trisilicate Nutrition 0.000 claims description 2
- 229940099273 magnesium trisilicate Drugs 0.000 claims description 2
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000006187 pill Substances 0.000 claims description 2
- 229940096701 plain lipid modifying drug hmg coa reductase inhibitors Drugs 0.000 claims description 2
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- 239000000843 powder Substances 0.000 claims description 2
- 239000008109 sodium starch glycolate Substances 0.000 claims description 2
- 229940079832 sodium starch glycolate Drugs 0.000 claims description 2
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- 229940033134 talc Drugs 0.000 claims description 2
- 229940029140 ezetimibe 10 mg Drugs 0.000 claims 12
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 claims 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 claims 2
- 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 2
- 239000003112 inhibitor Substances 0.000 claims 2
- 239000011734 sodium Substances 0.000 claims 2
- 229910052708 sodium Inorganic materials 0.000 claims 2
- 235000015424 sodium Nutrition 0.000 claims 2
- 239000005434 MCC/mannitol excipient Substances 0.000 claims 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 1
- 229940049950 atorvastatin 10 mg Drugs 0.000 claims 1
- 229940049949 atorvastatin 20 mg Drugs 0.000 claims 1
- 229940050446 atorvastatin 40 mg Drugs 0.000 claims 1
- 229940067134 atorvastatin 80 mg Drugs 0.000 claims 1
- 229960005168 croscarmellose Drugs 0.000 claims 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
- 239000008019 pharmaceutical lubricant Substances 0.000 claims 1
- 229940103117 simvastatin 10 mg Drugs 0.000 claims 1
- 229940103115 simvastatin 20 mg Drugs 0.000 claims 1
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- 239000004615 ingredient Substances 0.000 description 16
- 239000008194 pharmaceutical composition Substances 0.000 description 6
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 5
- 239000000654 additive Substances 0.000 description 5
- 229960001770 atorvastatin calcium Drugs 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- LALFOYNTGMUKGG-BGRFNVSISA-L rosuvastatin calcium Chemical compound [Ca+2].CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O.CC(C)C1=NC(N(C)S(C)(=O)=O)=NC(C=2C=CC(F)=CC=2)=C1\C=C\[C@@H](O)C[C@@H](O)CC([O-])=O LALFOYNTGMUKGG-BGRFNVSISA-L 0.000 description 4
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- 239000002245 particle Substances 0.000 description 2
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- 239000000243 solution Substances 0.000 description 2
- 239000004322 Butylated hydroxytoluene Substances 0.000 description 1
- NLZUEZXRPGMBCV-UHFFFAOYSA-N Butylhydroxytoluene Chemical compound CC1=CC(C(C)(C)C)=C(O)C(C(C)(C)C)=C1 NLZUEZXRPGMBCV-UHFFFAOYSA-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
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- PNAMDJVUJCJOIX-IUNFJCKHSA-N [(1s,3r,7s,8s,8ar)-8-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-3,7-dimethyl-1,2,3,7,8,8a-hexahydronaphthalen-1-yl] 2,2-dimethylbutanoate;(3r,4s)-1-(4-fluorophenyl)-3-[(3s)-3-(4-fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)azetidin-2-one Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1.N1([C@@H]([C@H](C1=O)CC[C@H](O)C=1C=CC(F)=CC=1)C=1C=CC(O)=CC=1)C1=CC=C(F)C=C1 PNAMDJVUJCJOIX-IUNFJCKHSA-N 0.000 description 1
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- FQCKMBLVYCEXJB-MNSAWQCASA-L atorvastatin calcium Chemical compound [Ca+2].C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1.C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@@H](O)C[C@@H](O)CC([O-])=O)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 FQCKMBLVYCEXJB-MNSAWQCASA-L 0.000 description 1
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/397—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having four-membered rings, e.g. azetidine
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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
- A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
-
- 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
- A61K31/66—Phosphorus compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/06—Antihyperlipidemics
Definitions
- the present invention relates to stable pharmaceutical compositions of antihyperlipoproteinemic drugs.
- Ezetimibe chemically, (3R,4S)-1-(4-fluorophenyl)-3-[3(S)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone.
- Ezetimibe is a cholesterol absorption inhibitor.
- the therapeutic uses of ezetimibe and related compounds, and their preparations were disclosed in U.S. patent No.
- Ezetimibe is commercially available as 10 mg tablets. It is sold under the name ZETIA.
- Simvastatin chemically, 2,2-dimethylbutarioic acid (1S,3R,7S,8S,8aR)- 1 ,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-(tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester.
- Simvastatin is a 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
- HMG-CoA 3-hydroxy-3- methylglutaryl-coenzyme A
- Simvastatin is commercially available as 5 mg, 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name ZOCOR.
- Atorvastatin chemically, ( ⁇ R, ⁇ R)-2-(4-fluorophenyl)- ⁇ , ⁇ -dihydroxy-5- (1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid.
- Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor.
- HMG-CoA 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitor.
- the therapeutic uses of atorvastatin and related compounds, and their preparations were disclosed in U.S. patent No. 5,273,995.
- Atorvastatin is commercially available as 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name LIPITOR.
- Rosuvastatin chemically, [3R-[3R * ,5S*(E)]]-7-[4-(4-fluorophenyl)-6-(1- methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6- heptenoic acid.
- Rosuvastatin is a HMG-CoA reductase inhibitor. The therapeutic uses of rosuvastatin and related compounds, and their preparations were disclosed in U.S. patent No. 5,260,440.
- Rosuvastatin is commercially available as 5 mg, 10 mg, 20 mg and 40 mg tablets. It is sold under the name CRESTOR.
- the object of the present invention is to provide stable solid oral pharmaceutical compositions of antihyperlipoproteinemic drugs.
- the present invention relates to a stable antihyperlipoproteinemic combination of solid oral pharmaceutical compositions comprising ezetimibe, HMG-CoA reductase inhibitor, disintegrants and glidants.
- a stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations which comprises ezetimibe, an HMG-CoA reductase inhibitor, disintegrants selected from starch, croscarmellose sodium and crospovidone, glidants selected from colloidal anhydrous silica and magnesium stearate.
- Other additives conventionally used for pharmaceutical formulations may be included in the present formulation.
- the preferable HMG-CoA reductase inhibitors are simvastatin, atorvastatin and rosuvastatin; or a salt thereof.
- the particularly preferable stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations which comprises ezetimibe in the range of 1 to 15% by weight, more preferably 1.5 to 11% by weight; the HMG- CoA reductase inhibitor selected from simvastatin in the range of 1 to 25% by weight, more preferably 2 to 20% by weight; atorvastatin or a salt thereof in the range of 1 to 30% by weight, more preferably 2 to 25% by weight equivalent to atorvastatin and rosuvastatin or a salt thereof in the range of 2 to 12% by weight, more preferably 4 to 10% by weight equivalent to rosuvastatin; starch in the range of 2 to 25% by weight, more preferably 3 to 20% by weight; croscarmellose sodium in the range of 1 to 8% by weight, more preferably 1.5 to 6.5% by weight; crospovidone in the range of 1 to 8% by weight, more preferably 1.5 to 6.5% by weight; colloidal anhydrous silica in the range of 0.1 to 2.5% by weight
- a stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations according to the invention comprises additives, which are conventionally used in dosage forms. These include but are not limited to disintegrants, binders, lubricants, glidants, fillers or diluents, stabilizing agents and the like.
- disintegrants one can particularly mention sodium starch glycolate, starch, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, magnesium aluminum silicate or a mixture thereof.
- binders one can particularly mention starch, hydroxypropylcellulose, polyvinylpyrolidone k-30, hydroxypropylcellulose (low- substituted); or a mixture thereof.
- stearic acid pharmaceutically acceptable derivatives of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate, hydrogenated castor oil; or a mixture thereof.
- colloidal anhydrous silica talc or a mixture thereof.
- preservatives one can particularly mention butylated hydroxy anisole, butylated hydroxy toluene, methyl paraben, propyl paraben; or a mixture thereof.
- fillers one can particularly mention calcium carbonate, dibasic calcium phosphate, lactose, magnesium carbonate, sucrose, starch, magnesium oxide, lactose anhydrous, microcrystalline cellulose, mannitol; or a mixture thereof.
- Other ingredients such as coating materials, anti-adherents, plasticizer, colorants, opacifiers, antioxidants and solvents conventionally used for pharmaceutical formulations.
- the pharmaceutical composition may be for example, in the form of a tablet, a caplet, pellets, a capsule, granules, a pill, powder or a sachet.
- the pharmaceutical composition is in the form of a combination antihyperlipoproteinemic tablet.
- Stable mixture which is highly compressible, have good flow properties, thereby providing the tablets with excellent physical properties.
- the pharmaceutical composition of the present invention is administered orally.
- An improved stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations which comprises ezetimibe, simvastatin, starlac, ethanol, butylated hydroxy anisole, magnesium stearate, crospovidone, croscarmellose sodium, hydroxypropylcellulose (low-substituted), purified talc, lake brilliant blue, colloidal anhydrous silica, hydroxypropylmethylcellulose- 15cps, titanium dioxide and triacetin.
- the present invention provides a formulation suitable for forming ezetimibe and simvastatin combination tablets comprising ezetimibe in the range of 1 to 10% by weight, more preferably 1.5 to 7.5% by weight, simvastatin in the range of 2 to 23% by weight, more preferably 3 to 18% by weight, starlac in the range of 41 to 97% by weight, more preferably 61 to 87% by weight, butylated hydroxy anisole in the range of 0.01 to 0.004% by weight, more preferably 0.01 to 0.03% by weight, magnesium stearate in the range of 1 to 3% by weight, more preferably 1.5 to 2.5% by weight, crospovidone in the range of 1 to 6% by weight, more preferably 1.5 to 5% by weight, croscarmellose sodium in the range of 1 to 4% by weight, more preferably 1.5 to 3% by weight, hydroxypropylcellulose (low-substituted) in the range of 2 to 7% by weight, more preferably 2.5 to 6.5% by weight, colloidal anhydr
- solid dosage forms contain a number of additional additives used in single dosage units.
- the particularly preferable tablet formulations are: i) Ezetimibe (10mg) and simvastatin (5mg); which comprises ezetimibe is 6.7% by weight, simvastatin is 3.3% by weight, starlac is 77.3% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2.7% by weight, croscarmellose sodium is 2% by weight, hydroxypropylcellulose (low-substituted) is 5.3% by weight, colloidal anhydrous silica is 1% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-i ⁇ cps is 63.7% by weight, purified talc is 8% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based
- Ezetimibe (10mg) and simvastatin (40mg); which comprises ezetimibe is 2.6% by weight, simvastatin is 10.3% by weight, starlac is 75.1% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2.1% by weight, crospovidone is 2.1% by weight, croscarmellose sodium is 1.8% by weight, hydroxypropylcellulose (low-substituted) is 5.1% by weight, colloidal anhydrous silica is 1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.2% by weight, purified talc is 8.2% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 2.3% by weight, based on the total weight of the coating material.
- Ezetimibe (10mg) and simvastatin (80mg); which comprises ezetimibe is 2% by weight, simvastatin is 16% by weight, starlac is 67.8% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2% by weight, crospovidone is 4% by weight, croscarmellose sodium is 2.6% by weight, hydroxypropylcellulose (low-substituted) is 4.6% by weight, colloidal anhydrous silica is 1% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose ' ⁇ 15cps is 63.3% by weight, purified talc is 8.1% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.8% by weight, based on the total weight of the coating material.
- An improved stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations which comprises ezetimibe, atorvastatin and rosuvastatin or a salt thereof, light calcium carbonate, lactose, starch, croscarmellose sodium, polyvinylpyrrolidone k-30, isopropyl alcohol, titanium dioxide, magnesium stearate, colloidal anhydrous silica, crospovidone, hydroxypropylmethylcellulose-15cps, purified talc, lake sunset yellow and triacetin.
- the present invention provides a formulation suitable for forming ezetimibe and atorvastatin; or a salt thereof combination tablets comprising ezetimibe in the range of 1.5 to 13% by weight, more preferably 2 to 10% by weight, atorvastatin; or a salt thereof in the range of 3 to 31% by weight, more preferably 4 to 24% by weight equivalent to atorvastatin, light calcium carbonate in the range of 2 to 8% by weight, more preferably 3 to 6.5% by weight, lactose in the range of 27 to 80% by weight, more preferably 40 to 63% by weight, starch in the range of 5 to 24% by weight, more preferably 8 to 19% by weight, croscarmellose sodium in the range of 2 to 8% by weight, more preferably 3 to 6% by weight, polyvinylpyrrolidone k-30 in the range of 1 to 7% by weight, more preferably 2.5 to 6% by weight, magnesium stearate in the range of 1 to 4% by weight, more preferably 1.5 to 3% by
- solid dosage forms contain a number of additional additives used in single dosage units.
- the particularly preferable tablet formulations are: i) Ezetimibe (10mg) and atorvastatin (5mg); which comprises ezetimibe is 9.09% by weight, atorvastatin or a salt thereof is 4.92% by weight equivalent to atorvastatin, light calcium carbonate is 3.64% by weight, lactose is 51.4% by weight, starch is 17.3% by weight, croscarmellose sodium is 3.62% by weight, polyvinylpyrolidone k-30 is 4.09% by weight, magnesium stearate is 1.82% by weight, colloidal anhydrous silica is 1.36% by weight, crospovidone is 2.73% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.3% by weight, purified talc is 7.73% by weight, lake sunset yellow is 1.36% by weight,
- the present invention provides a formulation suitable for forming ezetimibe and rosuvastatin or a salt thereof combination tablets comprising ezetimibe in the range of 2 to 13% by weight, more preferably 3 to 10% by weight, rosuvastatin; or a salt thereof in the range of 2 to 10.5% by weight, more preferably 4 to 8.5% by weight equivalent to rosuvastatin, light calcium carbonate in the range of 1 to 4% by weight, more preferably 1.5 to 3% by weight, lactose in the range of 32 to 83% by weight, more preferably 49 to 65% by weight, starch in the range of 8 to 21% by weight, more preferably 12 to 16.5% by weight, croscarmellose sodium in the range of 2 to 6.5% by weight, more preferably 2.5 to 5% by weight, polyvinylpyrrolidone k-30 in the range of 1 to 5% by weight, more preferably 2 to 3.5% by weight, magnesium stearate in the range of 1 to 3.5% by weight, more preferably 1.5 to
- solid dosage forms contain a number of additional additives used in single dosage units.
- the particularly preferable tablet formulations are: i) Ezetimibe (10mg) and rosuvastatin (5mg); which comprises ezetimibe is 9.09% by weight, rosuvastatin or a salt thereof is 4.74% by weight equivalent to rosuvastatin, light calcium carbonate is 2.3% by weight, lactose is 54.5% by weight, starch is 13.9% by weight, croscarmellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 3.2% by weight, magnesium stearate is 1.8% by weight, colloidal anhydrous silica is 0.9% by weight, crospovidone is 5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 71.8% by weight, purified talc is 8.2% by weight, lake sunset yellow is 1.4% by weight, titanium dioxide is
- rosuvastatin or a salt thereof is 5.95% by weight equivalent to rosuvastatin
- light calcium carbonate is 2.3% by weight
- lactose is 57.5% by weight
- starch is 13.7% by weight
- croscarmellose sodium is 4% by weight
- ⁇ polyvinylpyrolidone k-30 is 2.9% by weight, magnesium stearate is 2.3% by weight, colloidal anhydrous silica is 1.1% by weight, crospovidone is 4.6% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 72.3% by weight, purified talc is 8% by weight, lake sunset yellow is 1.43% by weight, titanium dioxide is 12.6% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
- the ezetimibe, simvastatin and starlac are granulated using binder solution of butylated hydroxy anisole and ethanol in planetary mixer, rapid mixer granulator; or other suitable granulator. This wet mass may be then dried. The dried granulation may be then milled to acheive the desired particle size distribution and then blended with the other ingredients. This blend is compressed into tablets. These compressed tablets are coated using a non aqueous solution of hydroxypropylmethylcellulose-15cps, purified talc, lake brilliant blue, titanium dioxide and triacetin by using autocota, neocota; or other suitable coating pan.
- Example 1 Example 1
- Example 2 The components and their amounts were as follows: Ezetimibe (10mg) and simvastatin (10mg) tablets:
- Ezetimibe (10mg) and simvastatin (40mg) tablets were as follows: Ezetimibe (10mg) and simvastatin (40mg) tablets:
- the ezetimibe, HMG-CoA reductase inhibitor, light calcium carbonate, lactose, starch and croscarmellose sodium are granulated using binder solution of polyvinylpyrrolidone k-30 and isopropyl alcohol in planetary mixer, rapid mixer granulator; or other suitable granulator. This wet mass may be then dried. The dried granulation may be then milled to acheive the desired particle size distribution and then blended with the other ingredients. This blend is compressed into tablets.
- These compressed tablets are coated using a non aqueous solution of hydroxypropylmethylcellulose- 15cps, purified talc, lake sunset yellow, titanium dioxide and triacetin by using autocota, neocota; or other suitable coating pan.
- Ezetimibe (10mg) and atorvastatin (5mg) tablets Ingredients Quantity (mg) %(W ⁇ /V)
- Example 12 The components and their amounts were as follows: Ezetimibe (10mg) and rosuvastatin (10mg) tablets: Ingredients Quantity (mg) %(W ⁇ /V)
- Example 13 The components and their amounts were as follows: Ezetimibe (10mg) and rosuvastatin (20mg) tablets:
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Abstract
The present invention relates to stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations ezetimibe, HMG-CoA reductase inhibitor, disintegrants and glidants. For example, stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe, simvastatin, starlac, ethanol, butylated hydroxy anisole, magnesium stearate, crospovidone, croscarmellose sodium, hydroxypropylcellulose (low-substituted), purified talc, lake brilliant blue, colloidal anhydrous silica, hydroxypropylmethylcellulose-15cps, titanium dioxide and triacetin.
Description
COMBINATION COMPOSITION OF CHOLESTEROL ABSORPTION INHIBITOR AND 3-HYDROXY-S-METHYLGLUTARYL-COENZYME A (HMG-
COA) REDUCTASE INHIBITOR
FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of antihyperlipoproteinemic drugs.
BACKGROUND OF THE INVENTION
Ezetimibe, chemically, (3R,4S)-1-(4-fluorophenyl)-3-[3(S)-3-(4- fluorophenyl)-3-hydroxypropyl]-4-(4-hydroxyphenyl)-2-azetidinone. Ezetimibe is a cholesterol absorption inhibitor. The therapeutic uses of ezetimibe and related compounds, and their preparations were disclosed in U.S. patent No.
5,767,115.
Ezetimibe is commercially available as 10 mg tablets. It is sold under the name ZETIA.
Simvastatin, chemically, 2,2-dimethylbutarioic acid (1S,3R,7S,8S,8aR)- 1 ,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-(tetrahydro-4-hydroxy-6- oxo-2H-pyran-2-yl)ethyl]-1-naphthalenyl ester. Simvastatin is a 3-hydroxy-3- methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The therapeutic uses of simvastatin and related compounds, and their preparations were disclosed in U.S. patent No. 4,444,784.
Simvastatin is commercially available as 5 mg, 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name ZOCOR.
Atorvastatin, chemically, (βR,δR)-2-(4-fluorophenyl)-β,δ-dihydroxy-5- (1 -methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-1 H-pyrrole-1 -heptanoic acid. Atorvastatin is a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor. The therapeutic uses of atorvastatin and related compounds, and their preparations were disclosed in U.S. patent No. 5,273,995. Atorvastatin is commercially available as 10 mg, 20 mg, 40 mg and 80 mg tablets. It is sold under the name LIPITOR.
Rosuvastatin, chemically, [3R-[3R*,5S*(E)]]-7-[4-(4-fluorophenyl)-6-(1- methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6- heptenoic acid. Rosuvastatin is a HMG-CoA reductase inhibitor. The
therapeutic uses of rosuvastatin and related compounds, and their preparations were disclosed in U.S. patent No. 5,260,440.
Rosuvastatin is commercially available as 5 mg, 10 mg, 20 mg and 40 mg tablets. It is sold under the name CRESTOR. The object of the present invention is to provide stable solid oral pharmaceutical compositions of antihyperlipoproteinemic drugs.
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a stable antihyperlipoproteinemic combination of solid oral pharmaceutical compositions comprising ezetimibe, HMG-CoA reductase inhibitor, disintegrants and glidants.
According to the present invention, a stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe, an HMG-CoA reductase inhibitor, disintegrants selected from starch, croscarmellose sodium and crospovidone, glidants selected from colloidal anhydrous silica and magnesium stearate. Other additives conventionally used for pharmaceutical formulations may be included in the present formulation.
The preferable HMG-CoA reductase inhibitors are simvastatin, atorvastatin and rosuvastatin; or a salt thereof.
The particularly preferable stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe in the range of 1 to 15% by weight, more preferably 1.5 to 11% by weight; the HMG- CoA reductase inhibitor selected from simvastatin in the range of 1 to 25% by weight, more preferably 2 to 20% by weight; atorvastatin or a salt thereof in the range of 1 to 30% by weight, more preferably 2 to 25% by weight equivalent to atorvastatin and rosuvastatin or a salt thereof in the range of 2 to 12% by weight, more preferably 4 to 10% by weight equivalent to rosuvastatin; starch in the range of 2 to 25% by weight, more preferably 3 to 20% by weight; croscarmellose sodium in the range of 1 to 8% by weight, more preferably 1.5 to 6.5% by weight; crospovidone in the range of 1 to 8% by weight, more preferably 1.5 to 6.5% by weight; colloidal anhydrous silica in the range of 0.1 to 2.5% by weight, more preferably 0.5 to 2% by weight and magnesium
stearate in the range of 0.5 to 5% by weight, more preferably 1 to 4% by weight, based on the total weight of the pharmaceutical dosage unit.
A stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations according to the invention comprises additives, which are conventionally used in dosage forms. These include but are not limited to disintegrants, binders, lubricants, glidants, fillers or diluents, stabilizing agents and the like.
As disintegrants one can particularly mention sodium starch glycolate, starch, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium, magnesium aluminum silicate or a mixture thereof. As binders one can particularly mention starch, hydroxypropylcellulose, polyvinylpyrolidone k-30, hydroxypropylcellulose (low- substituted); or a mixture thereof. As lubricants one can particularly mention stearic acid, pharmaceutically acceptable derivatives of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate, hydrogenated castor oil; or a mixture thereof. As glidants one can particularly mention colloidal anhydrous silica, talc or a mixture thereof. As preservatives one can particularly mention butylated hydroxy anisole, butylated hydroxy toluene, methyl paraben, propyl paraben; or a mixture thereof. As fillers one can particularly mention calcium carbonate, dibasic calcium phosphate, lactose, magnesium carbonate, sucrose, starch, magnesium oxide, lactose anhydrous, microcrystalline cellulose, mannitol; or a mixture thereof. Other ingredients such as coating materials, anti-adherents, plasticizer, colorants, opacifiers, antioxidants and solvents conventionally used for pharmaceutical formulations.
The pharmaceutical composition may be for example, in the form of a tablet, a caplet, pellets, a capsule, granules, a pill, powder or a sachet. Preferably the pharmaceutical composition is in the form of a combination antihyperlipoproteinemic tablet. Stable mixture, which is highly compressible, have good flow properties, thereby providing the tablets with excellent physical properties. The pharmaceutical composition of the present invention is administered orally.
An improved stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe, simvastatin, starlac,
ethanol, butylated hydroxy anisole, magnesium stearate, crospovidone, croscarmellose sodium, hydroxypropylcellulose (low-substituted), purified talc, lake brilliant blue, colloidal anhydrous silica, hydroxypropylmethylcellulose- 15cps, titanium dioxide and triacetin. The present invention provides a formulation suitable for forming ezetimibe and simvastatin combination tablets comprising ezetimibe in the range of 1 to 10% by weight, more preferably 1.5 to 7.5% by weight, simvastatin in the range of 2 to 23% by weight, more preferably 3 to 18% by weight, starlac in the range of 41 to 97% by weight, more preferably 61 to 87% by weight, butylated hydroxy anisole in the range of 0.01 to 0.004% by weight, more preferably 0.01 to 0.03% by weight, magnesium stearate in the range of 1 to 3% by weight, more preferably 1.5 to 2.5% by weight, crospovidone in the range of 1 to 6% by weight, more preferably 1.5 to 5% by weight, croscarmellose sodium in the range of 1 to 4% by weight, more preferably 1.5 to 3% by weight, hydroxypropylcellulose (low-substituted) in the range of 2 to 7% by weight, more preferably 2.5 to 6.5% by weight, colloidal anhydrous silica in the range of 0.5 to 2% by weight, more preferably 0.5 to 1.5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps in the range of 37 to 89.5% by weight, more preferably 56 to 70% by weight, purified talc in the range of 4 to 12% by weight, more preferably 7 to 9.5% by weight, lake brilliant blue in the range of 4 to 14% by weight, more preferably 9 to 11% by weight, titanium dioxide in the range of 7 to 18% by weight, more preferably 11 to 14.5% by weight and triacetin in the range of 3 to 9% by weight, more preferably 5 to 6.5% by weight, based on the total weight of the coating material. Optionally additional excipients may be used. In addition to the active ingredient, solid dosage forms contain a number of additional additives used in single dosage units. The particularly preferable tablet formulations are: i) Ezetimibe (10mg) and simvastatin (5mg); which comprises ezetimibe is 6.7% by weight, simvastatin is 3.3% by weight, starlac is 77.3% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2.7% by weight, croscarmellose sodium is 2% by weight, hydroxypropylcellulose (low-substituted) is 5.3% by weight, colloidal anhydrous silica is 1% by weight, based on the total weight of the tablet,
hydroxypropylmethylcellulose-iδcps is 63.7% by weight, purified talc is 8% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material. ii) Ezetimibe (10mg) and simvastatin (10mg); which comprises ezetimibe is 5.6 % by weight, simvastatin is 5.6% by weight, starlac is 79.4% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2.2% by weight, croscarmellose sodium is 1.7% by weight, hydroxypropylcellulose (low-substituted) is 2.8% by weight, colloidal anhydrous silica is 1.1% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.6% by weight, purified talc is 8.1% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.6% by weight, based on the total weight of the coating material. iii) Ezetimibe (10mg) and simvastatin (20mg); which comprises ezetimibe is 3.3% by weight, simvastatin is 6.7% by weight, starlac is 78.1% by weight, butylated hydroxy anisole is 0.03% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2% by weight, croscarmellose sodium is 1.7% by weight, hydroxypropylcellulose (low-substituted) is 5.7% by weight, colloidal anhydrous silica is 0.8% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.5% by weight, purified talc is 8.2% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material. iv) Ezetimibe (10mg) and simvastatin (40mg); which comprises ezetimibe is 2.6% by weight, simvastatin is 10.3% by weight, starlac is 75.1% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2.1% by weight, crospovidone is 2.1% by weight, croscarmellose sodium is 1.8% by weight, hydroxypropylcellulose (low-substituted) is 5.1% by weight, colloidal anhydrous silica is 1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.2% by weight, purified talc is 8.2% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 2.3% by weight, based on the total weight of the coating material.
v) Ezetimibe (10mg) and simvastatin (80mg); which comprises ezetimibe is 2% by weight, simvastatin is 16% by weight, starlac is 67.8% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2% by weight, crospovidone is 4% by weight, croscarmellose sodium is 2.6% by weight, hydroxypropylcellulose (low-substituted) is 4.6% by weight, colloidal anhydrous silica is 1% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose'~15cps is 63.3% by weight, purified talc is 8.1% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.8% by weight, based on the total weight of the coating material.
An improved stable antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe, atorvastatin and rosuvastatin or a salt thereof, light calcium carbonate, lactose, starch, croscarmellose sodium, polyvinylpyrrolidone k-30, isopropyl alcohol, titanium dioxide, magnesium stearate, colloidal anhydrous silica, crospovidone, hydroxypropylmethylcellulose-15cps, purified talc, lake sunset yellow and triacetin.
The present invention provides a formulation suitable for forming ezetimibe and atorvastatin; or a salt thereof combination tablets comprising ezetimibe in the range of 1.5 to 13% by weight, more preferably 2 to 10% by weight, atorvastatin; or a salt thereof in the range of 3 to 31% by weight, more preferably 4 to 24% by weight equivalent to atorvastatin, light calcium carbonate in the range of 2 to 8% by weight, more preferably 3 to 6.5% by weight, lactose in the range of 27 to 80% by weight, more preferably 40 to 63% by weight, starch in the range of 5 to 24% by weight, more preferably 8 to 19% by weight, croscarmellose sodium in the range of 2 to 8% by weight, more preferably 3 to 6% by weight, polyvinylpyrrolidone k-30 in the range of 1 to 7% by weight, more preferably 2.5 to 6% by weight, magnesium stearate in the range of 1 to 4% by weight, more preferably 1.5 to 3% by weight, colloidal anhydrous silica in the range of 0.5 to 2.5% by weight, more preferably 0.5 to 2% by weight, crospovidone in the range of 1.5 to 6% by weight, more preferably 2 to 4.5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps in the range of 50 to 90% by weight, more preferably 65 to 80% by weight, purified talc in the range of 5 to
10% by weight, more preferably 7 to 9% by weight, lake sunset yellow in the range of 0.5 to 2% by weight, more preferably 1 to 1.5% by weight, titanium dioxide in the range of 8.5 to 18% by weight, more preferably 11 to 14.5% by weight and triacetin in the range of 4 to 8% by weight, more preferably 5 to 7% by weight, based on the total weight of the coating material. Optionally additional excipients may be used. In addition to the active ingredient, solid dosage forms contain a number of additional additives used in single dosage units. The particularly preferable tablet formulations are: i) Ezetimibe (10mg) and atorvastatin (5mg); which comprises ezetimibe is 9.09% by weight, atorvastatin or a salt thereof is 4.92% by weight equivalent to atorvastatin, light calcium carbonate is 3.64% by weight, lactose is 51.4% by weight, starch is 17.3% by weight, croscarmellose sodium is 3.62% by weight, polyvinylpyrolidone k-30 is 4.09% by weight, magnesium stearate is 1.82% by weight, colloidal anhydrous silica is 1.36% by weight, crospovidone is 2.73% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.3% by weight, purified talc is 7.73% by weight, lake sunset yellow is 1.36% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.91% by weight, based on the total weight of the coating material. ii) Ezetimibe (10mg) and atorvastatin (10mg); which comprises ezetimibe is 6.7% by weight, atorvastatin or a salt thereof is 7.2% by weight equivalent to atorvastatin, light calcium carbonate is 4.7% by weight, lactose is 56.8% by weight, starch is 10.7% by weight, croscarmellose sodium is 3.4% by weight, polyvinylpyrolidone k-30 is 5% by weight, magnesium stearate is 2% by weight, colloidal anhydrous silica is 1% by weight, crospovidone is 2.7% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 72.3% by weight, purified talc is 8% by weight, lake sunset yellow is 1.33% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material. iii) Ezetimibe (10mg) and atorvastatin (20mg); which comprises ezetimibe is 5.56% by weight, atorvastatin or a salt thereof is 12% by weight equivalent to atorvastatin, light calcium carbonate is 5.56% by weight, lactose is 51.3% by weight, starch is 8.89% by weight, croscarmellose sodium is 4.6% by weight,
polyvinylpyrrolidone k-30 is 3.33% by weight, magnesium stearate is 2.22% by weight, colloidal anhydrous silica is 1.7% by weight, crospovidone is 3.9% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 72.2% by weight, purified talc is 8.06% by weight, lake sunset yellow is 1.39% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.56% by weight, based on the total weight of the coating material, iv) Ezetimibe (10mg) and atorvastatin (40mg); which comprises ezetimibe is 3.3% by weight, atorvastatin or a salt thereof is 14.4% by weight equivalent to atorvastatin, light calcium carbonate is 5% by weight, lactose is 50.3% by weight, starch is 11.7% by weight, croscarmellose sodium is 4.4% by weight, polyvinylpyrolidone k-30 is 2.8% by weight, magnesium stearate is 2.7% by weight, colloidal anhydrous silica 1.3% by weight, crospovidone is 4% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 71.83% by weight, purified talc is 8.17% by weight, lake sunset yellow is 1.33% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.83% by weight, based on the total weight of the coating material, v) Ezetimibe (10mg) and atorvastatin (80mg); which comprises ezetimibe is 2.56% by weight, atorvastatin or a salt thereof is 22.2% by weight equivalent to atorvastatin, light calcium carbonate is 5.13% by weight, lactose is 44.9% by weight, starch is 10.3% by weight, croscarmellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 2.82% by weight, magnesium stearate is 2.31% by weight, colloidal anhydrous silica is 1.3% by weight, crospovidone is 3.9% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 71.8% by weight, purified talc is 8.21% by weight, lake sunset yellow is 1.41% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.77% by weight, based on the total weight of the coating material.
The present invention provides a formulation suitable for forming ezetimibe and rosuvastatin or a salt thereof combination tablets comprising ezetimibe in the range of 2 to 13% by weight, more preferably 3 to 10% by weight, rosuvastatin; or a salt thereof in the range of 2 to 10.5% by weight, more preferably 4 to 8.5% by weight equivalent to rosuvastatin, light calcium carbonate in the range of 1 to 4% by weight, more preferably 1.5 to 3% by weight, lactose in the range of 32 to 83% by weight, more preferably 49 to
65% by weight, starch in the range of 8 to 21% by weight, more preferably 12 to 16.5% by weight, croscarmellose sodium in the range of 2 to 6.5% by weight, more preferably 2.5 to 5% by weight, polyvinylpyrrolidone k-30 in the range of 1 to 5% by weight, more preferably 2 to 3.5% by weight, magnesium stearate in the range of 1 to 3.5% by weight, more preferably 1.5 to 3% by weight, colloidal anhydrous silica in the range of 0.5 to 2% by weight, more preferably 0.5 to 1.5% by weight, crospovidone in the range of 2 to 7% by weight, more preferably 4 to 5.5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps in the range of 52 to 93% by weight, more preferably 65 to 80% by weight, purified talc in the range of 5 to 10% by weight, more preferably 7 to 9% by weight, lake sunset yellow in the range of 0.5 to 2.5% by weight, more preferably i to 2% by weight, titanium dioxide in the range of 8 to 16% by weight, more preferably 11 to 14% by weight and triacetin in the range of 4 to 8% by weight, more preferably 5 to 6.5% by weight, based on the total weight of the coating material. Optionally additional excipients may be used. In addition to the active ingredient, solid dosage forms contain a number of additional additives used in single dosage units. The particularly preferable tablet formulations are: i) Ezetimibe (10mg) and rosuvastatin (5mg); which comprises ezetimibe is 9.09% by weight, rosuvastatin or a salt thereof is 4.74% by weight equivalent to rosuvastatin, light calcium carbonate is 2.3% by weight, lactose is 54.5% by weight, starch is 13.9% by weight, croscarmellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 3.2% by weight, magnesium stearate is 1.8% by weight, colloidal anhydrous silica is 0.9% by weight, crospovidone is 5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 71.8% by weight, purified talc is 8.2% by weight, lake sunset yellow is 1.4% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.9% by weight, based on the total weight of the coating material. ii) Ezetimibe (10mg) and rosuvastatin (10mg); which comprises ezetimibe is
5.7% by weight, rosuvastatin or a salt thereof is 5.95% by weight equivalent to rosuvastatin, light calcium carbonate is 2.3% by weight, lactose is 57.5% by weight, starch is 13.7% by weight, croscarmellose sodium is 4% by weight,
■ polyvinylpyrolidone k-30 is 2.9% by weight, magnesium stearate is 2.3% by
weight, colloidal anhydrous silica is 1.1% by weight, crospovidone is 4.6% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 72.3% by weight, purified talc is 8% by weight, lake sunset yellow is 1.43% by weight, titanium dioxide is 12.6% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material. iii) Ezetimibe (10mg) and rosuvastatin (20mg); which comprises ezetimibe is 3.6% by weight, rosuvastatin or a salt thereof is 7.4% by weight equivalent to rosuvastatin, light calcium carbonate is 2.1% by weight, lactose is 58.8% by weight, starch is 14.8% by weight, croscarmellose sodium is 3.2% by weight, polyvinylpyrolidone k-30 is 2.3% by weight, magnesium stearate is 1.8% by weight, colloidal anhydrous silica is 0.9% by weight, crospovidone is 5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps is 72.1% by weight, purified talc is 8.04% by weight, lake sunset yellow is 1.43% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
The invention is explained in detail in the examples given below which are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES In the following embodiments of the invention, the below listed quantities of drug substances and additional components are combined using standard pharmaceutical manufacturing techniques. The resulting formulations are used to compress into tablets.
Tablet formulation:
Method of manufacture: The ezetimibe, simvastatin and starlac are granulated using binder solution of butylated hydroxy anisole and ethanol in planetary mixer, rapid mixer granulator; or other suitable granulator. This wet mass may be then dried. The dried granulation may be then milled to acheive the desired particle size distribution and then blended with the other ingredients. This blend is compressed into tablets. These compressed tablets are coated using a non aqueous solution of hydroxypropylmethylcellulose-15cps, purified talc, lake brilliant blue, titanium dioxide and triacetin by using autocota, neocota; or other suitable coating pan.
Example 1
The components and their amounts were as follows: Ezetimibe (1 Omg) and simvastatin (5mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 6.7
Simvastatin 5 3.3
Starlac 59 39.3
Ethanol q.s -
Butylated hydroxy anisole 0.03 0.02
Starlac 56.97 38
Magnesium stearate 2.5 1.7
Crospovidone 4 2.7
Croscarmellose sodium 3 2
L-hydroxypropylcellulose (LH-11) 8 5.3
Colloidal anhydrous silica 1.5 1
Tablet weight 150 -
Hydroxypropylmethylcellulose-15cps 1.91 63.7
Purified talc 0.24 8
Lake brilliant blue 0.30 10
Titanium dioxide 0.38 12.7
Triacetin 0.17 5.7
Example 2 The components and their amounts were as follows: Ezetimibe (10mg) and simvastatin (10mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 5.6
Simvastatin 10 5.6
Starlac 70 38.9 Ethanol q.s
Butylated hydroxy anisole 0.04 0.02
Starlac 72.96 40.5
Magnesium stearate 3 1.7
Crospovidone 4 2.2
Croscarmellose sodium 3 1.7
L-hydroxypropylcelluIose (LH-11) 5 2.8
Colloidal anhydrous silica ' 2 1.1 Tablet weight 180
Hydroxypropylmethylcellulose-Iδcps 2.29 63.6
Purified talc 0.29 8.1
Lake brilliant blue 0.36 10
Titanium dioxide 0.46 12.8 Triacetin 0.2 5.6
Example 3
The components and their amounts were as follows: Ezetimibe (10mg) and simvastatin (20mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 3.3
Simvastatin 20 6.7
Starlac 120.71 40.2
Ethanol q.s -
Butylated hydroxy anisole 0.08 0.03
Starlac 113.71 37.9
Magnesium stearate 5 1.7
Crospovidone 6 2
Croscarmellose sodium 5 1.7
L-hydroxypropylcellulose (LH-11) 17 5.7
Colloidal anhydrous silica 2.5 0.8
Tablet weight 300 -
Hydroxypropylmethylcellulose-15cps 3.81 63.5
Purified talc 0.49 8.2
Lake brilliant blue 0.60 10
Titanium dioxide 0.76 12.7
Triacetin 0.34 5.7
Example 4
The components and their amounts were as follows: Ezetimibe (10mg) and simvastatin (40mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 2.6
Simvastatin 40 10.3
Starlac 148 37.9
Ethanol q.s -
Butylated hydroxy anisole 0.09 0.02
Starlac 144.91 37.2
Magnesium stearate 8 2.1
Crospovidone 8 2.1
Croscarmellose sodium 7 1.8
L-hydroxypropylcellulose (LH-11) 20 5.11
Colloidal anhydrous silica 4 1
Tablet weight . 390 -
Hydroxypropylmethylcellulose-15cps 4.93 63.2
Purified talc 0.64 8.2
Lake brilliant blue 0.78 10
Titanium dioxide 1 12.8
Triacetin 0.45 5.8
Example 5
The components and their amounts were as follows: Ezetimibe (10mg) and simvastatin (80mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 2
Simvastatin 80 16
Starlac 173 34.6
Ethanol q.s -
Butylated hydroxy anisole 0.1 0.02
Starlac 165.9 33.2
Magnesium stearate 10 2
Crospovidone 20 4 Croscarmellose sodium 13 2.6 L-hydroxypropylcellulose (LH-11) 23 4.6 Colloidal anhydrous silica 5 1 Tablet weight 500 -
Hydroxypropylmethylcellulose-Iδcps 6.33 63.3 Purified talc 0.81 8.1 Lake brilliant blue 1.0 10 Titanium dioxide 1.28 12.8 Triacetin 0.58 5.8
Method of manufacture: The ezetimibe, HMG-CoA reductase inhibitor, light calcium carbonate, lactose, starch and croscarmellose sodium are granulated using binder solution of polyvinylpyrrolidone k-30 and isopropyl alcohol in planetary mixer, rapid mixer granulator; or other suitable granulator. This wet mass may be then dried. The dried granulation may be then milled to acheive the desired particle size distribution and then blended with the other ingredients. This blend is compressed into tablets. These compressed tablets are coated using a non aqueous solution of hydroxypropylmethylcellulose- 15cps, purified talc, lake sunset yellow, titanium dioxide and triacetin by using autocota, neocota; or other suitable coating pan.
Example 6
The components and their amounts were as follows:
Ezetimibe (10mg) and atorvastatin (5mg) tablets: Ingredients Quantity (mg) %(WΛ/V)
Ezetimibe 10 9.09
Atorvastatin calcium
Eq .to atorvastatin 5.415 4.92
Light calcium carbonate 4 3.64 Lactose 56.585 51.4
Starch 19 17.3
Croscarmellose sodium 2 1.82
Polyvinylpyrrolidone k-30 4.5 4.09
Isopropyl alcohol q.s -
Magnesium stearate 2 1.82
Colloidal anhydrous silica 1.5 1.36
Crospovidone . 3 2.73 .
Croscarmellose sodium 2 1.82 Tablet weight 110
Hydroxypropylmethylcellulose-Iδcps 1.59 72.23
Purified talc 0.17 7.73
Lake sunset yellow 0.03 1.36
Titanium dioxide 0.28 12.7 Triacetin 0.13 5.91
Example 7
The components and their amounts were as follows:
Ezetimibe (10mg) and atorvastatin (10mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 6.7
Atorvastatin calcium
Eq .to atorvastatin 10.83. 7.2
Light calcium carbonate 7 4.7
Lactose 85.17 56.8
Starch 16 10.7
Croscarmellose sodium 2.5 1.7
Polyvinylpyrrolidone k-30 7.5 5 lsopropyl alcohol q.s -
Magnesium stearate 3 2
Colloidal anhydrous silica 1.5 1
Crospovidone 4 2.7
Croscarmellose sodium 2.5 1.7
Tablet weight 150 -
Hydroxypropylmethylcellulose-15cps 2.17 72.3
Purified talc 0.24 8
Lake sunset yellow 0.04 1.3
Titanium dioxide 0.38 12.7
Triacetin 0.17 5.7
Example 8
The components and their amounts were as follows: Ezetimibe (10mg) and atorvastatin (20mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 5.56
Atorvastatin calcium
Eq. to atorvastatin 21.66 12
Light calcium carbonate 10 5.56
Lactose 92.34 51.3
Starch 16 8.9
Croscarmellose sodium 5 2.8
Polyvinylpyrrolidone k-30 6 3.33 lsopropyl alcohol q.s -
Magnesium stearate 4 2.22
Colloidal anhydrous silica 3 1.7
Crospovidone 7 3.9
Croscarmellose sodium 5 2.8
Tablet weight 180 -
Hydroxypropylmethylcellulose-15cps 2.60 72.2
Purified talc 0.29 8.06
Lake sunset yellow 0.05 1.39
Titanium dioxide 0.46 12.8
Triacetin 0.20 5.56
Example 9
The components and their amounts were as follows:
Ezetimibe (10mg) and atorvastatin (40mg) tablets:
Ingredients Quantity (mg) %(WΛ/V)
Ezetimibe 10 3.3 Atorvastatin calcium
Eq.to atorvastatin 43.32 14.4
Light calcium carbonate 15 5
Lactose 151 50.3
Starch 35.18 11.7
Croscarmellose sodium 6.5 2.2
Polyvinylpyrrolidone k-30 8.5 2.8 lsopropyl alcohol q.s -
Magnesium stearate 8 2.7
Colloidal anhydrous silica 4 1.3
Crospovidone 12 4
Croscarmellose sodium 6.5 2.2
Tablet weight 300 -
Hydroxypropylmethylcellulose-15cps 4.31 7.80
Purified talc 0.49 8.17
Lake sunset yellow 0.08 1.33
Titanium dioxide 0.77 12.8
Triacetin 0.35 5.83
Example 10
The components and their amounts were as follows: Ezetimibe (10mg) and atorvastatin (80mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 2.56
Atorvastatin calcium
Eq.to atorvastatin 86.64 22.2
Light calcium carbonate 20 5.13
Lactose 175 44.9
Starch 40.36 10.3
Croscarmellose sodium 9 2.3
Polyvinylpyrrolidone k-30 11 . 2.82 lsopropyl alcohol q.s -
Magnesium stearate 9 2.3
Colloidal anhydrous silica 5 1.3
Crospovidone 15 • 3.9
Croscarmellose sodium 9 2.3
Tablet weight 390 -
Hydroxypropylmethylcellulose-Iδcps 5.60 71.8
Purified talc 0.64 8.21
Lake sunset yellow 0.11 1.41
Titanium dioxide 1.0 12.8
Triacetin 0.45 5.77
Example 11
The components and their amounts were as follows: Ezetimibe (10mg) and rosuvastatin (5mg) tablets:
Ingredients Quantity (mg) %(WΛ/V)
Ezetimibe 10 9.09
Rosuvastatin calcium
Eq. to rosuvastatin 5.21 4.74
Light calcium carbonate 2.5 2.3
Lactose anhydrous 60 54.5
Starch 15.29 13.9
Croscarmellose sodium 2.5 2.3
Polyvinylpyrrolidone k-30 3.5 3.2 lsopropyl alcohol q.s -
Magnesium stearate 2 1.8
Colloidal anhydrous silica 1 0.9
Crospovidone 5.5 5
Croscarmellose sodium 2.5 2.3
Tablet weight 110 -
Hydroxypropylmethylcellulose-15cps 1.58 71.8
Purified talc • 0.18 8.2
Lake sunset yellow 0.03 1.4
Titanium dioxide 0.28 12.7
Triacetin 0.13 5.9
Example 12 The components and their amounts were as follows: Ezetimibe (10mg) and rosuvastatin (10mg) tablets: Ingredients Quantity (mg) %(WΛ/V)
Ezetimibe 10 5.7
Rosuvastatin calcium
Eq.to rosuvastatin 10.42 5.95
Light calcium carbonate 4 2.3
Lactose anhydrous 100.58 57.5
Starch 24 13.7
Croscarmellose sodium 3.5 2
Polyvinylpyrrolidone k-30 5 2.9 lsopropyl alcohol q.s -
Magnesium stearate 4 2.3
Colloidal anhydrous silica 2 1.14
Crospovidone 8 4.6
Croscarmellose sodium 3.5 2
Tablet weight 175 -
Hydroxypropylmethylcellulose-15cps 2.53 72.3
Purified talc 0.28 8
Lake sunset yellow 0.05 1.43
Titanium dioxide 0.44 12.6
Triacetin 0.20 5.7
Example 13 The components and their amounts were as follows: Ezetimibe (10mg) and rosuvastatin (20mg) tablets:
Ingredients Quantity (mg) %(W/W)
Ezetimibe 10 3.6
Rosuvastatin calcium
Eq.to rosuvastatin 20.84 7.4
Light calcium carbonate 6 2.1
Lactose anhydrous 164.66 58.8
Starch 41.5 14.8
Croscarmellose sodium 4.5 1.6
Polyvinylpyrrolidone k-30 6.5 2.3 lsopropyl alcohol q.s -
Magnesium stearate 5 1.8
Colloidal anhydrous silica 2.5 0.9
Crospovidone 14 5
Croscarmellose sodium 4.5 1.6
Tablet weight 280
Hydroxypropylmethylcellulose-Iδcps 4.04 72.1
Purified taic 0.45 8.04
Lake sunset yellow 0.08 1.43
Titanium dioxide 0.71 12.7
Triacetin 0.32 5.7
Claims
1. Antihyperlipoproteinemic combination of solid oral pharmaceutical formulations, which comprises ezetimibe, an HMG-CoA reductase inhibitor, disintegrants selected from starch, croscarmellose sodium and crospovidone, glidants selected from colloidal anhydrous silica and magnesium stearate.
2. The formulation as claimed in claim 1 , wherein HMG-CoA reductase inhibitors are simvastatin, atorvastatin, rosuvastatin and or a salt thereof.
3. The formulation as claimed in claim 2, wherein ezetimibe in the range of 1 to 15% by weight; the HMG-CoA reductase selected from inhibitor simvastatin in the range of 1 to 25% by weight; atorvastatin or a salt thereof in the range of 1 to 30% by weight and rosuvastatin or a salt thereof in the range of 2 to 12% by weight; starch in the range of 2 to 25% by weight; croscarmellose sodium in the range of 1 to 8% by weight; crospovidone in the range of 1 to 8% by weight; colloidal anhydrous silica in the range of 0.1 to 2.5% by weight and magnesium stearate in the range of 0.5 to 5% by weight, based on the total weight of the pharmaceutical dosage unit.
4. The formulation as claimed in claim 3, wherein ezetimibe in the range of 1.5 to 11% by weight; the HMG-CoA reductase selected from inhibitor simvastatin in the range of 2 to 20% by weight; atorvastatin or a salt thereof in the range of 2 to 25% by weight equivalent to atorvastatin and rosuvastatin or a salt thereof in the range of 4 to 10% by weight equivalent to rosuvastatin; starch in the range of 3 to 20% by weight; croscarmellose sodium in the range of by weight; crospovidone in the range of by weight; colloidal anhydrous silica in the range of 0.5 to 2% by weight and magnesium stearate in the range of 1 to 4% by weight, based on the total weight of the pharmaceutical dosage unit.
5. The formulation as claimed in claim 1 , wherein the said formulation is in the form of a tablet, a caplet, pellets, a capsule, granules, a pill, powder or a sachet.
6. The formulation as claimed in claim 5, wherein the said formulation is in the form of a combination tablet.
7. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and simvastatin 5mg.
8. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and simvastatin 10mg.
9. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and simvastatin 20mg.
10. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and simvastatin 40mg.
11. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and atorvastatin 5mg.
12. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and atorvastatin 10mg.
13. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and atorvastatin 20mg.
14. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and atorvastatin 40mg.
15. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and atorvastatin 80mg.
16. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and rosuvastatin 5mg.
17. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and rosuvastatin 10mg.
18. The formulation as claimed in claim 6, wherein the tablet is selected from ezetimibe 10mg and rosuvastatin 20mg.
19. The formulation as claimed in claim 1 , wherein at least one additional excipient is used.
20. The formulation as claimed in claim 19, wherein the additional excipient is selected from pharmaceutical lubricants, disintegrators, binders, glidants, fillers or diluent and a mixture thereof
21. The formulation as claimed in claim 20, wherein the filler is selected from calcium carbonate, dibasic calcium phosphate, lactose, magnesium carbonate, sucrose, starch, magnesium oxide, lactose anhydrous, microcrystalline cellulose and mannitol; and a mixture thereof.
22. The formulation as claimed in claim 20, wherein the lubricant is selected from stearic acid, a salt of stearic acid, talc, sodium stearyl fumarate, glyceryl behenate, magnesium silicate, magnesium trisilicate and hydrogenated castor oil; and a mixture thereof.
23. The formulation as claimed in claim 20, wherein the disintegrator is selected from starch, sodium starch glycolate, croscarmellose sodium, crospovidone, carboxymethylcellulose calcium, carboxymethylcellulose sodium and magnesium aluminum silicate; and a mixture thereof.
24. The formulation as claimed in claim 20, wherein the glidant is selected from colloidal anhydrous silica and talc; and a mixture thereof.
25. The formulation as claimed in claim 20, wherein the binder is selected from hydroxypropyl cellulose, polyvinylpyrrolidone k-30, hydroxypropyl cellulose (low-substituted) and starch; and a mixture thereof.
26. The formulation as claimed in claim 1 , wherein ezetimibe, simvastatin, starlac, ethanol, butylated hydroxy anisole, magnesium stearate, crospovidone, croscarmellose sodium, hydroxypropylcellulose (low- substituted) purified talc, lake brilliant blue, colloidal anhydrous silica, hydroxypropylmethylcellulose-15cps, titanium dioxide and triacetin.
27. The formulation as claimed in claim 26, wherein ezetimibe in the raηge of 1 to 10% by weight, simvastatin in the range of 2 to 23% by weight, starlac in the range of 41 to 97% by weight, butylated hydroxy anisole in the range of 0.01 to 0.004% by weight, magnesium stearate in the range of 1 to 3% by weight, crospovidone in the range of 1 to 6% by weight, croscarmellose sodium in the range of 1 to 4% by weight, hydroxypropylcellulose (low- substituted) in the range of 2 to 7% by weight, colloidal anhydrous silica in the range of 0.5 to 2% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps in the range of 37 to 89.5% by weight, purified talc in the range of 4 to 12% by weight, lake brilliant blue in the range of 4 to 14% by weight, titanium dioxide in the range of 7 to 18% by weight and triacetin in the range of 3 to 9% by weight, based on the total weight of the coating material.
28. The formulation as claimed in claim 27, wherein ezetimibe in the range of 1.5 to 7.5% by weight, simvastatin in the range of 3 to 18% by weight, starlac in the range of 61 to 87% by weight, butylated hydroxy anisole in
the range of 0.01 to 0.03% by weight, magnesium stearate in the range of 1.5 to 2.5% by weight, crospovidone in the range of 1.5 to 5% by weight, croscarmellose sodium in the range of 1.5 to 3% by weight, hydroxypropylcellulose (low-substituted) in the range of 2.5 to 6.5% by weight, colloidal anhydrous silica in the range of 0.5 to 1.5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose- 15cps in the range of 56 to 70% by weight, purified talc in the range of 7 to 9.5% by weight, lake brilliant blue in the range of 9 to 11% by weight, titanium dioxide in the range of 1 1 to 14.5% by weight and triacetin in the range of 5 to 6.5% by weight, based on the total weight of the coating material.
29. The formulation as claimed in claim 28, wherein ezetimibe is 6.7% by weight, simvastatin is 3.3% by weight, starlac is 77.3% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2.7% by weight, croscarmellose sodium is 2% by weight, hydroxypropylcellulose (low-substituted) is 5.3% by weight, colloidal anhydrous silica is 1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.7% by weight, purified talc is 8% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
30. The formulation as claimed in claim 28, wherein ezetimibe is 5.6 % by weight, simvastatin is 5.6% by weight, starlac is 79.4% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 1.7% by weight, crospovidone is 2.2% by weight, croscarmellose sodium is 1.7% by weight, hydroxypropylcellulose (low-substituted) is 2.8% by weight, colloidal anhydrous silica is 1.1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.6% by weight, purified talc is 8.1 % by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.6% by weight, based on the total weight of the coating material.
31. The formulation as claimed in claim 28, wherein ezetimibe is 3.3% by weight, simvastatin is 6.7% by weight, starlac is 78.1% by weight, butylated hydroxy anisole is 0.03% by weight, magnesium stearate is 1.7%
by weight, crospovidone is 2% by weight, croscarmellose 'sodium is 1.7% by weight, hydroxypropylcellulose (low-substituted) is 5.7% by weight, colloidal anhydrous silica is 0.8% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.5% by weight, purified talc is 8.2% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
32. The formulation as claimed in claim 28, wherein ezetimibe is 2.6% by weight, simvastatin is 10.3% by weight, starlac is 75.1% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2.1 % by weight, crospovidone is 2.1% by weight, croscarmellose sodium is 1.8% by weight, hydroxypropylcellulose (low-substituted) is 5.1 % by weight, colloidal anhydrous silica is 1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.2% by weight, purified talc is 8.2% by weight, lake brilliant blue is 10% by weight, titanium dioxide is 12.8% by weight and triacetin is 2.3% by weight, based on the total weight of the coating material.
33. The formulation as claimed in claim 28, wherein ezetimibe is 2% by weight, simvastatin is 16% by weight, starlac is 67.8% by weight, butylated hydroxy anisole is 0.02% by weight, magnesium stearate is 2% by weight, crospovidone is 4% by weight, croscarmellose sodium is 2.6% by weight, hydroxypropylcellulose (low-substituted) is 4.6% by weight, colloidal anhydrous silica is 1 % by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 63.3% by weight, purified talc is 8.1% by weight, lake brilliant blue is 10% by weight, titanium dioxide is
12.8% by weight and triacetin is 5.8% by weight, based on the total weight of the coating material.
34. The formulation as claimed in claim 1 , wherein ezetimibe, atorvastatin and rosuvastatin or a salt thereof, light calcium carbonate, lactose, starch, croscarmellose sodium, polyvinylpyrrolidone k-30, isopropyl alcohol, magnesium stearate, purified talc, lake sunset yellow, colloidal anhydrous silica, crospovidone, hydroxypropylmethylcellulose-15cps, titanium dioxide and triacetin.
35. The formulation as claimed in claim 34, wherein ezetimibe in the range of 1.5 to 13% by weight, atorvastatin or a salt thereof in the range of 3 to 31 % by weight, light calcium carbonate in the range of 2 to 8% by weight, lactose in the range of 27 to 80% by weight, starch in the range of 5 to' 24% by weight, croscarmellose sodium in the range of 2 to 8% by weight, polyvinylpyrrolidone k-30 in the range of 1 to 7% by weight, magnesium stearate in the range of 1 to 4% by weight, colloidal anhydrous silica in the range of 0.5 to 2.5% by weight, crospovidone in the range of 1.5 to 6% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-iδcps in the range of 50 to 90% by weight, purified talc in the range of 5 to 10% by weight, lake sunset yellow in , the range of 0.5 to 2% by weight, titanium dioxide in the range of 8.5 to 18% by weight and triacetin in the range of 4 to 8% by weight, based on the total weight of the coating material.
36. The formulation as claimed in claim 35, wherein ezetimibe in the range of
2 to 10% by weight, atorvastatin or a salt thereof in the range of 4 to 24% by weight equivalent to atorvastatin, light calcium carbonate in the range of
3 to 6.5% by weight, lactose in the range of 40 to 63% by weight, starch in the range of 8 to 19% by weight, croscarmellose sodium in the range of 3 to 6% by weight, polyvinylpyrrolidone k-30 in the range of 2.5 to 6% by weight, magnesium stearate in the range of 1.5 to 3% by weight, colloidal anhydrous silica in the range of 0.5 to 2% by weight, crospovidone in the range of 2 to' 4.5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps in the range of 65 to 80% by weight, purified talc in the range of 7 to 9% by weight, lake sunset yellow in the range of 1 to 1.5% by weight, titanium dioxide in the range of 11 to 14.5% by weight and triacetin in the range of 5 to 7% by weight, based on the total weight of the coating material.
37. The formulation as claimed in claim 36, wherein ezetimibe is 9.09% by weight, atorvastatin or a salt thereof is 4.92% by weight equivalent to atorvastatin, light calcium carbonate is 3.64% by weight, lactose is 51.4% by weight, starch is 17.3% by weight, croscarmellose sodium is 3.62% by weight, polyvinylpyrolidone k-30 is 4.09% by weight, magnesium stearate is 1.82% by weight, colloidal anhydrous silica is 1.36% by weight,
crospovidone is 2.73% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.3% by weight, purified talc is 7.73% by weight, lake sunset yellow is 1.36% by weight, titanium dioxide is 12.7% by weight and triacetiπ is 5.91 % by weight, based on the total weight of the coating material.
38. The formulation as claimed in claim 36, wherein ezetimibe is 6.7% by weight, atorvastatin or a salt thereof is 7.2% by weight equivalent to atorvastatin, light calcium carbonate is 4.7% by weight, lactose is 56.8% by weight, starch is 10.7% by weight, croscarmellose sodium is 3.4% by weight, polyvinylpyrolidone k-30 is 5% by weight, magnesium stearate is
. 2% by weight, colloidal anhydrous silica is 1% by weight, crospovidone is
2.7% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.3% by weight, purified talc is 8% by weight, lake sunset yellow is 1.33% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
39. The formulation as claimed in claim 36, wherein ezetimibe is 5.56% by weight, atorvastatin or a salt thereof is 12% by weight equivalent to atorvastatin, light calcium carbonate is 5.56% by weight, lactose is 51.3% by weight, starch is 8.89% by weight, croscarmellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 3.33% by weight, magnesium stearate is 2.22% by weight, colloidal anhydrous silica is 1.7% by weight, crospovidone is 3.9% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.2% by weight, purified talc is 8.06% by weight, lake sunset yellow is 1.39% by weight, titanium dioxide is
12.8% by weight and triacetin is 5.56% by weight, based on the total weight of the coating material.
40. The formulation as claimed in claim 36, wherein ezetimibe is 3.3% by weight, atorvastatin or a salt thereof is 14.4% by weight equivalent to atorvastatin, light calcium carbonate is 5% by weight, lactose is 50.3% by weight, starch is 11.7% by weight, croscarmellose sodium is 4.4% by weight, polyvinylpyrolidone k-30 is 2.8% by weight, magnesium stearate is 2.7% by weight, colloidal anhydrous silica 1.3% by weight, crospovidone is 4% by weight, based on the total weight of the tablet,
hydroxypropylmethylcellulose-i δcps is 71.83% by weight, purified talc is 8.17% by weight, lake sunset yellow is 1.33% by weight, titanium dioxide is 12.8% by weight and triacetin is 5.83% by weight, based on the total weight of the coating material. 41. The formulation as claimed in claim 36, wherein ezetimibe is 2.56% by weight, atorvastatin or a salt thereof is 22.2% by weight equivalent to atorvastatin, light calcium carbonate is 5.13% by weight, lactose is 44.9% by weight, starch is 10.3% by weight, croscarm.ellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 2.82% by weight, magnesium stearate is 2.31 % by weight, colloidal anhydrous silica is 1.3% by weight, crospovidone is 3.9% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 71.8% by weight, purified talc is 8.21 % by weight, lake sunset yellow is 1.
41 % by weight, titanium dioxide is 12.8% by weight and triacetin is 5.77% by weight, based on the total weight of the coating material.
42. The formulation as claimed in claim 34, wherein ezetimibe in the range of
2 to 13% by weight, rosuvastatin; or a salt thereof in the range of 2 to . 10.5% by weight equivalent to rosuvastatin, light calcium carbonate in the range of 1 to 4% by weight, lactose in the range of 32 to 83% by weight, starch in the range of 8 to 21 % by weight, croscarmellose sodium in the range of 2 to 6.5% by weight, polyvinylpyrrolidone k-30 in the range of 1 to
5% by weight, magnesium stearate in the range of 1 to 3.5% by weight, colloidal anhydrous silica in the range of 0.5 to 2% by weight, crospovidone in the range of 2 to 7% by weight.based on the total weight of the tablet, hydroxypropylmethylcellulose-iδcps in the range of 52 to
93% by weight, purified talc in the range of 5 to 10% by weight, lake sunset yellow in the range of 0.5 to 2.5% by weight, titanium dioxide in the range of 8 to 16% by weight and triacetin in the range of 4 to 8% by weight, based on the total weight of the coating material.
43. The formulation as claimed in claim 42, wherein ezetimibe in the range of
3 to 10% by weight, rosuvastatin; or a salt thereof in the range of 4 to 8.5% by weight equivalent to rosuvastatin, light calcium carbonate in the range of 1.5 to 3% by weight, lactose in the range of 49 to 65% by weight, starch in the range of 12 to 16.5% by weight, croscarmellose sodium in the range
of 2.5 to 5% by weight, polyvinylpyrrolidone k-30 in the range of 2 to 3.5% by weight, magnesium stearate in the range of 1.5 to 3% by weight, colloidal anhydrous silica in the range of 0.5 to 1.5% by weight, crospovidone in the range of 4 to 5.5% by weight; based on the total weight of the tablet, hydroxypropylmethylcellulose-iδcps in the range of
65 to 80% by weight, purified talc in the range of 7 to 9% by weight, lake sunset yellow in the range of 1 to 2% by weight, titanium dioxide in the range of 11 to 14% by weight and triacetin in the range of 5 to 6.5% by weight, based on the total weight of the coating material.
44. The formulation as claimed in claim 43, wherein ezetimibe is 9.09% by weight, rosuvastatin or a salt thereof is 4.74% by weight equivalent to rosuvastatin, light calcium carbonate is 2.3% by weight, lactose is 54.5% by weight, starch is 13.9% by weight, croscarmellose sodium is 4.6% by weight, polyvinylpyrolidone k-30 is 3.2% by weight, magnesium stearate is 1.8% by weight, colloidal anhydrous silica is 0.9% by weight, crospovidone is 5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 71.8% by weight, purified talc is 8.2% by weight, lake sunset yellow is 1.4% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.9% by weight, based on the total weight of the coating material.
45. The formulation as claimed in claim 43, wherein ezetimibe is 5.7% by weight, rosuvastatin or a salt thereof is 5.95% by weight equivalent to rosuvastatin, light calcium carbonate is 2.3% by weight, lactose is 57.5% by weight, starch is 13.7% by weight, croscarmellose sodium is 4% by weight, polyvinylpyrolidone k-30 is 2.9% by weight, magnesium stearate is
2.3% by weight, colloidal anhydrous silica is 1.1% by weight, crospovidone is 4.6% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.3% by weight, purified talc is 8% by weight, lake sunset yellow is 1.43% by weight, titanium dioxide is 12.6% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
46. The formulation as claimed in claim 43, wherein ezetimibe is 3.6% by weight, rosuvastatin or a salt thereof is 7.4% by weight equivalent to rosuvastatin, light calcium carbonate is 2.1 % by weight, lactose is 58.8%
by weight, starch is 14.8% by weight, croscarmellose sodium is 3.2% by weight, polyvinylpyrrolidone k-30 is 2.3% by weight, magnesium stearate is 1.8% by weight, colloidal anhydrous silica is 0.9% by weight, crospovidone is 5% by weight, based on the total weight of the tablet, hydroxypropylmethylcellulose-15cps is 72.1% by weight, purified talc is 8.04% by weight, lake sunset yellow is 1.43% by weight, titanium dioxide is 12.7% by weight and triacetin is 5.7% by weight, based on the total weight of the coating material.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2005/000196 WO2006134604A1 (en) | 2005-06-15 | 2005-06-15 | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/IN2005/000196 WO2006134604A1 (en) | 2005-06-15 | 2005-06-15 | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
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| WO2006134604A1 true WO2006134604A1 (en) | 2006-12-21 |
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/IN2005/000196 WO2006134604A1 (en) | 2005-06-15 | 2005-06-15 | Combination composition of cholesterol absorption inhibitor and 3-hydroxy-3-methylglutaryl-coenzyme a (hmg-coa) reductase inhibitor |
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