MXPA06008815A - Hypocholesterolemic compositions comprising a statin and an antiflatulent agent - Google Patents
Hypocholesterolemic compositions comprising a statin and an antiflatulent agentInfo
- Publication number
- MXPA06008815A MXPA06008815A MXPA/A/2006/008815A MXPA06008815A MXPA06008815A MX PA06008815 A MXPA06008815 A MX PA06008815A MX PA06008815 A MXPA06008815 A MX PA06008815A MX PA06008815 A MXPA06008815 A MX PA06008815A
- Authority
- MX
- Mexico
- Prior art keywords
- pharmaceutical composition
- composition according
- chosen
- tablets
- simethicone
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 24
- 230000000871 hypocholesterolemic Effects 0.000 title abstract description 4
- CXQXSVUQTKDNFP-UHFFFAOYSA-N Simethicone Chemical compound C[Si](C)(C)O[Si](C)(C)O[Si](C)(C)C CXQXSVUQTKDNFP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 19
- 229940083037 Simethicone Drugs 0.000 claims abstract description 14
- 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 13
- 229960002855 simvastatin Drugs 0.000 claims abstract description 13
- 229960005370 atorvastatin Drugs 0.000 claims abstract description 9
- 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 abstract description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 9
- 239000011780 sodium chloride Substances 0.000 claims abstract description 9
- FJLGEFLZQAZZCD-JUFISIKESA-N (3S,5R)-fluvastatin Chemical compound C12=CC=CC=C2N(C(C)C)C(\C=C\[C@H](O)C[C@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 FJLGEFLZQAZZCD-JUFISIKESA-N 0.000 claims abstract description 7
- SEERZIQQUAZTOL-ANMDKAQQSA-N Cerivastatin Chemical compound COCC1=C(C(C)C)N=C(C(C)C)C(\C=C\[C@@H](O)C[C@@H](O)CC(O)=O)=C1C1=CC=C(F)C=C1 SEERZIQQUAZTOL-ANMDKAQQSA-N 0.000 claims abstract description 7
- PCZOHLXUXFIOCF-BXMDZJJMSA-N Lovastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)[C@@H](C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 PCZOHLXUXFIOCF-BXMDZJJMSA-N 0.000 claims abstract description 7
- 229960002965 Pravastatin Drugs 0.000 claims abstract description 7
- TUZYXOIXSAXUGO-PZAWKZKUSA-N Pravastatin Chemical compound C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(O)=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 TUZYXOIXSAXUGO-PZAWKZKUSA-N 0.000 claims abstract description 7
- 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 abstract description 7
- 229960005110 cerivastatin Drugs 0.000 claims abstract description 7
- 229960003765 fluvastatin Drugs 0.000 claims abstract description 7
- 229960004844 lovastatin Drugs 0.000 claims abstract description 7
- 229960000672 rosuvastatin Drugs 0.000 claims abstract description 7
- VGYFMXBACGZSIL-MCBHFWOFSA-N Pitavastatin Chemical compound OC(=O)C[C@H](O)C[C@H](O)\C=C\C1=C(C2CC2)N=C2C=CC=CC2=C1C1=CC=C(F)C=C1 VGYFMXBACGZSIL-MCBHFWOFSA-N 0.000 claims abstract description 5
- 229940008099 dimethicone Drugs 0.000 claims abstract description 5
- 235000013870 dimethyl polysiloxane Nutrition 0.000 claims abstract description 5
- 239000004205 dimethyl polysiloxane Substances 0.000 claims abstract description 5
- 229960002797 pitavastatin Drugs 0.000 claims abstract description 5
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 claims abstract description 5
- 150000004677 hydrates Chemical class 0.000 claims abstract description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 10
- 239000003826 tablet Substances 0.000 claims description 10
- 229920002472 Starch Polymers 0.000 claims description 6
- QIQXTHQIDYTFRH-UHFFFAOYSA-N Stearic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 6
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 6
- 239000008107 starch Substances 0.000 claims description 6
- 235000019698 starch Nutrition 0.000 claims description 6
- 239000000454 talc Substances 0.000 claims description 6
- 229910052623 talc Inorganic materials 0.000 claims description 6
- 235000012222 talc Nutrition 0.000 claims description 6
- GUBGYTABKSRVRQ-UUNJERMWSA-N Lactose Natural products O([C@@H]1[C@H](O)[C@H](O)[C@H](O)O[C@@H]1CO)[C@H]1[C@@H](O)[C@@H](O)[C@H](O)[C@H](CO)O1 GUBGYTABKSRVRQ-UUNJERMWSA-N 0.000 claims description 5
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 5
- 239000008101 lactose Substances 0.000 claims description 5
- GUBGYTABKSRVRQ-XLOQQCSPSA-N 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
- 239000000314 lubricant Substances 0.000 claims description 5
- 235000019359 magnesium stearate Nutrition 0.000 claims description 5
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 5
- VUKAUDKDFVSVFT-UHFFFAOYSA-N 2-[6-[4,5-bis(2-hydroxypropoxy)-2-(2-hydroxypropoxymethyl)-6-methoxyoxan-3-yl]oxy-4,5-dimethoxy-2-(methoxymethyl)oxan-3-yl]oxy-6-(hydroxymethyl)-5-methoxyoxane-3,4-diol Chemical compound COC1C(OC)C(OC2C(C(O)C(OC)C(CO)O2)O)C(COC)OC1OC1C(COCC(C)O)OC(OC)C(OCC(C)O)C1OCC(C)O VUKAUDKDFVSVFT-UHFFFAOYSA-N 0.000 claims description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 0.000 claims description 4
- 239000008119 colloidal silica Substances 0.000 claims description 4
- 239000003085 diluting agent Substances 0.000 claims description 4
- 238000007907 direct compression Methods 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 239000000839 emulsion Substances 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 239000000049 pigment Substances 0.000 claims description 4
- 159000000000 sodium salts Chemical class 0.000 claims description 4
- STFSJTPVIIDAQX-LTRPLHCISA-M sodium;(E)-4-octadecoxy-4-oxobut-2-enoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCCOC(=O)\C=C\C([O-])=O STFSJTPVIIDAQX-LTRPLHCISA-M 0.000 claims description 4
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 claims description 4
- FBPFZTCFMRRESA-KAZBKCHUSA-N D-Mannitol Natural products OC[C@@H](O)[C@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KAZBKCHUSA-N 0.000 claims description 3
- FBPFZTCFMRRESA-KVTDHHQDSA-N Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 3
- 235000021355 Stearic acid Nutrition 0.000 claims description 3
- 230000000111 anti-oxidant Effects 0.000 claims description 3
- 239000003963 antioxidant agent Substances 0.000 claims description 3
- 239000002775 capsule Substances 0.000 claims description 3
- 239000008187 granular material Substances 0.000 claims description 3
- 239000000594 mannitol Substances 0.000 claims description 3
- 235000010355 mannitol Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000843 powder Substances 0.000 claims description 3
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 3
- 239000000243 solution Substances 0.000 claims description 3
- 239000008117 stearic acid Substances 0.000 claims description 3
- 239000006188 syrup Substances 0.000 claims description 3
- 235000020357 syrup Nutrition 0.000 claims description 3
- 229960005168 Croscarmellose Drugs 0.000 claims description 2
- 229920002594 Polyethylene Glycol 8000 Polymers 0.000 claims description 2
- QORWJWZARLRLPR-UHFFFAOYSA-H Tricalcium phosphate Chemical class [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 2
- 239000001506 calcium phosphate Substances 0.000 claims description 2
- 235000011010 calcium phosphates Nutrition 0.000 claims description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims description 2
- 239000003906 humectant Substances 0.000 claims description 2
- 229920000058 polyacrylate Polymers 0.000 claims description 2
- 239000004408 titanium dioxide Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 22
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims 1
- 239000004480 active ingredient Substances 0.000 claims 1
- 238000004040 coloring Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 claims 1
- 239000001069 triethyl citrate Substances 0.000 claims 1
- 235000013769 triethyl citrate Nutrition 0.000 claims 1
- 239000002471 hydroxymethylglutaryl coenzyme A reductase inhibitor Substances 0.000 abstract description 15
- 206010016766 Flatulence Diseases 0.000 abstract description 8
- 230000002265 prevention Effects 0.000 abstract description 2
- 159000000007 calcium salts Chemical class 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 150000004684 trihydrates Chemical class 0.000 description 5
- HVYWMOMLDIMFJA-DPAQBDIFSA-N (3β)-Cholest-5-en-3-ol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 description 4
- 229950002273 Simeticone Drugs 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- 208000004981 Coronary Disease Diseases 0.000 description 3
- 229940096802 Simethicone 125 MG Drugs 0.000 description 3
- 229940032147 Starch Drugs 0.000 description 3
- 201000008739 coronary artery disease Diseases 0.000 description 3
- 239000000377 silicon dioxide Substances 0.000 description 3
- 229920003084 Avicel® PH-102 Polymers 0.000 description 2
- 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 2
- 229940107161 Cholesterol Drugs 0.000 description 2
- 229960001681 Croscarmellose Sodium Drugs 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- -1 and the like Substances 0.000 description 2
- 230000003254 anti-foaming Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 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 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000003605 opacifier Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 235000012239 silicon dioxide Nutrition 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- FWIQGIQRNBVZEN-UHFFFAOYSA-M 4-ethoxy-2-(2-ethoxy-2-oxoethyl)-2-hydroxy-4-oxobutanoate Chemical compound CCOC(=O)CC(O)(C([O-])=O)CC(=O)OCC FWIQGIQRNBVZEN-UHFFFAOYSA-M 0.000 description 1
- 229910002012 Aerosil® Inorganic materials 0.000 description 1
- 206010003210 Arteriosclerosis Diseases 0.000 description 1
- 229940043253 Butylated Hydroxyanisole Drugs 0.000 description 1
- 239000004255 Butylated hydroxyanisole Substances 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- PHOQVHQSTUBQQK-SQOUGZDYSA-N Glucono δ-lactone Chemical compound OC[C@H]1OC(=O)[C@H](O)[C@@H](O)[C@@H]1O PHOQVHQSTUBQQK-SQOUGZDYSA-N 0.000 description 1
- 229960003681 Gluconolactone Drugs 0.000 description 1
- 239000004705 High-molecular-weight polyethylene Substances 0.000 description 1
- 102000004286 Hydroxymethylglutaryl CoA Reductases Human genes 0.000 description 1
- 108090000895 Hydroxymethylglutaryl CoA Reductases Proteins 0.000 description 1
- 229940002661 Lipitor Drugs 0.000 description 1
- 210000004940 Nucleus Anatomy 0.000 description 1
- 229960001495 Pravastatin Sodium Drugs 0.000 description 1
- 229940043573 Pravastatin Sodium 10 MG Drugs 0.000 description 1
- 229920003110 Primojel Polymers 0.000 description 1
- 229940103115 Simvastatin 20 MG Drugs 0.000 description 1
- 229940103114 Simvastatin 40 MG Drugs 0.000 description 1
- MSJMDZAOKORVFC-SEPHDYHBSA-L Sodium fumarate Chemical compound [Na+].[Na+].[O-]C(=O)\C=C\C([O-])=O MSJMDZAOKORVFC-SEPHDYHBSA-L 0.000 description 1
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Vitamin C Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000002156 adsorbate Substances 0.000 description 1
- 239000003463 adsorbent Substances 0.000 description 1
- 229910052784 alkaline earth metal Inorganic materials 0.000 description 1
- 150000001342 alkaline earth metals Chemical class 0.000 description 1
- 239000003529 anticholesteremic agent Substances 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 201000001320 atherosclerosis Diseases 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019282 butylated hydroxyanisole Nutrition 0.000 description 1
- 230000000271 cardiovascular Effects 0.000 description 1
- 235000012000 cholesterol Nutrition 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 229940079593 drugs Drugs 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000009472 formulation Methods 0.000 description 1
- 235000012209 glucono delta-lactone Nutrition 0.000 description 1
- 238000005469 granulation Methods 0.000 description 1
- 230000003179 granulation Effects 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- VWBQYTRBTXKKOG-IYNICTALSA-M pravastatin sodium Chemical compound [Na+].C1=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC([O-])=O)[C@H]2[C@@H](OC(=O)[C@@H](C)CC)C[C@H](O)C=C21 VWBQYTRBTXKKOG-IYNICTALSA-M 0.000 description 1
- 231100000486 side effect Toxicity 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- KEAYESYHFKHZAL-UHFFFAOYSA-N sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 235000014214 soft drink Nutrition 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 238000002636 symptomatic treatment Methods 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000002194 synthesizing Effects 0.000 description 1
- 230000001225 therapeutic Effects 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
Abstract
The present invention relates to hypocholesterolemic compositions comprising statins plus antiflatulent agents. In particular the compositions of the present invention comprise a statin selected from the group consisting of atorvastatin, cerivastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin and simvastatin, whether in free form or as pharmaceutically acceptable salts and hydrates thereof, plus an antiflatulent agent. selected from the group consisting of simethicone and dimethicone. The combination of statins plus antiflatulent agents is useful in the prevention and management of flatulence caused by statins.
Description
EMIANTES HYPOCOLESTERO COMPOSITIONS
Field of the Invention
The present invention relates to hypocholesterolemic compositions of statins with agents with antiflatulent pharmacological action.
BACKGROUND OF THE INVENTION
Statins are inhibitors of hydroxymethylglutaryl-CoA reductase, a key enzyme in the synthesis of cholesterol, which directly decrease cholesterol levels. These compounds are considered safe and effective hypocholesterolemic agents and therefore constitute an important therapeutic contribution in the treatment of coronary heart disease and in the reduction of morbidity and mortality due to this serious cardiovascular pathology.
The statins commonly used in medicine are Atorvastatin (USP 5273995), Cerivastatin (USP 5177080), Fluvastatin (USP 4739073), Lovastatin (USP 4231938), Pravastatin (USP 4346227), Rosuvastatin (USP RE 37314). and Simvastatin (USP 4444784). They can be used in free form or in the form of their pharmaceutically acceptable salts, usually alkaline and alkaline earth metal, whether they are anhydrous or hydrated, the sodium and calcium salts generally being preferred. Thus, in clinical practice, Atorvastatin is used as a calcium salt (2: 1) trihydrate, Cerivastatin, Fluvastatin and Pravastatin as the sodium salt,
Rosuvastatin as calcium salt and Lovastatin and Simvastatin in free form. A more recent compound, Pitavastatin (EP 304063) is currently under development in Phase III in Europe.
Among the most important and frequent side effects of statins is flatulence (Bakker-Arkema et al, Atherosclerosis 2000 Mar, 149 (1), 123-9 [PubMed 10704623], Black et al, Arch Intezn Med 1998 Mar 23, 158 (6), 577-84 [PubMed 9521221]; Posvar et al, J Clin Pharmacol 1996
Aug, 36 (8), 728-31 [PubMed 8877677]; Boccuzzi et al, Am J
Cardiol 1991 Nov 1, 68 (11), 1127-31 [Pubmed 1951069]; Zeller et al, Drug Intell Clin Pharm 1988 Jul-Aug, 22 (7-8), 542-5
[PubMed 3046888]) which can be cause of discomfort and symptomatic confusion, since its symptoms can be similar to those of the coronary heart disease object of the lipid-lowering treatment with statins.
Among the compounds that can decrease flatulence, there are antiflatulent agents that have an antifoaming action. Simethicone and Dimethicone, for example, are commonly used with good results in the symptomatic treatment of flatulence and meteorism. These compounds are effective if you also observe the appropriate hygienic-dietary measures, such as the avoidance of soft drinks and flatulent foods.
Some commercial preparations containing statins, such as Lipitor (Atorvastatin calcium salt 2: 1, trihydrate), already have in their formulation an antifoaming agent. In said
Case is an emulsion of Simethicone. However, the proportion of this compound is very low and simply serves as an excipient. Object of the invention
The object of the present invention is to provide hypocholesterolemic compositions comprising a statin and an antiflatulent agent by antifoaming action in proportion of active principle, in order to alleviate the flatulence due to the statin.
The association of statins with antiflatulent agents is useful in the prevention and treatment of flatulence caused by statins, which results in a better adherence of patients to treatment and a better clinical knowledge of the symptoms, given that Both coronary heart disease and flatulence are accompanied by thoracic-abdominal discomfort.
Compendium of the invention
The compositions of the present invention comprise a statin chosen from Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin and Simvastatin, either in free form or in the form of their pharmaceutically acceptable salts and hydrates. , and an antiflatulent agent chosen between Simethicone and Dimethicone.
The compositions of the present invention are administered orally in the form of tablets, capsules, coated tablets, syrups, solutions, powders, granules, emulsions and the like. The tablets and in particular the coated tablets are preferred.
Statins may be present in the tablets in amounts of 0.1 to 100 mg / comp. In turn, antiflatulent agents can be present in the tablets in a proportion of 25 to 250 mg / comp.
The compositions of the present invention further comprise other components, chosen from diluents, binders, disintegrants and lubricants commonly used in pharmaceutical technology, and mixtures thereof. Optionally other excipients can be added, such as antioxidants and humectants.
Since statins are photosensitive, it is convenient to protect the tablets with a coating comprising cellulose or acrylic derivatives, as well as plasticizers and opacifiers. Optionally it is possible to add various pigments to color the tablets.
Brief description of the figure
Figure 1 shows the in vitro dissolution profile, in average values, of the tablets of Example 4, comprising Simvastatin and Simethicone, and other similar tablets without Simethicone.
Detailed description of the invention
The compositions of the present invention comprise a statin chosen from Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin and Simvastatin, either in free form or in the form of their pharmaceutically acceptable salts and hydrates. , and an antiflatulent agent chosen between Simethicone and Dimethicone.
Preferably, Atorvastatin is used as the calcium salt (2: 1) trihydrate, Cerivastatin, Fluvastatin and Pravastatin as the sodium salt, Rosuvastatin as calcium salt and Lovastatin and Simvastatin in free form.
The compositions of the present invention are administered orally in the form of tablets, capsules, coated tablets, syrups, solutions, powders, granules, emulsions and the like. The tablets and in particular the coated tablets are preferred.
Statins may be present in the tablets in amounts of 0.1 to 100 mg / comp. Thus, assuming a standard tablet of a total weight of 400 mg, the proportion of statin can be considered to range between 0.025 and 25%. Typically, the amounts of statin per tablet are 0.1, 2.5, 5, 10, 20, 40, and 80 mg. Therefore, for a standard 400 mg tablet, the statin ratio would be 0.025%, 0.625%, 1.25%, 2.5%, 5%, 10% and 20% respectively.
In turn, antiflatulent agents may be present in the tablets in amounts of 25 to 250 mg / comp. Therefore, in a standard 400 mg tablet the proportion of antiflatulent agent oscillate between 6.25 and 62.5%.
Preferred diluents in the tablets of the present invention are microcrystalline celluloses and their derivatives, such as Prosolv, which is a mixture of microcrystalline cellulose and anhydrous colloidal silica, lactose, mannitol, calcium phosphates, starch, and the like. Preferably the microcrystalline celluloses are Avicel PH102® and Prosolv®.
As binders in the tablets of the present invention, starch, polyethylene glycols, polyvinylpyrrolidone, cellulose derivatives such as hydroxypropylmethylcellulose, and the like are preferred.
Disintegrants in the tablets of the present invention are anhydrous colloidal silica, croscarmellose, polyvinylpyrrolidone, starch and its pregelatinized derivatives, such as Primojel®, which is sodium starch glycolate, and the like. Preferably, Aerosil®, Acdisol® and polyvinylpyrrolidone are used.
As lubricants in the tablets of the present invention, talc, magnesium stearate, stearic acid, sodium stearyl fumarate, high molecular weight polyethylene glycol (4000-8000) such as PEG 8000 are preferred.
and similar. Preference is given to using sodium stearyl fumarate, talc and magnesium stearate.
Optionally in the present invention other excipients may be employed, such as antioxidants, such as butylated hydroxyanisole, ascorbic acid or gluconolactone, and the like, and wetting agents such as sodium lauryl sulfate, and the like.
The tablets of the present invention have a coating for protection from light. Preferably the coating consists of a layer consisting of cellulose derivatives, such as sodium hydroxypropylmethylcellulose (HPMC), acrylic polymers, plasticizers such as diethyl citrate, opacifiers such as titanium dioxide, talc and stearic acid. Optionally they can contain various pigments in order to color the tablets. As pigments, the iron oxide derivatives are preferred.
The technique for obtaining the statin nuclei with antiflatulent agents can be precompression, that is, a previous compaction of the mixture, followed by sieving and final compression. They can also be obtained by granulation via anhydrous, with the help of a hydroalcoholic solvent. These procedures are the usual ones in pharmaceutical technology.
However, applicants have discovered that the tablets of the present invention can be prepared
advantageously by direct compression, that is, by directly compressing the mixture of all the components. Thus, Simethicone, which is liquid, is incorporated by forming an adsorbate with an adsorbent substance such as Prosolv, mannitol, anhydrous colloidal silica (silicon dioxide) and lactose. It is sifted and mixed with the other components to give the final mixture. The direct compression procedure is preferable to the usual precompression procedures, because it results in lower economic cost and easy industrialization.
The solubility of the tablets of the present invention is not affected by the presence of the antiflatulent agent. Thus, in Figure 1 it is shown that the dissolution profiles of the new tablets of Example 4, which contain the antiflatulent agent, in this case Simethicone, do not show significant differences compared to conventional tablets without antiflatulent agent. Consequently, there are no appreciable differences in the pharmaceutical behavior of both preparations, so that the treatment of patients taking statins with the tablets of the present invention can be easily replaced.
The present invention is illustrated, but not limited, to the following examples.
Example 1: 400 mg tablet containing 40 mg of Atorvastatin calcica trihydrate and 115 mg of Simethicone
Atorvastatin calcica trihydrate 40 mg
Simeticone 115 mg
Colloidal anhydrous silica 10 mg
Croscarmellose sodium 10 mg
Stearyl fumarate sodium 15 mg
Microcrystalline cellulose avicel PH102 c.s.p.400 mg
Example 2: 400 mg tablet containing 20 mg Simvastatin and 125 mg Simeticone
Simvastatin 20 mg
Simethicone 125 mg
Polyvinyl pyrrolidone 15 mg
Croscarmellose sodium 5 mg Estearil fumarate sodium 15 mg
Sodium lauryl sulfate 4 mg
Butylhydroxyanisole 5 mg Lactose c.s.p. 400 mg
Example 3: 400 mg tablets containing 10 mg Pravastatin sodium and 125 mg Simeticone
Pravastatin sodium 10 mg
Simethicone 125 mg Primoj 20 mg
Talc 12 mg
Magnesium stearate 4 mg Prosolv c.s.p. 400 mg
Example 4: 400 mg tablets containing 40 mg Simvastatin and 125 mg Simeticone
Simvastatin 40 mg Simethicone 125 mg
Primoj 16 mg
Silicon dioxide 43 mg
Talc 12 mg
Magnesium stearate 4 mg Direct compression lactose c.s.p. 400 mg
Claims (22)
1. A pharmaceutical composition comprising a statin and an antiflatulent agent in suitable proportion as active ingredient.
2. A pharmaceutical composition according to claim 1 wherein the statin is chosen from Atorvastatin, Cerivastatin, Fluvastatin, Lovastatin, Pitavastatin, Pravastatin, Rosuvastatin and Simvastatin, and their pharmaceutically acceptable salts and their hydrates.
3. A pharmaceutical composition according to claim 2 wherein the statin is Simvastatin or a pharmaceutically acceptable salt.
4. A pharmaceutical composition according to any of claims 1 to 3 wherein the antiflatulent agent is chosen from Simethicone and Dimethicone.
5. A pharmaceutical composition according to claim 4 wherein the antiflatulent agent is Simethicone.
A pharmaceutical composition according to any of the preceding claims wherein the composition is in the form of tablets, capsules, coated tablets, syrup, solution, powder, granules or emulsion.
7. A pharmaceutical composition according to claim 6 wherein the composition is in the form of a coated tablet.
8. A pharmaceutical composition according to claims 6 or 7 wherein the Simvastatin is in proportions comprised from 2.5 to 100 mg per tablet.
9. A pharmaceutical composition according to claim 8 wherein the Simvastatin is in proportions comprised from 5 to 80 mg per tablet.
10. A pharmaceutical composition according to claims 6 or 7 wherein the Simethicone is in proportions comprised from 25 to 250 mg per tablet.
11. A pharmaceutical composition according to claim 10 wherein Simethicone is in the proportion of 125 mg per tablet.
12. A pharmaceutical composition according to any of the preceding claims further comprising one or more diluents, one or more binders, one or more disintegrants and one or more lubricants.
13. A pharmaceutical composition according to claim 12 wherein the diluent is chosen from microcrystalline celluloses and their derivatives, lactose, mannitol, calcium phosphates, starch, and mixtures thereof.
14. A pharmaceutical composition according to claim 12 wherein the binder is chosen from starch, polyethylene glycols, polyvinyl pyrrolidone, cellulose derivatives, and mixtures thereof.
15. A pharmaceutical composition according to any of the preceding claims wherein the disintegrant is chosen from anhydrous colloidal silica, croscarmellose, polyvinylpyrrolidone, starch and its pregelatinized derivatives, and mixtures thereof.
16. A pharmaceutical composition according to claim 12 wherein the lubricant is chosen from talc, magnesium stearate, stearic acid, sodium stearyl fumarate, PEG 8000, and mixtures thereof.
17. A pharmaceutical composition according to any of the preceding claims which may further comprise one or more antioxidants and one or more humectants.
18. A pharmaceutical composition according to claim 7 wherein the coating of the tablets comprises a cellulose derivative or its pharmaceutically acceptable salts, an acrylic polymer, triethyl citrate, titanium dioxide and one or more lubricants.
19. A pharmaceutical composition according to claim 18 wherein the cellulose derivative is the hydroxypropylmethylcellulose or a pharmaceutically acceptable salt.
20. A pharmaceutical composition according to claim 18 or 19 wherein the pharmaceutically acceptable salt is the sodium salt.
21. A pharmaceutical composition according to any of the preceding claims which may further comprise one or more pigments for coloring.
22. A process for preparing a pharmaceutical composition according to any of the preceding claims by direct compression of its components.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP04002317 | 2004-02-03 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| MXPA06008815A true MXPA06008815A (en) | 2007-04-10 |
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