EP2303239A1 - Comprimés d'aliskirène fabriqués par compression directe - Google Patents
Comprimés d'aliskirène fabriqués par compression directeInfo
- Publication number
- EP2303239A1 EP2303239A1 EP09780419A EP09780419A EP2303239A1 EP 2303239 A1 EP2303239 A1 EP 2303239A1 EP 09780419 A EP09780419 A EP 09780419A EP 09780419 A EP09780419 A EP 09780419A EP 2303239 A1 EP2303239 A1 EP 2303239A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- pharmaceutical composition
- aliskiren
- tablet
- composition according
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
- UXOWGYHJODZGMF-QORCZRPOSA-N Aliskiren Chemical compound COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC UXOWGYHJODZGMF-QORCZRPOSA-N 0.000 title claims abstract description 97
- 229960004601 aliskiren Drugs 0.000 title claims abstract description 97
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 81
- 238000000034 method Methods 0.000 claims abstract description 49
- 238000003825 pressing Methods 0.000 claims abstract description 15
- 206010020772 Hypertension Diseases 0.000 claims abstract description 11
- 238000004519 manufacturing process Methods 0.000 claims abstract description 11
- 239000000203 mixture Substances 0.000 claims description 61
- 239000004480 active ingredient Substances 0.000 claims description 58
- 239000003814 drug Substances 0.000 claims description 45
- 229940079593 drug Drugs 0.000 claims description 31
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 28
- 239000002671 adjuvant Substances 0.000 claims description 24
- 238000007907 direct compression Methods 0.000 claims description 24
- 150000001720 carbohydrates Chemical class 0.000 claims description 22
- 235000014633 carbohydrates Nutrition 0.000 claims description 22
- JZUFKLXOESDKRF-UHFFFAOYSA-N Chlorothiazide Chemical compound C1=C(Cl)C(S(=O)(=O)N)=CC2=C1NCNS2(=O)=O JZUFKLXOESDKRF-UHFFFAOYSA-N 0.000 claims description 21
- 239000013543 active substance Substances 0.000 claims description 21
- 229960002003 hydrochlorothiazide Drugs 0.000 claims description 21
- 230000008569 process Effects 0.000 claims description 20
- 239000000314 lubricant Substances 0.000 claims description 19
- 150000003839 salts Chemical class 0.000 claims description 18
- 238000007906 compression Methods 0.000 claims description 17
- 230000006835 compression Effects 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- 239000011248 coating agent Substances 0.000 claims description 14
- 238000000576 coating method Methods 0.000 claims description 14
- 239000012453 solvate Substances 0.000 claims description 14
- 238000002360 preparation method Methods 0.000 claims description 13
- 239000001506 calcium phosphate Substances 0.000 claims description 10
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 10
- 235000011010 calcium phosphates Nutrition 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 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 claims description 10
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical group [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 9
- 238000005056 compaction Methods 0.000 claims description 9
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 9
- 201000010099 disease Diseases 0.000 claims description 7
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims description 7
- 239000002934 diuretic Substances 0.000 claims description 7
- 239000002464 receptor antagonist Substances 0.000 claims description 7
- 229940044551 receptor antagonist Drugs 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
- 239000007884 disintegrant Substances 0.000 claims description 6
- 239000005541 ACE inhibitor Substances 0.000 claims description 5
- 229940123338 Aldosterone synthase inhibitor Drugs 0.000 claims description 5
- 229940127291 Calcium channel antagonist Drugs 0.000 claims description 5
- 102000003979 Mineralocorticoid Receptors Human genes 0.000 claims description 5
- 108090000375 Mineralocorticoid Receptors Proteins 0.000 claims description 5
- 229940044094 angiotensin-converting-enzyme inhibitor Drugs 0.000 claims description 5
- 239000002876 beta blocker Substances 0.000 claims description 5
- 229940097320 beta blocking agent Drugs 0.000 claims description 5
- 239000000480 calcium channel blocker Substances 0.000 claims description 5
- 229940030606 diuretics Drugs 0.000 claims description 5
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- 208000019901 Anxiety disease Diseases 0.000 claims description 3
- 206010007559 Cardiac failure congestive Diseases 0.000 claims description 3
- 208000031229 Cardiomyopathies Diseases 0.000 claims description 3
- 208000010412 Glaucoma Diseases 0.000 claims description 3
- 206010019280 Heart failures Diseases 0.000 claims description 3
- 206010020571 Hyperaldosteronism Diseases 0.000 claims description 3
- 230000002159 abnormal effect Effects 0.000 claims description 3
- 238000002399 angioplasty Methods 0.000 claims description 3
- 230000036506 anxiety Effects 0.000 claims description 3
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 3
- 208000010877 cognitive disease Diseases 0.000 claims description 3
- 206010012601 diabetes mellitus Diseases 0.000 claims description 3
- 230000004410 intraocular pressure Effects 0.000 claims description 3
- 208000017169 kidney disease Diseases 0.000 claims description 3
- 201000001119 neuropathy Diseases 0.000 claims description 3
- 230000007823 neuropathy Effects 0.000 claims description 3
- 208000033808 peripheral neuropathy Diseases 0.000 claims description 3
- 201000009395 primary hyperaldosteronism Diseases 0.000 claims description 3
- 208000037803 restenosis Diseases 0.000 claims description 3
- 230000006444 vascular growth Effects 0.000 claims description 3
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical class [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 claims description 2
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical class [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 claims description 2
- 239000011575 calcium Substances 0.000 claims description 2
- 229910052791 calcium Inorganic materials 0.000 claims description 2
- 230000002496 gastric effect Effects 0.000 claims description 2
- 239000011777 magnesium Chemical class 0.000 claims description 2
- 229910052749 magnesium Chemical class 0.000 claims description 2
- 208000019553 vascular disease Diseases 0.000 claims 1
- 238000005550 wet granulation Methods 0.000 abstract description 14
- 239000004615 ingredient Substances 0.000 abstract description 3
- 239000003826 tablet Substances 0.000 description 87
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 26
- 238000009472 formulation Methods 0.000 description 20
- 229920000642 polymer Polymers 0.000 description 16
- 235000019359 magnesium stearate Nutrition 0.000 description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 11
- 239000013078 crystal Substances 0.000 description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 11
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 9
- 239000002245 particle Substances 0.000 description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 8
- LQIAZOCLNBBZQK-UHFFFAOYSA-N 1-(1,2-Diphosphanylethyl)pyrrolidin-2-one Chemical compound PCC(P)N1CCCC1=O LQIAZOCLNBBZQK-UHFFFAOYSA-N 0.000 description 7
- 229910002012 Aerosil® Inorganic materials 0.000 description 7
- 239000002202 Polyethylene glycol Substances 0.000 description 7
- 229920001223 polyethylene glycol Polymers 0.000 description 7
- 239000000126 substance Substances 0.000 description 7
- 229920000084 Gum arabic Polymers 0.000 description 6
- 241000978776 Senegalia senegal Species 0.000 description 6
- 235000010489 acacia gum Nutrition 0.000 description 6
- 239000000205 acacia gum Substances 0.000 description 6
- 239000002552 dosage form Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 238000005469 granulation Methods 0.000 description 6
- 230000003179 granulation Effects 0.000 description 6
- 238000012545 processing Methods 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 5
- 239000002585 base Substances 0.000 description 5
- 238000007908 dry granulation Methods 0.000 description 5
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 5
- 229920003023 plastic Polymers 0.000 description 5
- 239000004033 plastic Substances 0.000 description 5
- 229940069328 povidone Drugs 0.000 description 5
- 239000003381 stabilizer Substances 0.000 description 5
- 229910002016 Aerosil® 200 Inorganic materials 0.000 description 4
- 239000004372 Polyvinyl alcohol Substances 0.000 description 4
- 230000008901 benefit Effects 0.000 description 4
- 238000000227 grinding Methods 0.000 description 4
- 238000004128 high performance liquid chromatography Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 238000003801 milling Methods 0.000 description 4
- 229920002451 polyvinyl alcohol Polymers 0.000 description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 4
- -1 2-carbamoyl-2-methyl-propyl Chemical group 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 3
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 3
- 239000008187 granular material Substances 0.000 description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 3
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- 229920003085 Kollidon® CL Polymers 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- KLRSDBSKUSSCGU-KRQUFFFQSA-N aliskiren fumarate Chemical compound OC(=O)\C=C\C(O)=O.COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC.COCCCOC1=CC(C[C@@H](C[C@H](N)[C@@H](O)C[C@@H](C(C)C)C(=O)NCC(C)(C)C(N)=O)C(C)C)=CC=C1OC KLRSDBSKUSSCGU-KRQUFFFQSA-N 0.000 description 2
- 239000002333 angiotensin II receptor antagonist Substances 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- 239000004067 bulking agent Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 230000015556 catabolic process Effects 0.000 description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 208000029078 coronary artery disease Diseases 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 230000001882 diuretic effect Effects 0.000 description 2
- 239000000890 drug combination Substances 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 239000012458 free base Substances 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000155 melt Substances 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 239000004570 mortar (masonry) Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 230000006641 stabilisation Effects 0.000 description 2
- 238000011105 stabilization Methods 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 150000005846 sugar alcohols Chemical class 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- 238000009827 uniform distribution Methods 0.000 description 2
- 235000015112 vegetable and seed oil Nutrition 0.000 description 2
- 239000008158 vegetable oil Substances 0.000 description 2
- 241000416162 Astragalus gummifer Species 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 102100032530 Glypican-3 Human genes 0.000 description 1
- 101001014668 Homo sapiens Glypican-3 Proteins 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 201000010538 Lactose Intolerance Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 229920003091 Methocel™ Polymers 0.000 description 1
- 229920001615 Tragacanth Polymers 0.000 description 1
- 238000005299 abrasion Methods 0.000 description 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 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
- 230000009471 action Effects 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 238000005054 agglomeration Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229960004863 aliskiren hemifumarate Drugs 0.000 description 1
- 239000012298 atmosphere Substances 0.000 description 1
- 230000036772 blood pressure Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000005018 casein Substances 0.000 description 1
- BECPQYXYKAMYBN-UHFFFAOYSA-N casein, tech. Chemical compound NCCCCC(C(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(CC(C)C)N=C(O)C(CCC(O)=O)N=C(O)C(CC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(C(C)O)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=N)N=C(O)C(CCC(O)=O)N=C(O)C(CCC(O)=O)N=C(O)C(COP(O)(O)=O)N=C(O)C(CCC(O)=N)N=C(O)C(N)CC1=CC=CC=C1 BECPQYXYKAMYBN-UHFFFAOYSA-N 0.000 description 1
- 235000021240 caseins Nutrition 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 229920006184 cellulose methylcellulose Polymers 0.000 description 1
- 229920003174 cellulose-based polymer Polymers 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 238000002648 combination therapy Methods 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000002596 correlated effect Effects 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000013461 design Methods 0.000 description 1
- 239000003085 diluting agent Substances 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000011156 evaluation Methods 0.000 description 1
- 239000003925 fat Substances 0.000 description 1
- 238000013467 fragmentation Methods 0.000 description 1
- 238000006062 fragmentation reaction Methods 0.000 description 1
- 239000007789 gas Substances 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
- 238000009499 grossing Methods 0.000 description 1
- 239000004574 high-performance concrete Substances 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 238000003475 lamination Methods 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 230000007246 mechanism Effects 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000008185 minitablet Substances 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 238000009481 moist granulation Methods 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 150000002482 oligosaccharides Chemical class 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 150000003904 phospholipids Chemical class 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 238000003672 processing method Methods 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002461 renin inhibitor Substances 0.000 description 1
- 229940086526 renin-inhibitors Drugs 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000008279 sol Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 229940058889 tekturna Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth 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
- A61K9/28—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
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
- A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
-
- 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
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
Definitions
- the invention relates to pharmaceutical compositions containing the active substance aliskiren and are suitable for Maisverpressung or dry processing, so that can be dispensed with a prior Nrustgranulierung the active ingredient with excipients. Furthermore, the invention relates to tablets which are obtainable by direct compression of these pharmaceutical compositions, as well as a process for the preparation of these tablets. Furthermore, the invention relates to the use of the new pharmaceutical compositions and tablets for the treatment of hypertension and associated diseases.
- Aliskiren (lUPAC name: (2S, 4S, 5S, 7S) -5-amino- ⁇ / - (2-carbamoyl-2-methyl-propyl) -4-hydroxy-7 - ⁇ [4-methoxy-3-one 3-methoxypropoxy) phenyl] methyl ⁇ -8-methyl-2-propan-2-ynonanamide) is a direct renin inhibitor used to lower elevated blood pressure. Aliskiren has the following chemical structure:
- the hemifumarate salt of aliskiren is known, as disclosed for example in EP 678,503 in Example 83.
- the hemifumarate has the following structure:
- aliskiren in this application includes the free base as well as salts and solvates thereof
- aliskiren In the prior art administration forms of aliskiren are known which have a high active ingredient content and release the active substance substantially without a time delay.
- WO 2004/002466 A1 describes the addition of surface-active agents ("surfactants") for increasing the bioavailability of aliskiren.
- Aliskiren is classified as a class III drug under the Biopharmaceutics Classification System (BCS). That is, the active ingredient has poor permeability but high solubility. The limiting factor for bioavailability is therefore the permeation rate.
- BCS Biopharmaceutics Classification System
- WO 2005/089729 A2 and US 2006/0018960 A1 disclose fast-dissolving aliskiren tablets and aliskirent tablets with immediate release, which are characterized by an active ingredient content of> 46%, based on the total weight of the formulation. It is described that aliskiren hemifumarate is difficult to process, i.a. because of its needle shape, it is prone to interparticular bridging and consequently exhibits poor flowability and processability. To prevent problems with the uniform distribution of the drug in the drug form must therefore be worked with an active ingredient content> 46%. Furthermore, the processing by wet granulation is described, which is also intended to counteract the poor properties of the drug.
- WO 2005/089729 A2 and US 2006/0018960 A1 disclose a wet granulation process for the preparation of medicaments containing more than 46% aliskiren.
- the multi-stage process of wet granulation, drying and subsequent compression to tablets is generally relatively unproblematic in terms of its feasibility.
- moist granules can be tabletted most reliably and without complications, especially in the case of low-dose dosage forms. Therefore, wet granulation is usually the drug of choice, and wet granules are the usual intermediate in the manufacture of tablets.
- a disadvantage of wet granulation is that special machines must be used for granulation, solvents are required for the preparation of the moist mass and the active ingredient is exposed to a prolonged period of granulation until completion of drying. This can lead to stability problems. Furthermore, the drying step subsequent to the granulation requires additional energy, as a result of which the active ingredient is exposed to thermal influences over a relatively long period of time. Overall, the method of wet granulation in a tendency to polymorphism and stability-unstable drug with respect to the influence of moisture is unsuitable.
- WO 2007/147596 A1 teaches that direct compression of aliskiren is not possible (page 3, first paragraph). As a solution, it is proposed to use a carbohydrate as a filler. Even so, however, a wet granulation should be carried out (claim 30).
- WO 2008/074001 A1 relates to the use of aliskiren for the treatment of obese patients. This document does not address the difficult processability of aliskiren, but merely refers to commonly used manufacturing processes.
- EP 1 972 335 A1 describes processes for the production of medicaments containing aliskiren, in which initially a granulate is produced by a melt. This method has the disadvantage that it is expensive and exposes the ingredients to higher temperatures, which can lead to partial degradation of the active ingredient. The Further disadvantages are the special requirements placed on the machines on a large-scale and the high unintentional introduction of energy around the melt.
- the pharmaceutical dosage forms should in particular be simple and economical to produce and nevertheless have good administration properties.
- the drug should be distributed as evenly as possible within the pharmaceutical dosage form, even at an active ingredient content below 46 wt .-%.
- the tablets produced according to the invention do not tend to "cap” during tabletting even at high compression pressures. Lids are the breaking off of one or more layers from the tablet surface during ejection from the matrix. In the case of active substances such as aliskiren, which have high plasticity and poor flowability, a high tendency to cover is observed in the case of dry compression by customary methods, which is attributable to the high elastic re-expansion of plastic substances at the end of the press process.
- the present invention relates, in a first aspect, to a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 10% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical Composition.
- Another aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active ingredient aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 5% by weight of a lubricant, based on the total weight of the pharmaceutical composition.
- the invention in another aspect relates to a pharmaceutical composition suitable for direct compression or dry processing in tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts or a solvate of a salt in free-flowing form. That is, aliskiren is in a formulation with at least one other substance that is free-flowing.
- Another aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts, characterized in that the pharmaceutical composition is free of carbohydrates as a filler. Preferably, the pharmaceutical composition is completely free of carbohydrates.
- the invention also relates to the tablets obtainable by direct compression from these pharmaceutical compositions and to the process by which the compositions are compressed into tablets.
- the invention in a further aspect relates to a process for the preparation of a tablet comprising the direct compression or dry compacting of a pharmaceutical composition of the present invention.
- the invention further relates to a process for the preparation of a medicament, comprising the following steps:
- Another aspect of the invention is a tablet obtainable by a method of the present invention.
- Another aspect of the invention is a tablet containing aliskiren, 20-70% by weight of a brittle inorganic adjuvant, based on the total weight of the tablet, and at least one disintegrant.
- Another aspect of the invention is a tablet containing aliskiren, at least 5% by weight of a lubricant, based on the total weight of the tablet, and at least one disintegrant.
- Another aspect of the present invention is the use of a pharmaceutical composition or a tablet according to the invention for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith.
- compositions according to the invention contain as active substance aliskiren.
- All crystal forms of aliskiren can be used, e.g., the crystal forms of aliskirene hemifumarate described in WO 2008/061622 A1.
- the disclosure of WO 2008/061622 A1 is incorporated by reference into the disclosure of the present application.
- the concentration of aliskiren in the pharmaceutical composition of the invention may be about 10 to 80% by weight, based on the total weight of the pharmaceutical composition.
- the concentration of aliskiren in the pharmaceutical composition is about 10 to ⁇ 46% by weight, more preferably about 20 to 45%, most preferably about 35 to 42% by weight, based on the total weight of the pharmaceutical composition.
- weights of aliskiren refer to the salt or solvate, not the free base.
- compositions of the invention may contain, in addition to aliskiren, one or more other active ingredients selected from the group consisting of AT 1 receptor antagonists, ACE inhibitors, beta-blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics. Examples of these agents are well known to those skilled in the art.
- Preferred diuretic is hydrochlorothiazide (HCT).
- HCT hydrochlorothiazide
- aliskiren is combined with HCT.
- the HCT may be in a formulation with aliskiren, which is preferred.
- aliskiren and HCT are in separate formulations but in a drug combination.
- the concentration of HCT is usually in the range of 5 to 50 mg per unit dosage form, preferably in the range of 10 to 40 mg, more preferably in the range of 12.5 to 30 mg, most preferably in the range of 12.5 to 25 mg.
- the weight ratio of aliskiren to HCT is usually in the range of from 3: 1 to 40: 1, preferably from 5: 1 to 30: 1, more preferably from 7: 1 to 25: 1, most preferably from 10: 1 to 20: 1.
- the first aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active ingredient aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 10% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical composition.
- the active substance aliskiren is mixed with at least one brittle adjuvant. It has surprisingly been found that the pharmaceutical composition has a better compressibility in the presence of a brittle adjuvant than in the absence of the brittle adjuvant. As a result, the formulation can be easily compressed into tablets or processed in a dry granulation. It could be shown that with different settings of the pressing force, the hardness of the tablet increases without inclining to cover, shown in a pressing force-hardness profile (see FIG. 1). Based on this graph, a lid tilt of the tablet would become visible through the formation of a pietational phase. A wet granulation is therefore not required.
- Hiifsstoffe can generally about their behavior, resp. the change in the particle shape can be classified under pressing pressure (compression): plastic materials are characterized by plastic deformation, while brittle materials show a fracture of the particles into smaller particles under the influence of a pressing force. A brittle behavior of the excipient can be quantified by the increase of the surface in the pressing.
- pressing pressure compression
- yield pressure describes the tension that has to be reached in order for the substance to begin to flow plastically or can be regarded as a measure of the internal resistance. He knows about the reciprocal value of Slope of the Heckel plots are determined. "Yield pressure" values below 80 MPa are considered to be an indicator of plastic flow behavior (York, P., Drug Dev. Ind. Pharm.
- an adjuvant is considered to be a brittle adjuvant when it has a yield pressure of at least 80 MPa as determined by the ejected tablef method, see WA Ritschel and A. Bauer-Brandl, The Tablet, 2nd Ed , Editio Cantor Verlag Aulendorf, 2002, page 442 and the references cited therein.
- the brittle adjuvant is an inorganic brittle adjuvant.
- inorganic, pharmaceutically acceptable salts of calcium or magnesium e.g. Calcium carbonate, calcium phosphate, calcium sulfate, gastric oxide, are used.
- Calcium hydrogen phosphate (e.g., available as Di-Cafos AN from Chemische Fabrik Budenheim).
- the concentration of the brittle adjuvant in the pharmaceutical composition is typically about 10 to 80 wt.%, Preferably 20 to 70 wt.%, More preferably 30 to 65 wt.%, Most preferably 40 to 60 wt. z. B. about 50 wt .-%, each based on the total weight of the pharmaceutical composition.
- the weight ratio of aliskiren to brittle adjuvant is usually 1: 5 to 5: 1, preferably 1: 3 to 3: 1, more preferably 1: 2 to 2: 1, most preferably 1: 1 to 1: 1.5.
- the second aspect of the invention is a pharmaceutical composition suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts and at least 5% by weight of a brittle adjuvant, based on the total weight of the pharmaceutical composition.
- the active substance aliskiren is mixed with a relatively high proportion of at least one lubricant. It has been found that by mixing with a high level of lubricant aliskiren can be converted into a formulation which can be easily compressed into tablets or processed in a dry granulation.
- lubricant it is possible to use all customary pharmaceutical auxiliaries - preferably magnesium stearate or dehydrated vegetable oils (for example Lubritab®).
- a lubricant it is also possible to use stearic acid, sodium stearyl fumarate and / or polyethylene glycol (PEG).
- the amount of lubricant according to this aspect of the invention should be at least 5% by weight, preferably 5 to 30% by weight, more preferably 10 to 20% by weight, based in each case on the total weight of the pharmaceutical composition.
- the lubricant content may be lower, as indicated below.
- the active ingredient is processed by comminution technologies prior to direct compression or dry compaction. This alters the crystal habit of the drug and prevents bridging. Since aliskiren fumarate tends under mechanical action to convert into the amorphous active ingredient, which has a lower stability, attention must be paid to the temperature during the comminution.
- the temperature should be below 40 ° C., preferably below 35 ° C., during comminution. B. at about 10 to about 34 0 C or about 20 to about 30 0 C, to prevent degradation.
- the active ingredient comminution preferably takes place in the form of a cover grinding with a surface-stabilizing auxiliary.
- a surface-stabilizing auxiliary preferably the addition of gum arabic has proved to be a surface stabilizing adjuvant in the cover grinding.
- the active ingredient is incorporated during the cover milling in the excipient.
- Other possible surface stabilizers are mentioned below. All known methods of pharmaceutical micronization or cover milling can be used, for example using an air jet mill or ball mill. When using an air jet mill, it is preferable to work with a process air of 4-6 bar. Processing under a protective gas atmosphere is also possible.
- the crushed crystals preferably have a mean size of 3 to 250 ⁇ m, preferably 5 to 150 ⁇ m, most preferably 10 to 120 ⁇ m.
- the average particle size can be determined by laser diffraction according to Pharm. Eur. 2.9.31. Version 6.6, z. In a Malvern Mastersizer.
- micronization, resp. Cover milling can be carried out with or without surface stabilizer.
- Possible agglomeration of the micronized active ingredient can be counteracted by the addition of one or more surface stabilizers. These can be added before or during comminution.
- surface stabilizers it is possible to use pharmaceutically acceptable organic or inorganic auxiliaries which are polymers or contain low molecular weight oligomers or nonionic, ionic, zwitterionic surface-active substances. They are added in an active ingredient: adjuvant weight ratio of from 1: 1 to 1: 100, preferably from 1: 2 to 1:50.
- ⁇ bervidstabilisatoren examples include hydroxypropyl methylcellulose (HPMC), casein, gelatin, polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), tragacanth, Stearin Texte, gum arabic, Polaxomer, polyethylene glycol (PEG), Tween ®, polysaccharides, alginates, phospholipids etc.
- HPMC hydroxypropyl methylcellulose
- PVP polyvinylpyrrolidone
- SDS sodium dodecyl sulfate
- tragacanth examples include hydroxypropyl methylcellulose (HPMC), casein, gelatin, polyvinylpyrrolidone (PVP), sodium dodecyl sulfate (SDS), tragacanth, Stearinklade, gum arabic, Polaxomer, polyethylene glycol (PEG), Tween ®, polysaccharides, alginates, phospho
- the crystal habit and the surface of the crystals of the active ingredient can be changed by a coating such that bridge formation is prevented and the flowability and thus the dose accuracy is increased.
- all common pharmaceutically acceptable polymers can be used, for example, polymers based on cellulose, methacrylates or polyvinyl alcohol (PVA).
- pharmaceutically acceptable polymers are cellulose ethers such as hydroxypropylcellulose, hydroxymethylcellulose, methylcellulose and hydroxypropylmethylcellulose, cellulose acetate phthalate, wherein Hydroxypropylmethylcellulose is particularly preferred.
- Hydroxypropylmethylcelluloses are available, for example, under the name “Methocel”. It is also referred to “Fiedler - Encyclopedia of adjuvants”, Editio Cantor-Verlag Aulendorf, 5th edition 2002.
- this method also leads to a smoothing due to phenomena of dissolution on the surface of the crystals, which in turn is advantageous for further processing by direct compression. Furthermore, the addition of such polymers, which are also considered as hydrophilizing, to improve the bioavailability of the drug.
- the coating of the active ingredient is preferably carried out in fluidized bed or by spray drying.
- the polymers are preferably used for coating in an amount of 2 to 20% by weight, more preferably 5 to 15% by weight, most preferably 7 to 12% by weight, based in each case on the weight of the active ingredient.
- the coating solution is prepared based on an organic solvent. Suitable organic solvents are ethanol or isopropanol.
- Another advantage of this processing method is the stabilization of the active ingredient against external influences, such as e.g. Moisture that promotes conversion to the thermolabile amorphous state. This allows the drug to be marketed in more cost-effective packaging.
- a modification of this technology is the incorporation of the active ingredient in an adjuvant (preferably a polymer) and the application of this solution to a carrier.
- the active ingredient is dissolved or suspended in a solution of a pharmaceutically acceptable excipient (eg polymer) in a solvent and applied to an inert core, by known layering techniques such as e.g. the fluidized bed. Any kind of "multiple units" pellets, minitablets, particles and so on are possible.
- a mixture of a water-soluble and a water-insoluble excipient is preferably used. It is also possible to use only water-insoluble or only water-soluble excipients.
- suitable water-soluble auxiliaries are HPMC, povidone, povidone VA 64 (copolymer of polyvinylpyrrolidone with polyvinyl acetate, available commercially from BASF), mannitol, sorbitol.
- Suitable water-insoluble auxiliaries are, for example, polyvinyl alcohol, cellulose acetate phthalate, various methacrylates, etc.
- This possibility combines both the improved stabilization of the active ingredient by an intimate embedding in a polymer, as well as the improved processability of the carrier-drug mixture. As a result, bridging of the active substance does not occur, reproducible production with regard to uniform distribution of the active ingredient is ensured.
- compositions suitable for dry compression into tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts, characterized that the pharmaceutical composition is free of carbohydrates as a filler.
- the pharmaceutical composition is completely free of carbohydrates.
- carboxymethyl starch for the purposes of the present invention encompasses monosaccharides, disaccharides, oligosaccharides, polysaccharides and sugar alcohols
- Modified carbohydrates are not carbohydrates for the purposes of this application. Modified carbohydrates are to be understood as meaning chemical derivatives of carbohydrates, in particular not naturally occurring but artificially produced carbohydrates Derivatives (eg, croscarmellose, HPMC, HPC, HEC, CMC, carboxymethyl starch, methyl cellulose, etc.).
- the pharmaceutical composition is free of carbohydrates as a bulking agent and free of modified carbohydrates as a bulking agent. In yet another embodiment, the pharmaceutical composition is completely free of carbohydrates and completely free of modified carbohydrates. These embodiments also have the advantage that they contain no lactose and thus can be taken by patients with lactose intolerance.
- the combination of adjuvants should be chosen so that the dry loss of the tableting mixture is between 0.2-6%, preferably between 1.0-0.4%.
- the drying loss is determined according to Pharm. Eur. 6.0 - 2.5.32. For this purpose, a temperature gradient with 5 7min of 50 -85 0 C is applied.
- the bulk density is preferably between 0.4 and 0.8 kg / l and the quotient of tamped and bulk density between 1, 01 and 1, 3 or between 1, 1 and 1.3.
- the invention relates to a process for the preparation of a medicament, comprising the following steps:
- step (b) is performed, it is a dry compaction or dry granulation. If step (b) is not carried out, it is a direct compression without granulation or precompacting.
- Preferred is a process for the preparation of a medicament comprising the following steps:
- compositions of the present invention prepared by mixing and optionally compacting can thus be dry-pressed into tablets.
- all currentzelkompaktier psychologist can be used by roll compaction or briquetting. Care should be taken that the pressing force is between 2 - 50 kN, preferably between 3 and 30 kN, e.g. 5 - 2O kN, lies.
- the drug can be compressed with common pharmaceutical excipients to form a tablet, which can be coated after the taste lamination of the bitter drug still.
- the binder used is preferably a water-soluble adjuvant, for example povidone, HPMC, HPC.
- a water-soluble excipient any pharmaceutically acceptable, tasteless material can be used.
- the amount of binder may be about 10 to 25% by weight, preferably 15 to 25% by weight, most preferably 17 to 24% by weight, based in each case on the total weight of the pharmaceutical composition.
- filler or diluent As lactose and / or other sugar alcohols or carbohydrates. These can be combined with a proportion of water-insoluble fillers, preferably with microcrystalline cellulose. Also conceivable as fillers are inorganic salts: calcium carbonate, calcium hydrogen phosphate, etc.
- the amount of filler may be about 10 to 80 wt .-%, preferably 10 to 70 wt .-%, most preferably 15 to 60 wt .-%, each based on the total weight of the pharmaceutical composition.
- a disintegrant should be used.
- cross-povidone Preferably cross-povidone,
- Sodium carboxymethyl starch or similar superdesintegrants The amount of disintegrant is usually about 1 to 20 wt .-%, preferably 2 to 10 wt .-%, most preferably 3 to 8 wt .-%, each based on the total weight of the pharmaceutical composition.
- lubricant it is possible to use all customary pharmaceutical auxiliaries - preferably magnesium stearate or dehydrated vegetable oils (for example Lubritab®).
- a lubricant it is also possible to use stearic acid, sodium stearyl fumarate and / or polyethylene glycol (PEG).
- the amount of lubricant may be about 1 to 10% by weight, preferably 2 to 8% by weight, most preferably 3 to 7% by weight, based in each case on the total weight of the pharmaceutical composition.
- the ingredients are usually mixed together in a free-fall mixer (Turbula) and then pressed on a rotary press (fats) into tablets.
- the tabletting mixtures showed good compressibility.
- the applied main compressive forces are usually in the range of 2 to 50 kN, preferably 5 to 12 kN, depending on the size and type of press used.
- the present invention further relates to a process for the preparation of a medicament, comprising the following steps:
- the invention further relates to a process for the preparation of a medicament, comprising the following steps:
- the invention further relates to a process for the preparation of a medicament, comprising the following steps:
- no wet granulation or wet granulation is carried out, in particular no aqueous wet or moist granulation.
- the temperature during granulation is preferably below the melting point of all auxiliaries used. For example, the temperature below 40 0 C, or below 35 ° C. A so-called "hot-melt" granulation is therefore not preferred.
- the tablets according to the invention generally have a hardness between 60-160 N, preferably 60-120 N, more preferably 70-110 N.
- the hardness can be determined by methods known per se, for. B. Pharm. Eur. 6.0 ⁇ 2.9.8>.
- the tablets of the invention show a low rolling and Scblinlverschl fashion (friability) or a good abrasion resistance.
- the friability is preferably less than 1% (for example 0.1 to 0.8%, preferably 0.2 to 0.5%).
- the friability can be determined by methods known per se, e.g. according to Pharm. Eur. 4.0 / 2.09.07.00.
- the tablets according to the invention generally have a geometry which is adapted to the amount of active substance contained.
- a particular advantage of the tablets according to the invention is their advantageous release profile.
- the tablets release a substantial proportion of the active ingredient within 30 minutes, measured according to USP 28, Method ⁇ 711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C. and 75 rpm.
- the tablets show a drug release of at least 15% at 5 minutes, at least 40% at 10 minutes, at least 60% at 15 minutes, and at least 70% at 20 minutes, determined according to USP 28, method ⁇ 711 >, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets show a drug release of at least 20% at 5 minutes, at least 50% at 10 minutes, at least 70% at 15 minutes, and at least 80% at 20 minutes, determined according to USP 28, method ⁇ 711 >, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets show a drug release of at least 20% after 5 minutes, of at least 50% after 10 minutes, of at least 80% after 15 minutes, and of at least 90% after 20 minutes, determined according to USP 28, Method ⁇ 711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets after 5 minutes, show a drug release of at least 10%, preferably at least 15%, most preferably at least 20%, as determined by USP 28, Method ⁇ 711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 0 C and 75 rpm.
- the tablets show a drug release of at least 30%, preferably at least 40%, more preferably at least 50%, most preferably at least 60% or even at least 75% as determined by USP 28, method ⁇ 711> , Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets after 15 minutes, show a drug release of at least 50%, preferably at least 60%, more preferably at least 70%, most preferably at least 80% or even at least 90%, determined according to USP 28, Method ⁇ 711> , Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets show a drug release of at least 70%, preferably at least 75%, more preferably at least 80%, most preferably at least 90%, determined according to USP 28, method ⁇ 711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 ° C and 75 rpm.
- the tablets After 30 minutes, the tablets usually show a drug release of at least 90%, usually of at least 95%, determined according to USP 28, Method ⁇ 711>, Apparatus 2, in 500 ml of 0.1 HCl pH 1, 1 at 37 0 C and 75 rpm.
- the tablets have a release profile similar to that of the drug Rasilez®, or substantially the same as the release profile of Rasilez®.
- the skilled person can slow down the very rapid drug release of the tablets described above so that a release profile is obtained, which is similar to that of Rasilez® or similar (in each case at most 10% deviation of the drug release after 5, 10, 15, 20 and 30 minutes).
- the invention relates to the use of the above-described pharmaceutical composition or tablet for the treatment of hypertension or a disease associated therewith.
- hypertension or a disease associated therewith include congestive heart failure, cardiac hypertension, cardiofibrosis, postinfarct cardiomyopathy, complications of diabetes such as nephropathy, vasculopathy and neuropathy, coronary artery disease, restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety, and cognitive disorders.
- the invention further relates to the use of aliskiren for the manufacture of a medicament for the treatment of hypertension or a disease associated therewith, characterized in that an aliskiren-containing pharmaceutical composition is directly compressed into tablets.
- an aliskiren-containing pharmaceutical composition is directly compressed into tablets.
- the active substance aliskiren is coated before direct compression by at least one pharmaceutically acceptable polymer.
- the aliskiren crystals or partially crystalline aliskiren may be comminuted prior to direct compression, for example by micronization as described above.
- the pharmaceutical compositions and tablets described herein are administered in a combination therapy.
- the medicaments according to the invention can be administered simultaneously with another active ingredient or at intervals.
- Other active ingredients include, for example, the following active ingredient categories: AT 1 receptor antagonists, ACE inhibitors, beta blockers, calcium channel blockers, aldosterone synthase inhibitors, aldosterone receptor antagonists, and diuretics. Examples of these agents are well known to those skilled in the art.
- Preferred diuretic is hydrochlorothiazide (HCT).
- aliskiren is combined with HCT.
- the HCT may be in a formulation with aliskiren, which is preferred.
- Aliskiren and HCT in separate formulations, but in a drug combination.
- the concentration of HCT is usually in the range of 5 to 50 mg per unit dosage form, preferably in the range of 10 to 40 mg, more preferably in the range of 12.5 to 35 mg, most preferably in the range of 12.5 to 25 mg.
- the weight ratio of aliskiren to HCT is usually in the range of from 3: 1 to 40: 1, preferably from 5: 1 to 30: 1, more preferably from 7: 1 to 25: 1, most preferably from 10: 1 to 20: 1.
- the present invention further relates to the following items (1) to (16):
- a pharmaceutical composition suitable for directly compressing tablets comprising the active substance aliskiren or one of its pharmaceutically acceptable solvates or salts in free-flowing form.
- a pharmaceutical composition according to (1) or (2) characterized in that the active ingredient is coated by a pharmaceutically acceptable polymer.
- composition according to (3) characterized in that the pharmaceutically acceptable polymer is selected from the group consisting of cellulose-based polymers, methacrylates and polyvinyl alcohol.
- composition according to (3) or (4) characterized in that the content of the pharmaceutically acceptable polymer is 2 - 20 wt .-% based on the weight of the active ingredient.
- composition according to any one of the preceding items (1) to (5), characterized in that it contains a binder.
- composition according to any one of the preceding items (1) to (6) characterized in that the bulk density of the composition is between 0.4 and 0.7 kg / L.
- Pharmaceutical composition according to one of the preceding items (1) to (7) characterized in that the quotient of tamped density and bulk density between 1, 1 and 1, 3 is.
- the hypertensive disease is selected from the group consisting of congestive heart failure, cardiac hypertension, cardiofibrosis, postinfarct cardiomyopathy, complications due to diabetes such as nephropathy, vasculopathy and neuropathy, coronary artery disease, Restenosis after angioplasty, increased intraocular pressure, glaucoma, abnormal vascular growth, hyperaldosteronism, anxiety and cognitive disorders.
- Figure 1 shows a press force-hardness diagram with results of Example 8.
- Figures 2 and 3 show the release profiles determined in Examples 11a and 11b, respectively.
- Quantities are calculated based on the single dose.
- the active ingredient was compacted with 300 mg calcium phosphate, 5 mg Aerosil, 40 mg Crosscarmellose and 20 mg magnesium stearate in the compactor at 15-45 kN.
- the compact was crushed with a sieve and mixed with the remaining amounts of calcium phosphate, magnesium stearate and Aerosil on a free-fall mixer. This finished mixture was pressed on a rotary press into tablets. These had a hardness of 70 -110 N combined with a friability of less than 1%.
- the tablets were coated in a drum coater. For this purpose, a suspension of HPMC, PEG, talc, titanium dioxide and the dye was prepared. Table 1
- the active ingredient was introduced into a fluid-bed apparatus (Glatt GPC3) and coated with an isopropanolic solution of HPMC.
- the product temperature was between 35-40 ° C with applied supply air temperature of 40-80 0 C.
- the spray pressure was set with 1-2 bar.
- the coated active substance was premixed with Avicel, Aerosil and Crosscarmellose for 30 min on a free fall mixer.
- the final mixture was prepared with the addition of magnesium stearate. For this purpose, it was mixed again for 3 min.
- the finished mixture was then pressed on a rotary press into tablets (Fette 102i) having a hardness of 60-120 N.
- Example 3 Active ingredient comminution (cover grinding with gum arabic)
- the active ingredient was comminuted together with gum arabic in the air jet mill. A process air between 4 -6 bar was created. After milling, the drug-excipient mixture was mixed with Aerosil, Crospovidone and Avicel for 30 min on a free-fall mixer. It was then mixed again with magnesium stearate for 3 min. The finished mixture was pressed analogously to the previous examples and optionally coated.
- the final mixture showed good compressibility.
- the tablets had sufficient hardness.
- the residual amount of magnesium stearate was also added through a 0.5 mm sieve and the entire mixture was mixed on a Turbula T10B mixer for 5 minutes.
- the final mixture was pressed by means of a hydraulic one-hand press (Specac hydraulic press) with the setting 10 kN.
- the final mixture showed good compressibility.
- the tablets had sufficient hardness.
- Example 7 Active ingredient comminution (cover grinding with gum arabic)
- the final mixture showed good compressibility.
- the tablets had sufficient hardness.
- composition of the tested formulations is shown below:
- Example 10 Combination with HCT - Covermilling with PVP
- Aliskirene hemifumarate, HCT and povidone were mixed for 5 min in a Turbula T10B, followed by crushing in a mortar and subsequent sieving over 0.5 mm.
- Microcrystalline cellulose, Aerosil and Kollidon CL were added through a 0.5 mm sieve and mixed for 15 minutes.
- Magnesium stearate was added through a 0.5 mm sieve and the mixture was mixed for a further 3 minutes.
- the final mixture was compressed at 6-8 kN with a hydraulic one-hand press (Specac).
- the formulations according to the invention show a significantly more rapid release of active ingredient than the reference product, in particular for the period up to 30 minutes.
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Cardiology (AREA)
- Neurosurgery (AREA)
- Heart & Thoracic Surgery (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Diabetes (AREA)
- Hospice & Palliative Care (AREA)
- Ophthalmology & Optometry (AREA)
- Psychiatry (AREA)
- Vascular Medicine (AREA)
- Urology & Nephrology (AREA)
- Emergency Medicine (AREA)
- Endocrinology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP09780419A EP2303239A1 (fr) | 2008-07-11 | 2009-07-10 | Comprimés d'aliskirène fabriqués par compression directe |
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
EP08012558A EP2143425A1 (fr) | 2008-07-11 | 2008-07-11 | Tablettes d'aliskiren comprimées directement |
PCT/EP2009/058801 WO2010004022A1 (fr) | 2008-07-11 | 2009-07-10 | Comprimés d'aliskirène fabriqués par compression directe |
EP09780419A EP2303239A1 (fr) | 2008-07-11 | 2009-07-10 | Comprimés d'aliskirène fabriqués par compression directe |
Publications (1)
Publication Number | Publication Date |
---|---|
EP2303239A1 true EP2303239A1 (fr) | 2011-04-06 |
Family
ID=40076795
Family Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08012558A Withdrawn EP2143425A1 (fr) | 2008-07-11 | 2008-07-11 | Tablettes d'aliskiren comprimées directement |
EP09780419A Withdrawn EP2303239A1 (fr) | 2008-07-11 | 2009-07-10 | Comprimés d'aliskirène fabriqués par compression directe |
Family Applications Before (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP08012558A Withdrawn EP2143425A1 (fr) | 2008-07-11 | 2008-07-11 | Tablettes d'aliskiren comprimées directement |
Country Status (7)
Country | Link |
---|---|
US (1) | US20110165235A1 (fr) |
EP (2) | EP2143425A1 (fr) |
JP (1) | JP2011527316A (fr) |
CA (1) | CA2730112A1 (fr) |
IL (1) | IL210574A0 (fr) |
RU (1) | RU2010154501A (fr) |
WO (1) | WO2010004022A1 (fr) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TR201002256A1 (tr) * | 2010-03-24 | 2011-10-21 | Sanovel �La� Sanay� Ve T�Caret Anon�M ��Rket� | Stabil aliskiren formülasyonları |
WO2017138645A1 (fr) * | 2016-02-12 | 2017-08-17 | テイカ製薬株式会社 | Matériau granulé à sec, préparation solide comprenant le matériau granulé à sec et son procédé de fabrication |
Family Cites Families (9)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
MY119161A (en) | 1994-04-18 | 2005-04-30 | Novartis Ag | Delta-amino-gamma-hydroxy-omega-aryl-alkanoic acid amides with enzyme especially renin inhibiting activities |
DE60309472T2 (de) | 2002-06-28 | 2007-06-28 | Speedel Pharma Ag | Pharmazeutische formulierung mit einem nicht peptidischen renin-hemmer und surfactant |
US20040131672A1 (en) * | 2003-01-07 | 2004-07-08 | Nilobon Podhipleux | Direct compression pharmaceutical composition containing a pharmaceutically active ingredient with poor flowing properties |
AR048431A1 (es) | 2004-03-17 | 2006-04-26 | Novartis Ag | Formulaciones galenicas de compuestos organicos |
GB0612540D0 (en) * | 2006-06-23 | 2006-08-02 | Novartis Ag | Galenical formulations of organic compounds |
EP1891937A1 (fr) * | 2006-08-25 | 2008-02-27 | Novartis AG | Formulations galéniques de l'aliskiren |
CN101594857B (zh) * | 2006-11-07 | 2012-10-31 | 诺瓦提斯公司 | 阿利吉仑半富马酸盐的晶形 |
KR20090090384A (ko) * | 2006-12-15 | 2009-08-25 | 노파르티스 아게 | 비만 환자에서 고혈압의 예방 및 치료를 위한 레닌 억제제 |
EP1972335A1 (fr) * | 2007-03-23 | 2008-09-24 | Krka | Formes de dosage solide comportant de l'aliskiren et ses sels pharmaceutiques acceptables |
-
2008
- 2008-07-11 EP EP08012558A patent/EP2143425A1/fr not_active Withdrawn
-
2009
- 2009-07-10 RU RU2010154501/15A patent/RU2010154501A/ru not_active Application Discontinuation
- 2009-07-10 JP JP2011517167A patent/JP2011527316A/ja active Pending
- 2009-07-10 CA CA2730112A patent/CA2730112A1/fr not_active Abandoned
- 2009-07-10 US US13/003,612 patent/US20110165235A1/en not_active Abandoned
- 2009-07-10 EP EP09780419A patent/EP2303239A1/fr not_active Withdrawn
- 2009-07-10 WO PCT/EP2009/058801 patent/WO2010004022A1/fr active Application Filing
-
2011
- 2011-01-11 IL IL210574A patent/IL210574A0/en unknown
Non-Patent Citations (1)
Title |
---|
See references of WO2010004022A1 * |
Also Published As
Publication number | Publication date |
---|---|
CA2730112A1 (fr) | 2010-01-14 |
JP2011527316A (ja) | 2011-10-27 |
RU2010154501A (ru) | 2012-10-20 |
IL210574A0 (en) | 2011-03-31 |
US20110165235A1 (en) | 2011-07-07 |
EP2143425A1 (fr) | 2010-01-13 |
WO2010004022A1 (fr) | 2010-01-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1762230B2 (fr) | Tablette enrobé ou granulate comprenante un pyridylpyrimidine | |
DE69629755T2 (de) | Irbesartanhaltiges Arzneimittel | |
EP2334284B1 (fr) | Cinacalcet compacté | |
EP2355802A1 (fr) | Produits intermédiaires et formes galéniques orales contenant de la lénalidomide | |
EP2595607A2 (fr) | Médicament d'administration orale contenant un mélange de silodosine et d'un copolymère basique | |
EP2408431A1 (fr) | Rétigabine solide sous forme non cristalline | |
WO2011076412A1 (fr) | Forme d'administration orale contenant de l'entecavir | |
EP2309995A1 (fr) | Formulation pharmaceutique pour la réduction de la pression artérielle pulmonaire | |
WO2011047837A2 (fr) | Cinacalcet granulé par fusion | |
DE102008057284A1 (de) | Tabletten enthaltend Lenalidomid und Adhäsionsverstärker | |
EP2408424A2 (fr) | Transformation à sec de rétigabine | |
WO2011138037A2 (fr) | Tapentadol solide sous forme non cristalline | |
EP2303239A1 (fr) | Comprimés d'aliskirène fabriqués par compression directe | |
EP2445484A1 (fr) | Aprépitant sous forme de solution solide | |
EP3349733A1 (fr) | Formulation à libération retardée contrôlée du principe actif | |
WO2006069705A1 (fr) | Comprimes d'indapamide a liberation differee du principe actif obtenus par compression directe | |
WO2007093168A2 (fr) | Composition pharmaceutique contenant de l'irbesartan à libération rapide | |
WO2005041855A2 (fr) | Formulation de medicament contenant un antagoniste de ltb4, et procedes de production et utilisation de cette formulation de medicament | |
DE102008045854A1 (de) | Partikel aus Ziprasidone und einem Sprengmittel enthaltende Pharmazeutische Zusammensetzung | |
EP2382967A1 (fr) | Aliskiren sous forme d'une dispersion solide | |
DE102009060194A1 (de) | Orale Darreichungsform umfassend Entecavir | |
EP1886684A1 (fr) | Composition pharmaceutique comprenant du rimonabant | |
EP2349215A1 (fr) | Comprimés contenant du valsartan |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20101223 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO SE SI SK SM TR |
|
AX | Request for extension of the european patent |
Extension state: AL BA RS |
|
RIN1 | Information on inventor provided before grant (corrected) |
Inventor name: MUSKULUS, FRANK Inventor name: PAETZ, JANA |
|
DAX | Request for extension of the european patent (deleted) | ||
RAP1 | Party data changed (applicant data changed or rights of an application transferred) |
Owner name: RATIOPHARM GMBH |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20150203 |