WO2009112870A1 - Pharmaceutical composition comprising rosuvastatin calcium and magnesium carbonate hydroxide pentahydrate as a stabilizer - Google Patents
Pharmaceutical composition comprising rosuvastatin calcium and magnesium carbonate hydroxide pentahydrate as a stabilizer Download PDFInfo
- Publication number
- WO2009112870A1 WO2009112870A1 PCT/HR2008/000007 HR2008000007W WO2009112870A1 WO 2009112870 A1 WO2009112870 A1 WO 2009112870A1 HR 2008000007 W HR2008000007 W HR 2008000007W WO 2009112870 A1 WO2009112870 A1 WO 2009112870A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- pharmaceutical composition
- 4mgco
- xmg
- magnesium carbonate
- carbonate hydroxide
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 31
- 239000003381 stabilizer Substances 0.000 title claims abstract description 15
- PWRJGELXVCNTCM-UHFFFAOYSA-L magnesium;carbonate;hexahydrate Chemical compound O.O.O.O.O.O.[Mg+2].[O-]C([O-])=O PWRJGELXVCNTCM-UHFFFAOYSA-L 0.000 title claims description 27
- 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 title description 30
- 229960004796 rosuvastatin calcium Drugs 0.000 title description 21
- 239000004480 active ingredient Substances 0.000 claims abstract description 11
- 125000004528 pyrimidin-5-yl group Chemical group N1=CN=CC(=C1)* 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 22
- 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 claims description 21
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 12
- 239000003963 antioxidant agent Substances 0.000 claims description 12
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 12
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 12
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 12
- 235000019359 magnesium stearate Nutrition 0.000 claims description 11
- 229940080313 sodium starch Drugs 0.000 claims description 11
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 10
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 8
- 239000000945 filler Substances 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 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 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- 235000010980 cellulose Nutrition 0.000 claims description 4
- 229920002678 cellulose Polymers 0.000 claims description 4
- 239000001913 cellulose Substances 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 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 3
- 230000003078 antioxidant effect Effects 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000600 sorbitol Substances 0.000 claims description 3
- 235000010356 sorbitol Nutrition 0.000 claims description 3
- 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 3
- 239000008101 lactose Substances 0.000 claims 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 claims 2
- 229960001375 lactose Drugs 0.000 claims 2
- 239000011575 calcium Substances 0.000 claims 1
- 229910052791 calcium Inorganic materials 0.000 claims 1
- 239000011777 magnesium Substances 0.000 abstract description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 abstract 1
- CACDWRVXMWGLKR-UHFFFAOYSA-N ac1l9mop Chemical compound O.O.O.O.O.O CACDWRVXMWGLKR-UHFFFAOYSA-N 0.000 abstract 1
- 229910052749 magnesium Inorganic materials 0.000 abstract 1
- VZGDMQKNWNREIO-UHFFFAOYSA-N tetrachloromethane Chemical compound ClC(Cl)(Cl)Cl VZGDMQKNWNREIO-UHFFFAOYSA-N 0.000 abstract 1
- SOEGVMSNJOCVHT-VEUZHWNKSA-N Rosuvastatin lactone Chemical compound C(\[C@H]1OC(=O)C[C@H](O)C1)=C/C=1C(C(C)C)=NC(N(C)S(C)(=O)=O)=NC=1C1=CC=C(F)C=C1 SOEGVMSNJOCVHT-VEUZHWNKSA-N 0.000 description 13
- 238000002156 mixing Methods 0.000 description 9
- 238000009472 formulation Methods 0.000 description 8
- 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 description 6
- 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 description 6
- 229960001021 lactose monohydrate Drugs 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 5
- 238000002474 experimental method Methods 0.000 description 5
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical class O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 4
- 238000000576 coating method Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 230000003647 oxidation Effects 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000012430 stability testing Methods 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 239000004135 Bone phosphate Substances 0.000 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 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 2
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- ILRRQNADMUWWFW-UHFFFAOYSA-K aluminium phosphate Chemical compound O1[Al]2OP1(=O)O2 ILRRQNADMUWWFW-UHFFFAOYSA-K 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- IPCSVZSSVZVIGE-UHFFFAOYSA-N hexadecanoic acid Chemical compound CCCCCCCCCCCCCCCC(O)=O IPCSVZSSVZVIGE-UHFFFAOYSA-N 0.000 description 2
- 239000008240 homogeneous mixture Substances 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N iron oxide Chemical class [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 235000019426 modified starch Nutrition 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229940127557 pharmaceutical product Drugs 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 229960000672 rosuvastatin Drugs 0.000 description 2
- 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 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 235000000346 sugar Nutrition 0.000 description 2
- 239000004408 titanium dioxide Substances 0.000 description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 2
- 235000019731 tricalcium phosphate Nutrition 0.000 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 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 235000006491 Acacia senegal Nutrition 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 1
- 241000416162 Astragalus gummifer Species 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 208000035150 Hypercholesterolemia Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 235000021314 Palmitic acid Nutrition 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 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 description 1
- VTYYLEPIZMXCLO-UHFFFAOYSA-L calcium carbonate Substances [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 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
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 239000001175 calcium sulphate Substances 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 229940125782 compound 2 Drugs 0.000 description 1
- 229940126214 compound 3 Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 239000007857 degradation product Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- RUZYUOTYCVRMRZ-UHFFFAOYSA-N doxazosin Chemical compound C1OC2=CC=CC=C2OC1C(=O)N(CC1)CCN1C1=NC(N)=C(C=C(C(OC)=C2)OC)C2=N1 RUZYUOTYCVRMRZ-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- UOVKYUCEFPSRIJ-UHFFFAOYSA-D hexamagnesium;tetracarbonate;dihydroxide;pentahydrate Chemical compound O.O.O.O.O.[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O.[O-]C([O-])=O UOVKYUCEFPSRIJ-UHFFFAOYSA-D 0.000 description 1
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 150000002596 lactones Chemical class 0.000 description 1
- 229940031958 magnesium carbonate hydroxide Drugs 0.000 description 1
- GVALZJMUIHGIMD-UHFFFAOYSA-H magnesium phosphate Chemical compound [Mg+2].[Mg+2].[Mg+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O GVALZJMUIHGIMD-UHFFFAOYSA-H 0.000 description 1
- 230000014759 maintenance of location Effects 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- WQEPLUUGTLDZJY-UHFFFAOYSA-N n-Pentadecanoic acid Natural products CCCCCCCCCCCCCCC(O)=O WQEPLUUGTLDZJY-UHFFFAOYSA-N 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000006186 oral dosage form Substances 0.000 description 1
- 230000001590 oxidative effect Effects 0.000 description 1
- NDLPOXTZKUMGOV-UHFFFAOYSA-N oxo(oxoferriooxy)iron hydrate Chemical compound O.O=[Fe]O[Fe]=O NDLPOXTZKUMGOV-UHFFFAOYSA-N 0.000 description 1
- 239000001814 pectin Substances 0.000 description 1
- 235000010987 pectin Nutrition 0.000 description 1
- 229920001277 pectin Polymers 0.000 description 1
- 150000004686 pentahydrates Chemical class 0.000 description 1
- 150000003013 phosphoric acid derivatives Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- BPRHUIZQVSMCRT-VEUZHWNKSA-M rosuvastatin(1-) 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-M 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 229960000999 sodium citrate dihydrate Drugs 0.000 description 1
- 229960002920 sorbitol Drugs 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2009—Inorganic compounds
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
- C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
- C07D471/04—Ortho-condensed systems
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
Definitions
- the present invention relates to a pharmaceutical composition containing (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5- yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt which is a well known under the generic name rosuvastatin calcium (1).
- Rosuvastatin calcium (1) as a very potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase is used in the treatment of hypercholesterolemia, hyperlipidproteinemia and atherosclerosis [European Patent Application 0521471; Bioorg. Med. Chem. 5 (1997) 437-444].
- rosuvastatin calcium (1) is a salt of ⁇ , ⁇ -dihydroxycarboxylic acid, it is prone to lactonisation giving 6-[(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methanesulfonyl)pyrimidin-5-yl]ethen-l-yl]-(3R)-hydroxy-(5S)- ⁇ - valerolactone (2).
- the compound 2 (referred to hereinafter as ,,rosuvastatin lactone”) and oxidation product of rosuvastatin (compound 3) are the most important degradation products of rosuvastatin calcium (1).
- rosuvastatin calcium (1) Because of the tendency of rosuvastatin calcium (1) to undergo the lactonisation process affording the respective lactone 2, it is difficult to develop the pharmaceutical product with sufficient shelf life.
- the minimisation of the formation of oxidation product 3 can be realised by addition of common antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), other antioxidants or their mixtures.
- BHT butylhydroxytoluene
- BHA butylhydroxyanisole
- stabilization of rosuvastatin calcium to lactonisation process is a significant problem in existing pharmaceutical technology.
- AstraZeneca PCT WO 01/54668 Al]. They use tribasic phosphate salts, e.g.
- tribasic calcium phosphate Ca 3 (PO 4 )2
- tribasic magnesium phosphate Mg 3 (PO 4 ) 2
- tribasic aluminum phosphate AlPO 4
- Our novel pharmaceutical composition is based on magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O) which has a profound stabilizing effect on rosuvastatin calcium (1) in pharmaceutical composition. It drastically supress the formation of rosuvastatin lactone (2) by lactonisation of rosuvastatin calcium (1) during prolonged storage. At the same time it obviously acts as a sinergist to antioxidant butylhydroxytoluene (BHT) providing significantly increased oxidative stability of the pharmaceutical formulation.
- BHT butylhydroxytoluene
- (4MgCO 3 XMg(OH) 2 XSH 2 O) to rosuvastatin calcium (1) is within the range 50:1 to 1:25, and more particularly from 10:1 to 1:5 by weight.
- the pharmaceutical composition includes an oral dosage form, such as a tablet. It is comprised of magnesium carbonate hydroxide pentahydrate
- Suitable fillers include, for example, cellulose derivative (e.g. microcrystalline cellulose), sorbitol, lactose monohydrate, starches, inorganic salts (e.g. calcium sulphate) or other suitable sugars or sugar-related compounds (e.g. mannitol or xylitol).
- cellulose derivative e.g. microcrystalline cellulose
- sorbitol e.g. sorbitol
- lactose monohydrate e.g. starches
- inorganic salts e.g. calcium sulphate
- suitable sugars or sugar-related compounds e.g. mannitol or xylitol
- Suitable binders include, for example, polyvinylpyrrolidone, crospovidone, gum tragacanth, gum acacia, guar gum, sodium alginate, pectin, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, starches, modified starches, gelatin, and wax-based binders.
- Suitable disintegrants include, for example, polyvinylpyrrolidone, polyvinylpyrrolidone co-polymers, starches, modified starches, cellulose derivatives (e.g. microcrystalline cellulose, hydroxypropylcellulose), and sodium starch glycollate.
- Suitable lubricants include, for example, magnesium stearate, calcium stearate, palmitic acid, stearic acid, talc, carnauba wax, polyethylene glycols, and hydrogenated vegetable oils.
- Suitable antioxidants include, for example, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), or tocoferol acetate.
- BHT butylhydroxytoluene
- BHA butylhydroxyanisole
- tocoferol acetate The present invention includes the pharmaceutical composition where:
- - rosuvastatin calcium (1) is present in an amount within the range of 0.5 to 50%, and preferably from 0.5-10% by weight of the formulation,
- composition stabilizer is present in an amount 0.1 to 50%, and particularly from 1 to 15% by weight of the formulation,
- one or more fillers is present in an amount 20 to 90% by weight of the formulation
- - one or more binders is present in an amount of 2 to 90% by weight of the formulation
- one or more disintegrants is present in an amount 2 to 5% by weight of the formulation
- one or more lubricant is present in an amount 0.5 to 2.5% by weight of the formulation
- one or more antioxidants is present in an amount 0.001 to 0.2%, and particularly from 0.01 to 0.06% by weight of the formulation.
- compositions of the invention include, for example, those comprising rosuvastatin calcium (1), magnesium carbonate hydroxide pentahydrate (4MgCO 3 XMg(OH) 2 XSH 2 O), and excipients selected from microcrystalline cellulose, lactose monohydrate, sorbitol, mannitol, polyvinylpyrrolidone, crospovidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene (BHT).
- rosuvastatin calcium (1) magnesium carbonate hydroxide pentahydrate (4MgCO 3 XMg(OH) 2 XSH 2 O)
- excipients selected from microcrystalline cellulose, lactose monohydrate, sorbitol, mannitol, polyvinylpyrrolidone, crospovidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene (BHT).
- the pharmaceutical composition of the invention may be prepared, employing standard manufacturing processes known in the art, but preferably by dry blending of the components.
- one or more antioxidants are first adsorbed on the surface of the one or more fillers.
- rosuvastatin calcium (1), magnesium carbonate hydroxide pentahydrate (4MgCO 3 XMg(OH) 2 XSH 2 O) one or more fillers with adsorbed antioxidants, one or more binders, one or more disintegrants, as well as other additional excipients if desired are blended together.
- one or more antioxidants are added directly to the blend, and blended for 5-15 minutes in order to obtain a homogeneous mixture.
- the components or final blend may be passed through a mesh screen.
- the coating of thus obtained tablets may be applied, for example by spray coating.
- the coating may comprise titanium dioxide and/or ferric oxides, lactose monohydrate or cellulose derivatives. Titanium dioxide and/or ferric oxide pigments-based coatings help to improve stability of the formulation by significant decreasing of amount of light which comes onto the surface of the tablets.
- the coating may comprise 1 to 5% by weight of the tablet composition, and preferably 2 to 3%.
- a further aspect of the present invention comprises a method for producing a highly stabilized pharmaceutical composition containing rosuvastatin calcium (1) as the active ingredient and magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O) as the stabilizer.
- magnesium stearate (0.10 g; 1%) was added and blending was continued for for additional 5 minutes. The resulting mixture was compressed into tablets.
- magnesium carbonate hydroxide pentahydrate 0.10 g; 1%)
- microcrystalline cellulose was added.
- the stability study of the tablets was carried out by HPLC analysis after storage at 90 0 C / 100% relative humidity (RH) for 96 h.
- Temperature room temperature (r.i); Flow: 1.0 mL/min; Detection: UV at 254 nm; Volume: 25 ⁇ L.
- Rosuvastatin calcium (1; 0.20 g; 2%), microcrystalline cellulose (3.00 g; 30%), lactose monohydrate (6.10 g, 61%), magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O; 0.20 g; 3%), sodium starch glycollate (0.15 g; 1.5%) and polyvinylpyrrolidone (0.15 g; 1.5%) were mixed together and blended for 10 minutes. To a resulting mixture, butylhydroxytoluene (BHT; 2 mg; 0.02%) and butylhydroxyanisole (BHA; 2 mg; 0.02%) were added and blending was continued for additional 5 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes. The resulting mixture was compressed into tablets.
- BHT butylhydroxytoluene
- BHA butylhydroxyanisole
- Rosuvastatin calcium (1; 0.25 g, 2.5%), microcrystalline cellulose (4.00 g; 40%), lactose monohydrate (5.15 g, 51.5%), magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O; 0.10 g; 1%), sodium starch glycollate (0.20 g; 2%) and polyvinylpyrrolidone (0.20 g; 2%) were mixed together and blended for 5 minutes. To a resulting mixture, butylhydroxytoluene (BHT; 3 mg; 0.03%) was added and blending was continued for additional 10 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes.
- BHT butylhydroxytoluene
- the resulting mixture was compressed into tablets.
- the stability testing was performed at 90 0 C / 100% RH for 96 h.
- the HPLC analyses (see Example 1) have shown that the content of rosuvastatin lactone (2) was only 0.09% versus 0.81% in the control experiment without addition of magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O).
- Rosuvastatin calcium (1; 0.20 g; 2%), microcrystalline cellulose (4.00 g; 35%), mannitol (5.60 g, 56%), magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O; 0.20 g; 2%), crospovidone (0.20 g; 2%) and sodium starch glycollate (0.20 g; 2%) were mixed together and blended for 5 minutes.
- butylhydroxytoluene (BHT; 3 mg; 0.03%) was added and blending was continued for additional 10 minutes.
- magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes.
- the resulting mixture was compressed into tablets.
- the stability testing was performed at 90 0 C / 100% RH for 96 h.
- the HPLC analyses (see Example 1) have shown that the content of rosuvastatin lactone (2) was only 0.05% versus 0.74% in the control experiment without addition of magnesium carbonate hydroxide pentahydrate (4MgCO 3 xMg(OH) 2 x5H 2 O).
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Abstract
A pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient and magnesium carbona hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as stabilizer is desribed.
Description
PHARMACEUTICAL COMPOSITION COMPRISING ROSUVAST ATIN
CALCIUM AND MAGNESIUM CARBONATE HYDROXIDE
PENTAHYDRATE AS A STABILIZER
Int. classification: C07D
The present invention relates to a pharmaceutical composition containing (E)-7- [4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5- yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt which is a well known under the generic name rosuvastatin calcium (1).
Rosuvastatin calcium (1) as a very potent inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) is used in the treatment of hypercholesterolemia, hyperlipidproteinemia and atherosclerosis [European Patent Application 0521471; Bioorg. Med. Chem. 5 (1997) 437-444]. Since rosuvastatin calcium (1) is a salt of β,δ-dihydroxycarboxylic acid, it is prone to lactonisation giving 6-[(E)-2-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methanesulfonyl)pyrimidin-5-yl]ethen-l-yl]-(3R)-hydroxy-(5S)-δ- valerolactone (2). The compound 2 (referred to hereinafter as ,,rosuvastatin lactone") and oxidation product of rosuvastatin (compound 3) are the most important degradation products of rosuvastatin calcium (1).
Because of the tendency of rosuvastatin calcium (1) to undergo the lactonisation process affording the respective lactone 2, it is difficult to develop the pharmaceutical product with sufficient shelf life. The minimisation of the formation of oxidation product 3 can be realised by addition of common antioxidants such as butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), other antioxidants or their mixtures. However, stabilization of rosuvastatin calcium to lactonisation process is a significant problem in existing pharmaceutical technology. One technical solution was patented by the company AstraZeneca [PCT WO 01/54668 Al]. They use tribasic phosphate salts, e.g. tribasic calcium phosphate (Ca3(PO4)2), tribasic magnesium phosphate (Mg3(PO4)2) or tribasic aluminum phosphate (AlPO4) as stabilizers in concentration ranging from 1 to 50% by weight of the composition. We have found that tribasic calcium phosphate is not such effective stabilizer as claimed. Thus we have conducted an extensive research in order to find a really efficient and pharmaceutically acceptable stabilizer of rosuvastatin calcium (1) in pharmaceutical formulations.
We have discovered a novel pharmaceutical composition of rosuvastatin calcium (1) which has advantageous property concerning an enhanced stability under prolonged storage of the pharmaceutical product.
Our novel pharmaceutical composition is based on magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) which has a profound stabilizing effect on rosuvastatin calcium (1) in pharmaceutical composition. It drastically supress the formation of rosuvastatin lactone (2) by lactonisation of
rosuvastatin calcium (1) during prolonged storage. At the same time it obviously acts as a sinergist to antioxidant butylhydroxytoluene (BHT) providing significantly increased oxidative stability of the pharmaceutical formulation.
The ratio of magnesium carbonate hydroxide pentahydrate
(4MgCO3XMg(OH)2XSH2O) to rosuvastatin calcium (1) is within the range 50:1 to 1:25, and more particularly from 10:1 to 1:5 by weight.
The pharmaceutical composition includes an oral dosage form, such as a tablet. It is comprised of magnesium carbonate hydroxide pentahydrate
(4MgCO3xMg(OH)2x5H2O), one or more fillers, one or more binders, one or more disintegrants, one or more lubricants, and one or more antioxidant.
Suitable fillers include, for example, cellulose derivative (e.g. microcrystalline cellulose), sorbitol, lactose monohydrate, starches, inorganic salts (e.g. calcium sulphate) or other suitable sugars or sugar-related compounds (e.g. mannitol or xylitol).
Suitable binders include, for example, polyvinylpyrrolidone, crospovidone, gum tragacanth, gum acacia, guar gum, sodium alginate, pectin, hydroxyethylcellulose, hydroxypropylcellulose, methylcellulose, sodium carboxymethylcellulose, starches, modified starches, gelatin, and wax-based binders.
Suitable disintegrants include, for example, polyvinylpyrrolidone, polyvinylpyrrolidone co-polymers, starches, modified starches, cellulose derivatives (e.g. microcrystalline cellulose, hydroxypropylcellulose), and sodium starch glycollate.
Suitable lubricants include, for example, magnesium stearate, calcium stearate, palmitic acid, stearic acid, talc, carnauba wax, polyethylene glycols, and hydrogenated vegetable oils.
Suitable antioxidants include, for example, butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), or tocoferol acetate.
The present invention includes the pharmaceutical composition where:
- rosuvastatin calcium (1) is present in an amount within the range of 0.5 to 50%, and preferably from 0.5-10% by weight of the formulation,
- magnesium carbonate hydroxide pentahydrate (4MgCO3XMg(OH)2XSH2O) as the composition stabilizer is present in an amount 0.1 to 50%, and particularly from 1 to 15% by weight of the formulation,
- one or more fillers is present in an amount 20 to 90% by weight of the formulation,
- one or more binders is present in an amount of 2 to 90% by weight of the formulation,
- one or more disintegrants is present in an amount 2 to 5% by weight of the formulation,
- one or more lubricant is present in an amount 0.5 to 2.5% by weight of the formulation,
- one or more antioxidants is present in an amount 0.001 to 0.2%, and particularly from 0.01 to 0.06% by weight of the formulation.
Preferred compositions of the invention include, for example, those comprising rosuvastatin calcium (1), magnesium carbonate hydroxide pentahydrate (4MgCO3XMg(OH)2XSH2O), and excipients selected from microcrystalline cellulose, lactose monohydrate, sorbitol, mannitol, polyvinylpyrrolidone, crospovidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene (BHT).
The pharmaceutical composition of the invention may be prepared, employing standard manufacturing processes known in the art, but preferably by dry blending of the components. For example, one or more antioxidants are first adsorbed on the surface of the one or more fillers. Then rosuvastatin calcium (1), magnesium carbonate hydroxide pentahydrate (4MgCO3XMg(OH)2XSH2O), one or more fillers with adsorbed antioxidants, one or more binders, one or more disintegrants, as well as other additional excipients if desired are blended together. Alternatively, one or more antioxidants are added directly to the blend,
and blended for 5-15 minutes in order to obtain a homogeneous mixture. The components or final blend may be passed through a mesh screen. Then, one or more lubricants are added to thus prepared blend, and blending is continued until a homogeneous mixture is produced. Then the blend is compressed into tablets. The coating of thus obtained tablets may be applied, for example by spray coating. The coating may comprise titanium dioxide and/or ferric oxides, lactose monohydrate or cellulose derivatives. Titanium dioxide and/or ferric oxide pigments-based coatings help to improve stability of the formulation by significant decreasing of amount of light which comes onto the surface of the tablets. The coating may comprise 1 to 5% by weight of the tablet composition, and preferably 2 to 3%.
In contrast to existing patent literature [PCT WO 01/54668 Al], the use of a wet granulation technology is highly undesirable due to the fact that these conditions favour oxidation of rosuvastatin calcium (1).
A further aspect of the present invention comprises a method for producing a highly stabilized pharmaceutical composition containing rosuvastatin calcium (1) as the active ingredient and magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as the stabilizer.
Example 1
To microcrystalline cellulose (4.00 g; 40%), a solution of butylhydroxytoluene (BHT; 5 mg; 0.05%) in 96% ethanol was added. The wet product was dried in a high vacuum at 50 0C for 5 hours. Then rosuvastatin calcium (1; 0.30 g; 3%), lactose monohydrate (5.00 g, 50%), magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O; 0.20 g; 2%), sodium starch glycollate (0.20 g; 2%) and polyvinylpyrrolidone (0.20 g; 2%) were added. The resulting mixture was blended together for 15 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for for additional 5 minutes. The resulting mixture was compressed into tablets.
In the control experiment by using the same procedure an alternative batch of the tablets was prepared, but instead of magnesium carbonate hydroxide pentahydrate
(4MgCO3xMg(OH)2x5H2O), microcrystalline cellulose was added.
The stability study of the tablets was carried out by HPLC analysis after storage at 90 0C / 100% relative humidity (RH) for 96 h.
Analytical method:
Column: Zorbax Bonus RP (4.6x150 mm; 5 μm); Time: 55 min; Mobile phase:
MeCN / buffer (sodium citrate dihydrate; 20 mM; adjusted to pH = 6 with 30% citric acid) = 40 / 60, V / V; Temperature: room temperature (r.i); Flow: 1.0 mL/min; Detection: UV at 254 nm; Volume: 25 μL. Retention times: tR
(rosuvastatin (1))= 4.2-4.4 min; tR (rosuvastatin lactone (2))= 14.5-14.9 min;
The analyses have shown that the content of rosuvastatin lactone (2) was only
0.07% after 96 h at 90 0C / 100% RH versus 0.57% in the control experiment without magnesium carbonate hydroxide pentahydrate
(4MgCO3xMg(OH)2x5H2O).
Example 2
Rosuvastatin calcium (1; 0.20 g; 2%), microcrystalline cellulose (3.00 g; 30%), lactose monohydrate (6.10 g, 61%), magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O; 0.20 g; 3%), sodium starch glycollate (0.15 g; 1.5%) and polyvinylpyrrolidone (0.15 g; 1.5%) were mixed together and blended for 10 minutes. To a resulting mixture, butylhydroxytoluene (BHT; 2 mg; 0.02%) and butylhydroxyanisole (BHA; 2 mg; 0.02%) were added and blending was continued for additional 5 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes. The resulting mixture was compressed into tablets.
The stability testing was performed at 90 0C / 100% RH for 96 h. The HPLC analyses (see Example 1) have shown that the content of rosuvastatin lactone (2) was only 0.05% versus 0.65% in the control experiment without addition of magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O).
Example 3
Rosuvastatin calcium (1; 0.25 g, 2.5%), microcrystalline cellulose (4.00 g; 40%), lactose monohydrate (5.15 g, 51.5%), magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O; 0.10 g; 1%), sodium starch glycollate (0.20 g; 2%) and polyvinylpyrrolidone (0.20 g; 2%) were mixed together and blended for 5 minutes. To a resulting mixture, butylhydroxytoluene (BHT; 3 mg; 0.03%) was added and blending was continued for additional 10 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes. The resulting mixture was compressed into tablets. The stability testing was performed at 90 0C / 100% RH for 96 h. The HPLC analyses (see Example 1) have shown that the content of rosuvastatin lactone (2) was only 0.09% versus 0.81% in the control experiment without addition of magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O).
Example 4
Rosuvastatin calcium (1; 0.20 g; 2%), microcrystalline cellulose (4.00 g; 35%), mannitol (5.60 g, 56%), magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O; 0.20 g; 2%), crospovidone (0.20 g; 2%) and sodium starch glycollate (0.20 g; 2%) were mixed together and blended for 5 minutes. To a resulting mixture, butylhydroxytoluene (BHT; 3 mg; 0.03%) was added and blending was continued for additional 10 minutes. Then magnesium stearate (0.10 g; 1%) was added and blending was continued for additional 5 minutes. The resulting mixture was compressed into tablets.
The stability testing was performed at 90 0C / 100% RH for 96 h. The HPLC analyses (see Example 1) have shown that the content of rosuvastatin lactone (2) was only 0.05% versus 0.74% in the control experiment without addition of magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O).
Claims
1. A pharmaceutical composition comprising (E)-7-[4-(4-fluorophenyl)-6- isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]-(3R,5S)-3,5- dihydroxyhept-6-enoic acid calcium salt as the active ingredient and magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as stabilizer.
2. A pharmaceutical composition as claimed in claim 1 wherein the ratio of magnesium carbonate hydroxide pentahydrate (4MgCO3XMg(OH)2XSH2O) to the active ingredient is in the range of 50:1 to 1:25 by weight.
3. A pharmaceutical composition as claimed in claims 1 and 2 additionally comprising one or more fillers, binders, disintegrants, lubricants, and antioxidants.
4. A pharmaceutical composition for oral administration comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2θ) as the stabilizer, one or more fillers, one or more binders, one or more disintegrants, one or more lubricants, and one or more antioxidants.
5. A pharmaceutical composition as claimed in claim 4 wherein the active ingredient is present in an amount 1 to 50% by weight of the composition.
6. A pharmaceutical composition as claimed in claims 4 and 5 wherein magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) is present in an amount 0.1 to 50% by weight of the composition.
7. A pharmaceutical composition as claimed in claim 4, 5 or 6 wherein the filler is present in an amount 20 to 90% by weight of the composition.
8. A pharmaceutical composition as claimed in any of claims 4 to 7 wherein the binder is present in an amount 2 to 90% by weight of the composition.
9. A pharmaceutical composition as claimed in any of claims 4 to 8 wherein the disintegrant is present in an amount 2 to 5% by weight of the composition.
10. A pharmaceutical composition as claimed in any of claims 4 to 9 wherein the lubricant is present in an amount 0.5 to 2.5% by weight of the composition.
11. A pharmaceutical composition as claimed in any of claims 4 to 10 wherein the antioxidant is present in an amount 0.001 to 0.2% by weight of the composition.
12. A pharmaceutical composition as claimed in claim 4 comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as the stabilizer, microcrystalline cellulose, lactose, polyvinylpyrrolidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene.
13. A pharmaceutical composition as claimed in claim 4 comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2θ) as the stabilizer, macrocrystalline cellulose, mannitol, polyvinylpyrrolidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene.
14. A pharmaceutical composition as claimed in claim 4 comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]ρyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3XMg(OH)2XSH2O) as the stabilizer, microcrystalline cellulose, sorbitol, polyvinylpyrrolidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene.
15. A pharmaceutical composition as claimed in claim 4 comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as the stabilizer, microcrystalline cellulose, lactose, crospovidone, sodium starch glycollate, magnesium stearate and butylhydroxytoluene.
16. A pharmaceutical composition as claimed in claim 4 comprising (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt as the active ingredient, magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) as the stabilizer, microcrystalline cellulose, lactose, sodium starch glycollate, magnesium stearate and butylhydroxytoluene.
17. The use of magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2O) to stabilize the compound (E)-7-[4-(4- fluorophenyl)-6-isopropyl-2-[N-methyl-N-methanesulfonyl]pyrimidin-5-yl]- (3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt.
18. A method of producing a stabilized pharmaceutical composition which comprises incorporating magnesium carbonate hydroxide pentahydrate (4MgCO3xMg(OH)2x5H2θ) in a pharmaceutical composition containing the compound (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[N-methyl-N- methanesulfonyl]pyrimidin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid calcium salt.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| WO2010030201A3 (en) * | 2008-09-09 | 2010-07-22 | Zaklady Farmaceutyczne Polpharma Sa | Stable oral pharmaceutical composition containing a pharmaceutically acceptable salt of [(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3r, 5s) - 3,5 dihydroxyhept-6- enoic acid |
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| WO2008035128A1 (en) * | 2006-09-18 | 2008-03-27 | Richter Gedeon Nyrt. | Pharmaceutical compositions containing rosuvastatin calcium |
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| US6635278B1 (en) * | 1998-12-15 | 2003-10-21 | Gilead Sciences, Inc. | Pharmaceutical formulations |
| WO2001054668A1 (en) * | 2000-01-26 | 2001-08-02 | Astrazeneca Ab | Pharmaceutical compositions comprising a hmg reductase inhibitor |
| US20080038332A1 (en) * | 2006-08-10 | 2008-02-14 | Cai Gu Huang | Stable pharmaceutical formulation comprising atorvastatin calcium |
| WO2008035128A1 (en) * | 2006-09-18 | 2008-03-27 | Richter Gedeon Nyrt. | Pharmaceutical compositions containing rosuvastatin calcium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010030201A3 (en) * | 2008-09-09 | 2010-07-22 | Zaklady Farmaceutyczne Polpharma Sa | Stable oral pharmaceutical composition containing a pharmaceutically acceptable salt of [(e)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidine-5-yl] (3r, 5s) - 3,5 dihydroxyhept-6- enoic acid |
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