TR2021007428A2 - Pharmaceutical composition containing Benidipine. - Google Patents
Pharmaceutical composition containing Benidipine.Info
- Publication number
- TR2021007428A2 TR2021007428A2 TR2021/007428 TR2021007428A2 TR 2021007428 A2 TR2021007428 A2 TR 2021007428A2 TR 2021/007428 TR2021/007428 TR 2021/007428 TR 2021007428 A2 TR2021007428 A2 TR 2021007428A2
- Authority
- TR
- Turkey
- Prior art keywords
- film
- coated tablet
- tablet core
- diluent
- cellulose
- Prior art date
Links
- QZVNQOLPLYWLHQ-ZEQKJWHPSA-N benidipine Chemical compound C1([C@H]2C(=C(C)NC(C)=C2C(=O)OC)C(=O)O[C@H]2CN(CC=3C=CC=CC=3)CCC2)=CC=CC([N+]([O-])=O)=C1 QZVNQOLPLYWLHQ-ZEQKJWHPSA-N 0.000 title claims abstract description 41
- 229960004916 benidipine Drugs 0.000 title claims abstract description 41
- 239000008194 pharmaceutical composition Substances 0.000 title description 8
- 239000007941 film coated tablet Substances 0.000 claims abstract description 46
- 239000003085 diluting agent Substances 0.000 claims abstract description 23
- 229920002678 cellulose Polymers 0.000 claims abstract description 15
- 239000001913 cellulose Substances 0.000 claims abstract description 15
- 239000008385 outer phase Substances 0.000 claims abstract description 11
- 239000000314 lubricant Substances 0.000 claims abstract description 10
- 239000008384 inner phase Substances 0.000 claims abstract description 7
- 150000003839 salts Chemical class 0.000 claims abstract description 7
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 15
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 15
- 239000000203 mixture Substances 0.000 claims description 15
- 235000010980 cellulose Nutrition 0.000 claims description 14
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 14
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 14
- 238000000034 method Methods 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 7
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 6
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 6
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 6
- 238000005550 wet granulation Methods 0.000 claims description 6
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 claims description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000011734 sodium Substances 0.000 claims description 2
- 229910052708 sodium Inorganic materials 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- PTHCMJGKKRQCBF-UHFFFAOYSA-N Cellulose, microcrystalline Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC)C(CO)O1 PTHCMJGKKRQCBF-UHFFFAOYSA-N 0.000 claims 1
- 239000003826 tablet Substances 0.000 abstract description 24
- 206010020772 Hypertension Diseases 0.000 abstract description 9
- 239000003814 drug Substances 0.000 abstract description 5
- 238000002360 preparation method Methods 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 12
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 12
- 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 11
- 239000008101 lactose Substances 0.000 description 11
- 229960001375 lactose Drugs 0.000 description 11
- 239000000243 solution Substances 0.000 description 8
- 239000008187 granular material Substances 0.000 description 7
- 239000012071 phase Substances 0.000 description 7
- 229920000881 Modified starch Polymers 0.000 description 6
- 239000008367 deionised water Substances 0.000 description 6
- 229910021641 deionized water Inorganic materials 0.000 description 6
- 238000004519 manufacturing process Methods 0.000 description 6
- 229920000642 polymer Polymers 0.000 description 6
- 238000004090 dissolution Methods 0.000 description 5
- 108091006146 Channels Proteins 0.000 description 4
- 229920003091 Methocel™ Polymers 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 3
- 206010002383 Angina Pectoris Diseases 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 description 3
- 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 3
- 239000011230 binding agent Substances 0.000 description 3
- 239000011248 coating agent Substances 0.000 description 3
- 238000000576 coating method Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 description 3
- 206010038464 renal hypertension Diseases 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical class C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 2
- -1 1-benzyl-3-piperidyl Chemical group 0.000 description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 2
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
- 102000004016 L-Type Calcium Channels Human genes 0.000 description 2
- 108090000420 L-Type Calcium Channels Proteins 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000005054 agglomeration Methods 0.000 description 2
- 230000002776 aggregation Effects 0.000 description 2
- 239000007864 aqueous solution Substances 0.000 description 2
- 235000021152 breakfast Nutrition 0.000 description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 description 2
- 229920002301 cellulose acetate Polymers 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 239000007884 disintegrant Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000007888 film coating Substances 0.000 description 2
- 238000009501 film coating Methods 0.000 description 2
- 239000013538 functional additive Substances 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 230000002401 inhibitory effect Effects 0.000 description 2
- 229960001021 lactose monohydrate Drugs 0.000 description 2
- 229960001300 metoprolol tartrate Drugs 0.000 description 2
- 238000002156 mixing Methods 0.000 description 2
- 150000004682 monohydrates Chemical class 0.000 description 2
- 230000035699 permeability Effects 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 2
- 238000009475 tablet pressing Methods 0.000 description 2
- WUBVEMGCQRSBBT-UHFFFAOYSA-N tert-butyl 4-(trifluoromethylsulfonyloxy)-3,6-dihydro-2h-pyridine-1-carboxylate Chemical compound CC(C)(C)OC(=O)N1CCC(OS(=O)(=O)C(F)(F)F)=CC1 WUBVEMGCQRSBBT-UHFFFAOYSA-N 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- OJRHUICOVVSGSY-RXMQYKEDSA-N (2s)-2-chloro-3-methylbutan-1-ol Chemical compound CC(C)[C@H](Cl)CO OJRHUICOVVSGSY-RXMQYKEDSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 1
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 description 1
- 229940127291 Calcium channel antagonist Drugs 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 125000000066 S-methyl group Chemical group [H]C([H])([H])S* 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 229960001770 atorvastatin calcium Drugs 0.000 description 1
- 229960000074 biopharmaceutical Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 239000000480 calcium channel blocker Substances 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 239000004203 carnauba wax Substances 0.000 description 1
- 235000013869 carnauba wax Nutrition 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 238000003618 dip coating Methods 0.000 description 1
- 238000007907 direct compression Methods 0.000 description 1
- 239000007919 dispersible tablet Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- 235000019441 ethanol Nutrition 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 238000009477 fluid bed granulation Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 229940057948 magnesium stearate Drugs 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 210000003205 muscle Anatomy 0.000 description 1
- 239000003605 opacifier Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Abstract
Mevcut buluş, a) iç fazında Benidipin veya bunun farmasötik olarak kabul edilebilir tuzu, birinci seyreltici ve selüloz türevi ve b) dış fazında ikinci seyreltici, kaydırıcı (lubrikant) içeren film kaplı tablet çekirdeği ile ilgilidir. Buluş ayrıca söz konusu tablet çekirdeğinin hazırlanması ve hipertansiyon tedavisinde ilaç olarak kullanılmasıyla ilgilidir.The present invention relates to a film-coated tablet core containing a) Benidipine or its pharmaceutically acceptable salt, first diluent and cellulose derivative in its inner phase and b) second diluent, lubricant in its outer phase. The invention also relates to the preparation of the said tablet core and its use as a medicine in the treatment of hypertension.
Description
TARIFNAME BENIDIPIN IÇEREN FARMASÖTIK BILESIM BULUSUN DAHIL OLDUGU TEKNIK ALAN Mevcut bulus, a) iç fazinda Benidipin veya bunun farmasötik olarak kabul edilebilir tuzu, birinci seyreltici ve selüloz türevi ve b) dis fazinda ikinci seyreltici, kaydirici (lubrikant) içeren film kapli tablet çekirdegi ile ilgilidir. Bulus ayrica söz konusu tablet çekirdeginin hazirlanmasi ve hipertansiyon tedavisinde ilaç olarak kullanilmasiyla TEKNIGIN BILINEN DURUMU Benidipin (Formül 1), kimyasal adiyla 3-(3R)-1-benzilpiperidin-S-yl S-metil (4R)-2,6- dimetiI-4-(3-nitr0fenil)-1,4-dihidropiridine-3,5-dikarb0ksilet olarak bilinir. Benidipin, dihidropiridin reseptörlerine yüksek afinite ve yüksek özgüllük ile baglanabilen ve Ca2+ kanali üzerinde güçlü bir inhibitör etki gösteren dihidropiridin reseptör antagonistine aittir. Benidipin sadece kas (L tipi) Ca2 + kanali üzerinde inhibe edici bir etkiye sahip olmakla kalmaz, ayni zamanda voltaja bagli N ve T tipi Ca +2 kanallari üzerinde inhibe edici bir etkiye sahiptir. Benidipin, simdiye kadar üç Ca +2 kanalini da inhibe edebilen tek kalsiyum antagonist olarak bilinir. Ayrica benidipin, hücre membrani ile yüksek afiniteye sahiptir, vasküler seçicilige ve böbrek koruyucu etkiye sahiptir. Bu nedenle hipertansiyon ve renal parankimal hipertansiyon ve anjin tedavisi için ideal, güvenli ve etkili bir ajandir. Benidipin, yüksek tansiyon (hipertansiyon), renal parankimal hipertansiyon ve anjina pektoris tedavisi için benidipin film kapli tabletin bir hidroklorür tuzu olarak Kyowa Hakko Kogyo tarafindan Coniel® ticari adi altinda pazarlanmaktadir. Coniel®, hipertansiyon ve renal parankimal hipertansiyon tedavisi için yetiskin popülasyonunda kahvaltidan sonra günde bir kez 2-4 mg alinabilir. Doz yeterli degilse hastanin yasi ve semptomlarina göre günde bir kez 8 mg'a çikarilabilir. Anjina pektoris tedavisinde yetiskin popülasyonu için kahvalti ve aksam yemeginden sonra günde iki kez 4 mg alinabilir. Coniel® film kapli tablet, Iaktoz, patates nisastasi, kismen hidrolize polivinil alkol, magnezyum stearat, Opadry OY LS 22820 ve karnauba balmumu içeren standart bir çabuk salimli tablettir. Yayinlanmis Iiteratüre göre, Benidipin BCS (Biyofarmasötik Siniflandirma Sistemi) Sinif II ilaç olarak kabul edilir, yani yüksek geçirgenlige ve düsük çözünürlüge sahiptir. Ilaç aktif maddesinin zayif çözünürlügü nedeniyle, yardimci maddelerin seçimi ve üretim yöntemi, kritik kalite özelliklerinin elde edilmesinde önemli bir rol oynar. EP 0063365 B1 Benidipini bir bilesik olarak, hazirlama prosesini, farmasötik bilesimini ve bunun hipertansiyon tedavisi için kullanimini ilk kez açiklamaktadir. (1-benziI-3-piperidil)ester-5-metil esterin diastereomerleri arasindan hidrokloridin nitrofeniI)-1,4-dihidropiridin-3,5-dikarboksilik asit-3-(1-benziI-3-piperidil) ester-5-metil esterini açiklamaktadir. hizlandirmak için hizli çözünmeyi saglama özelligine sahip bir tibbi benidipin hidroklorür bilesimini açiklar. Bilesim, ortalama partikül çap hacmi 1.0 ila 50.0 um olan benidipin hidroklorür kristalleri veya ortalama partikül çap hacmi 1.0 ila 50.0 um olan partikülleri ve su içinde çözünürlüge sahip veya suya afinitesi olan fonksiyonel bir katki maddesi içermesiyle karakterize edilir. WO '448'e göre, suda çözünürlüge sahip tercih edilen islevsel katki maddesi, suda kismen hidrolize edilmis polivinil alkoldür. spesifik olarak, basit bir üretim prosesine sahip bir dihidropiridin türevi tabletini veya isik stabilitesi açisindan mükemmel bir dihidropiridin türevinin bir filmini açiklamaktadir. CN 102579442, laktoz, mikrokristalin selüloz, prejelatinize nisasta, karboksimetil nisasta, hipromelloz, magnezyum stearat gibi farkli eksipiyanlar ile Benidipin ve Atorvastatin kalsiyum içeren farmasötik bir kapsül bilesimini ve bunlarin üretim yöntemini açiklar. CN 102379875, benidipin hidroklorür ve metoprolol tartrat içeren bir farmasötik bilesimi ve bunlarin kullanimini açiklamaktadir; hazirlamak için benidipin hidroklorür ve metoprolol tartrat, uygun eksipiyanla birlikte aktif farmasötik bilesenler olarak alinir. malzeme C, % 0.5 ile 6.0 yardimci malzeme D ve % 0.2 ile 5.0 yardimci malzeme E içeren bir benidipin hidroklorür dagilan tableti açiklamaktadir. Yukarida bahsedilen teknigin bilinen durumuna göre, Benidipinin istenen eksipiyanlar ile stabil bir film kapli tablet bilesiminin elde edilmesinin daha fazla çalisma gerektirdigi açiktir. Tablet sertligi, dagilma süresi, çözünme, vb. gibi istenen kriterlere sahip tablet bilesimi saglayan benidipinin farmasötik bilesimine hala ihtiyaç duyulmaktadir. Mevcut bulusun bulus sahipleri, sasirtici bir sekilde, iç faz ve dis fazda eksipiyanlarin spesifik düzenlenmesi sirasinda selüloz türevinin, eksipiyan olarak kullanilirken, daha iyi sertlige ve istenen dagilma süresine sahip bir tablet sagladigini bulmuslardir. BULUSUN ÖZETI Bir açidan, mevcut bulus a) iç fazinda Benidipin veya bunun farmasötik olarak kabul edilebilir tuzu, birinci seyreltici ve selüloz türevi ve b) dis fazinda ikinci seyreltici, kaydirici (Iubrikant) içeren film kapli tablet çekirdegini açiklar. Baska bir açidan mevcut bulus, iç fazinda selüloz türevi olarak hidroksipropil metil selüloz içeren bir film kapli tablet çekirdegini saglar. Baska bir açidan mevcut bulus, dis fazinda ikinci seyreltici olarak laktoz içeren birfilm kapli tablet çekirdegini saglar. Baska bir açidan mevcut bulus, birinci seyreltici ve ikinci seyrelticisi ayni veya farkli olan bir film kapli tablet çekirdegini saglar. a) iç fazinda Benidipin veya farmasötik olarak kabul edilebilir tuzu, laktoz ve hidroksipropil metil selüloz; b) dis fazinda laktoz ve kaydirici(lubrikant) madde içeren film kapli tablet çekirdegi bilesimini açiklar. Baska bir açidan mevcut bulus, bir veya daha fazla eksipiyan içeren birfilm kapli tablet çekirdegini açiklar. Baska bir açidan mevcut bulus, bahsi geçen farmasötik bilesimi hazirlamak için kullanilan bir prosesin konvansiyonel proses oldugunu açiklar. Baska bir açidan mevcut bulus, bahsi geçen film kapli tablet çekirdeginin yas granülasyon yöntemiyle hazirlandigini açiklar. Baska bir açidan mevcut bulus, bu tür farmasötik bilesimin hipertansiyon tedavisinde ilaç olarak kullanimini açiklar. Mevcut bulusun bir veya daha fazla uygulamasinin detaylari asagida bulusun detayli açiklamasinda belirtilmistir. Bulusun diger özellikleri, amaçlari ve avantajlari da asagida açiklanmaktadir. BULUSUN DETAYLI AÇIKLANMASI Mevcut bulus asagida daha spesifik olarak açiklanacaktir. Mevcut bulusta kullanilan "film kapli tablet çekirdegi terimi, farmasötik bir tabletin, istenen salim hizina ulasmak için uygun bir polimer veya geleneksel bir kaplama malzemesi ile kaplanan farmasötik bir tablet anlamina gelir. Mevcut bulusta kullanilan "iç faz" terimi, granülasyondan önce, yani granül içine dahil edilen eksipiyanlari veya bilesenleri belirtir. Intragranüler terimi ile iç faz terimi birbirleriyle degistirilebilir sekilde kullanilabilir. Mevcut bulusta kullanilan "dis faz" terimi, granülasyondan sonra eklenen eksipiyanlari veya bilesenleri ifade eder. Ekstragranüler terimi ile dis faz terimi birbirleriyle degistirilebilir sekilde kullanilabilir. Mevcut bulusta kullanilan "Benidipin" terimi, bunlarla sinirli olmamak üzere, Benidipin, farmasötik olarak kabul edilebilir tuzlarini, farmasötik olarak kabul edilebilir solvatlarini, farmasötik olarak kabul edilebilir hidratlarini, farmasötik olarak kabul edilebilir enantiomerlerini, farmasötik olarak kabul edilebilir türevlerini, farmasötik olarak kabul edilebilir polimorflarini ve farmasötik olarak kabul edilebilir prodruglarini ve ayrica çesitli kristal ve amorf formlarini içerir. Benidipinin düsük çözünürlük ve yüksek geçirgenligi nedeniyle ve dozaj formunun türü dikkate alindiginda, kritik kalite özelliklerinin, üretim sirasinda tabletlerin basilabilirligi, kaplanmis tabletin dagilma süresi ve referans ürünle karsilastirmali çözünme profilleri makul oldugu görülmüstür. Iç faz ve dis fazda eksipiyanlarin spesifik düzenlenmesi sirasinda selüloz türevinin eksipiyan olarak kullanilirken daha iyi sertlige ve istenen dagilma süresine sahip bir tablet sagladigi sasirtici bir sekilde bulunmustur. Buna ek olarak, bulusun benidipin içeren film kapli tablet Coniel® referans ürünü ile benzer çözünme profili sagladigi da gözlemlenmistir. Genel uygulamalarda mevcut bulus, a) iç fazda Benidipin veya farmasötik olarak kabul edilebilir tuzu, birinci seyreltici ve selüloz türevi; b) dis fazda ikinci seyreltici ve kaydirici (Iubrikant) içeren film kapli tablet çekirdegini açiklar. Belirli uygulamalarda, mevcut bulusun film kapli tablet çekirdegi, film kapli tablet toplam agirligina göre agirlikça %2 ile %5 araliginda aktif madde Benidipin içerir. Belirli uygulamalarda, mevcut bulusun film kapli tablet çekirdegi, film kapli tablet çekirdeginin toplam agirligina göre agirlikça %2 ile %10, daha tercihen %2 ile %5 miktarinda bir selüloz türevi içerir. Selüloz türevi, bunlarla sinirli olmamak üzere, hidroksipropilmetil selüloz (HPMC) (bunun düsük ila orta viskoziteli versiyonlari), ör. Dow Chemical Company'den Methocel® markasi altinda ticari olarak temin edilebilen, örn. Methocel E15Premium, Methocel E3Premium LV, Methocel K (bunun düsük ila orta viskoziteli versiyonlari) ör. Hercules Inc., Dow Chemical Company, Aqualon bölümünden Klucel® markasi altinda ticari olarak temin edilebilen, Klucel GF, Klucel JF, Klucel LF ve Klucel EF; mikrokristalin selüloz (MCC), karboksimetilselüloz (CMC), sodyum karboksimetiletil selüloz; veya bunlarin iki veya daha fazlasinin bir kombinasyonunu içeren gruptan seçilebilir. Belirli uygulamalarda, mevcut bulusun film kapli tablet çekirdegi, film kapli tablet çekirdeginin toplam agirligina göre agirlikça %50 ile %75 miktarinda birinci seyrelticiyi Belirli uygulamalarda, mevcut bulusun film kapli tablet çekirdegi, film kapli tablet çekirdeginin toplam agirligina göre agirlikça %10 ile %20 miktarinda ikinci bir seyreltici Seyreltici, laktoz, sukroz ve kalsiyum fosfattan seçilebilir. Birinci seyreltici ve ikinci seyreltici ayni veya farkli olabilir. Belirli uygulamalarda, mevcut bulusun film kapli tablet çekirdegi ayrica film kapli tablet çekirdeginin toplam agirligina göre agirlikça %5 ile %10 miktarinda bir dagitici içerir. Dagitici, kroskarmeloz sodyum, sodyum nisasta glikolat, prejelatinize nisasta, sodyum karboksimetil selüloz, mikrokristalin selüloz, çapraz bagli polivinilpirolidon, sodyum aljinat, düsük ikame edilmis hidroksipropil selüloz ve bunlarin karisimlarini içerir, ancak bunlarla sinirli degildir. Bir uygulamada, mevcut bulusun film kapli tablet çekirdegi, film kapli tablet çekirdeginin toplam agirligina göre agirlikça %0,5 ile %2 miktarinda bir kaydirici(lubrikant) içerir. Kaydirici (Iubrikant), bunlarla sinirli olmamak üzere, magnezyum stearat, kalsiyum stearat, çinko stearat gibi metalik stearatlari; stearik asit, hidrojene bitkisel yag, hidrojene hint yagi, gliseril palmitostearat, gliseril behenat, polietilen glikoller, misir nisastasi, sodyum stearil fumarat, sodyum benzoat, mineral yag, talk ve bunlarin karisimlarini içerir. Mevcut bulusun film kapli tablet çekirdegi, bilinen geleneksel yöntemler, yani granülasyon veya direkt baski kullanilarak elde edilebilir. Granül elde etme islemi, bunlarla sinirli olmamak üzere, yas granülasyon, akiskan yatakli granülasyon, spreyle kurutma veya kuru granülasyonu içerir. Yas granülasyon için kullanilan uygun çözücüler, metil alkol, etil alkol, izopropil alkol, n-butil alkol, aseton, asetonitril, kloroform, metilen klorür, su veya bunlarin karisimlarini içeren gruptan seçilir. Bu bulusun film tablet bilesimi agizdan kullanim içindir ve film kapli tablet biçimindedir. Mevcut bulusun tablet çekirdegi, teknikte iyi bilinen teknikler kullanilarak bir film Olusturucu polimer ve bir veya daha fazla farmasötik olarak kabul edilebilir eksipiyan ile kaplanir, örn: geleneksel bir kaplama kazaninda sprey kaplama veya bir akiskan yatak islemcisi veya daldirmali kaplama. Alternatif olarak kaplama, sicak eritme teknigi kullanilarak da gerçeklestirilebilir. Film kaplama bir veya daha fazla film Olusturucu polimer ve istege bagli olarak bir veya daha fazla farmasötik olarak kabul edilebilir eksipiyan içerebilir. Uygun bir film Olusturucu polimer hidroksipropil metil selüloz, etil selüloz, metil selüloz, hidroksietil selüloz, hidroksipropil selüloz, sodyum karboksimetil selüloz, selüloz asetat, hidroksipropil metil selüloz ftalat, selüloz asetat trimellitat, metakrilik asit kopolimerleri, örn: Eudragit® , polivinilpirrolidon, polivinil alkol, polietilen glikol veya bunlarin karisimlarini içeren gruptan seçilir. Tercih edilen film olusturucu polimer, hidroksipropil metil selülozdur. Teknikte bilinen diger uygun film Olusturucu polimerler de kullanilabilir. Film kaplama ayrica titanyum dioksit gibi opaklastiricilar, talk gibi akis yardimcilari ve demir oksit sarisi gibi pigment içerebilir. Mevcut bulusa göre film kapli tablet çekirdegi bir ilaç olarak kullanilabilir. Farmasötik bilesim tipik olarak hipertansiyon tedavisinde kullanilabilir. Mevcut bulus asagidaki örnekler araciligiyla ile daha ayrintili bir sekilde tarif edilecektir. Örnek, bulusun kapsamini sinirlayici nitelikte olmayip, yukarida detaylari verilen tarifnamenin isigi altinda düsünülmelidir. Örnekler: Örnek 1: Dis fazinda Laktoz içeren Benidipin Film Kapli Tablet Içindekiler mg I tb Benidipin hidroklorür 8.00 Laktoz monohidrat 173.23 Prejelatinize nisasta 23.0 Baglayici Çözelti Deiyonize su 33.00 Spreyle kurutulmus laktoz 40.73 Magnezyum stearat 2.54 Deiyonize su 44.00 Üretim prosesi: 1. Benidipin, Iaktoz monohidrat, prejelatinize nisasta ve HPMC E5, topaklamayi engellemek için uygun bir elekten elendi ve uygun bir tamburlu karistiricida karistirildi. 2. Baglayici çözelti, HPMC E5"in sicak deionize suda çözünüp berrak çözelti elde edene kadar karistirmasiyla elde edildi. 3. Ikinci basamakta elde edilen baglayici çözelti kullanilarak yas granülasyon islemi yapildi. 4. Üçüncü basamakta elde edilen granüller, nemi (su içerigi) %2'den az olana kadar 50-60 °C'de uygun bir firinda kurutuldu. . Dördüncü basamakta elde edilen granüller uygun bir karistiricida püskürtülerek kurutulmus Iaktoz ve magnezyum stearat ile karistirildi. 6. Elde edilen karisim daha sonra uygun tablet basma makinesi kullanilarak tablet basildi. 7. Elde edilen tabletler daha sonra sulu Opadry ll Yellow 32K220070 çözeltisi ile kaplandi. Örnek-2: Dis fazinda Laktoz içermeyen Benidipin Film Kapli Tablet Içindekiler mg I tb Benidipin hidroklorür 8.00 Laktoz monohidrat 173.23 Prejelatinize nisasta 23.0 Baglayici Çözelti Deiyonize su 33.00 Magnezyum stearat 2.54 Deiyonize su 44.00 Üretim prosesi: 1. Benidipin, Iaktoz monohidrat, prejelatinize nisasta ve HPMC E5, topaklamayi engellemek için uygun bir elekten elendi ve uygun bir tamburlu karistiricida karistirildi. . Baglayici çözelti, HPMC E5'in sicak deionize suda çözünüp berrak çözelti elde edene kadar karistirmasiyla elde edildi. . Ikinci basamakta elde edilen baglayici çözelti kullanilarak yas granülasyon islemi yapildi. . Üçüncü basamakta elde edilen granüller, nemi (su içerigi) %2'den az olana kadar 50-60 °C'de uygun bir firinda kurutuldu. . Dördüncü basamakta elde edilen granüller uygun bir karistiricida magnezyum stearat ile karistirildi. . Elde edilen karisim daha sonra uygun tablet basma makinesi kullanilarak tablet basildi . Elde edilen tabletler daha sonra sulu Opadry II Yellow 32K220070 çözeltisi ile kaplandi. Tabletlerin Sertlik ve Dagilma Süresinin Test Edilmesi Parametreler Örnek 1 Örnek 2 Zimba sistemi: 9,0 mm, Yuvarlak 9.0 mm 9.0 mm Ana sikistirma kuvveti 23- 25 KN 23- 25 KN Ön sikistirma kuvveti 5- 6 KN 5- 6 KN Sertlik (kp) 8-9 kp 3-4 kp Dagilma süresi (dk) 11-12min 5-6 min Gözlem: Yukaridaki tablodan, dis fazda püskürtülerek kurutulmus laktoz içeren nihai tablet granüllerinin (Örnek-1) dis fazda püskürtülerek kurutulmus laktoz içermeyen tablete (Örnek 2) kiyasla daha iyi basilabilirlik gösterdigi açikça görülmektedir. Ayrintili olarak Örnek-1 tableti için sertlik degeri 8-9 kp iken, ayni test parametresi altinda Örnek 2 tableti için 5-6 kp oldugu söylenebilir ki bu da dis fazda püskürtülerek kurutulmus Iaktoz ile hazirlanan karisimin daha iyi basilabilirlik özelligini gösterir. Ayrica, Örnek-1 tabletin dagilma süresinin Coniel®'e benzer 11-12 dakika oldugu, Örnek-2'nin tabletin dagilma süresinin 5-6 dakika oldugu da gözlemlenmistir, bu çekirdek tabletin düsük sertliginden dolayi olabilir. TR TR TR DESCRIPTION PHARMACEUTICAL COMPOSITION CONTAINING BENIDIPINE TECHNICAL FIELD TO WHICH THE INVENTION INCLUDES The present invention relates to a film-coated tablet core containing a) Benidipine or its pharmaceutically acceptable salt, first diluent and cellulose derivative in the inner phase and b) second diluent, lubricant in the outer phase. . The invention also includes the preparation of the said tablet core and its use as a drug in the treatment of hypertension. BACKGROUND OF THE ART Benidipine (Formula 1), chemically known as 3-(3R)-1-benzylpiperidin-S-yl S-methyl (4R)-2,6-dimethyl- It is known as 4-(3-nitr0phenyl)-1,4-dihydropyridine-3,5-dicarb0xyleth. Benidipine belongs to the dihydropyridine receptor antagonist, which can bind to dihydropyridine receptors with high affinity and high specificity and exerts a strong inhibitory effect on the Ca2+ channel. Benidipine not only has an inhibitory effect on the muscle (L-type) Ca2+ channel, but also on voltage-dependent N- and T-type Ca2+ channels. Benidipine is known to be the only calcium antagonist so far that can inhibit all three Ca +2 channels. Additionally, Benidipine has a high affinity with the cell membrane, has vascular selectivity and a renal protective effect. Therefore, it is an ideal, safe and effective agent for the treatment of hypertension and renal parenchymal hypertension and angina. Benidipine is marketed under the trade name Coniel® by Kyowa Hakko Kogyo as a hydrochloride salt of Benidipine film-coated tablet for the treatment of high blood pressure (hypertension), renal parenchymal hypertension, and angina pectoris. Coniel® can be taken 2-4 mg once daily after breakfast in the adult population for the treatment of hypertension and renal parenchymal hypertension. If the dose is not sufficient, it can be increased to 8 mg once a day depending on the patient's age and symptoms. For the adult population in the treatment of angina pectoris, 4 mg can be taken twice a day after breakfast and dinner. Coniel® film-coated tablet is a standard immediate-release tablet containing Iactose, potato starch, partially hydrolyzed polyvinyl alcohol, magnesium stearate, Opadry OY LS 22820 and carnauba wax. According to published literature, Benidipine is considered a BCS (Biopharmaceutical Classification System) Class II drug, meaning it has high permeability and low solubility. Due to the poor solubility of the API, the selection of excipients and the production method play an important role in achieving critical quality characteristics. EP 0063365 B1 describes Benidipine as a compound for the first time, its preparation process, pharmaceutical composition and use for the treatment of hypertension. Among the diastereomers of (1-benzyl-3-piperidyl)ester-5-methyl ester, hydrochloride nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid-3-(1-benzyl-3-piperidyl)ester-5-methyl explains the ester. It discloses a medicinal composition of Benidipine hydrochloride, which has the property of providing rapid dissolution to accelerate dissolution. The composition is characterized by containing Benidipine hydrochloride crystals with an average particle diameter volume of 1.0 to 50.0 µm or particles with an average particle diameter volume of 1.0 to 50.0 µm and a functional additive having water solubility or affinity for water. According to WO '448, the preferred water-soluble functional additive is polyvinyl alcohol partially hydrolyzed in water. Specifically, it discloses a tablet of a dihydropyridine derivative having a simple production process or a film of a dihydropyridine derivative with excellent light stability. CN 102579442 discloses the composition of a pharmaceutical capsule containing Benidipine and Atorvastatin calcium with different excipients such as lactose, microcrystalline cellulose, pregelatinized starch, carboxymethyl starch, hypromellose, magnesium stearate and the method of their production. CN 102379875 discloses a pharmaceutical composition comprising Benidipine hydrochloride and metoprolol tartrate and their use; To prepare it, Benidipine hydrochloride and metoprolol tartrate are taken as active pharmaceutical ingredients together with the appropriate excipient. Material C discloses a Benidipine hydrochloride dispersible tablet containing 0.5 to 6.0% of co-material D and 0.2 to 5.0% of co-material E. Based on the above-mentioned state of the art, it is clear that obtaining a stable film-coated tablet composition of Benidipine with the desired excipients requires further work. Tablet hardness, disintegration time, dissolution, etc. There is still a need for a pharmaceutical composition of Benidipine that provides a tablet composition with the desired criteria such as. Surprisingly, the inventors of the present invention have found that the cellulose derivative, during the specific arrangement of excipients in the inner phase and outer phase, provides a tablet with better hardness and desired disintegration time when used as excipient. SUMMARY OF THE INVENTION In one aspect, the present invention discloses a film-coated tablet core comprising a) Benidipine or its pharmaceutically acceptable salt, first diluent and cellulose derivative in the inner phase and b) second diluent, lubricant in the outer phase. In another aspect, the present invention provides a film-coated tablet core containing hydroxypropyl methyl cellulose as a cellulose derivative in its inner phase. In another aspect, the present invention provides a film-coated tablet core containing lactose as a second diluent in the outer phase. In another aspect, the present invention provides a film-coated tablet core whose first diluent and second diluent are the same or different. a) Benidipine or its pharmaceutically acceptable salt, lactose and hydroxypropyl methyl cellulose in the internal phase; b) explains the composition of the film-coated tablet core, which contains lactose and lubricant substance in the outer phase. In another aspect, the present invention discloses a film-coated tablet core containing one or more excipients. In another aspect, the present invention discloses that a process used to prepare said pharmaceutical composition is a conventional process. In another aspect, the present invention discloses that said film-coated tablet core is prepared by wet granulation method. In another aspect, the present invention discloses the use of such pharmaceutical composition as a medicament in the treatment of hypertension. Details of one or more embodiments of the present invention are set forth below in the detailed description of the invention. Other features, purposes and advantages of the invention are also explained below. DETAILED DESCRIPTION OF THE INVENTION The present invention will be explained more specifically below. The term "film-coated tablet core" as used in the present invention means a pharmaceutical tablet coated with a suitable polymer or a conventional coating material to achieve the desired release rate. The term "internal phase" used in the present invention refers to the formation of a pharmaceutical tablet before granulation, that is, into the granule. The term "intragranular" and the term "internal phase" as used in the present invention refer to excipients or components added after granulation. The term "Benidipine" includes, but is not limited to Benidipine, its pharmaceutically acceptable salts, its pharmaceutically acceptable solvates, its pharmaceutically acceptable hydrates, its pharmaceutically acceptable enantiomers, its pharmaceutically acceptable derivatives, its pharmaceutically acceptable polymorphs and its pharmaceutically acceptable derivatives. It includes acceptable products as well as various crystalline and amorphous forms. Due to the low solubility and high permeability of Benidipine and considering the type of dosage form, the critical quality characteristics are reasonable, the compressibility of the tablets during production, the disintegration time of the coated tablet, and the dissolution profiles comparative to the reference product. During the specific arrangement of excipients in the inner phase and outer phase, it was surprisingly found that the use of cellulose derivative as excipient provides a tablet with better hardness and desired disintegration time. In addition, it has been observed that the invention provides a similar dissolution profile as the film-coated tablet Coniel® reference product containing Benidipine. In general applications, the present invention includes a) Benidipine or its pharmaceutically acceptable salt, first diluent and cellulose derivative in the internal phase; b) explains the film-coated tablet core containing the second diluent and lubricant in the outer phase. In certain embodiments, the film-coated tablet core of the present invention contains between 2% and 5% by weight of the active ingredient Benidipine, based on the total weight of the film-coated tablet. In certain embodiments, the film-coated tablet core of the present invention contains a cellulose derivative in an amount of 2% to 10%, more preferably 2% to 5% by weight, based on the total weight of the film-coated tablet core. Cellulose derivative includes, but is not limited to, hydroxypropylmethyl cellulose (HPMC) (low to medium viscosity versions thereof), e.g. commercially available from Dow Chemical Company under the trade name Methocel®, e.g. Methocel E15Premium, Methocel E3Premium LV, Methocel K (low to medium viscosity versions thereof) e.g. Klucel GF, Klucel JF, Klucel LF and Klucel EF, commercially available under the trade name Klucel® from Hercules Inc., Dow Chemical Company, Aqualon division; microcrystalline cellulose (MCC), carboxymethylcellulose (CMC), sodium carboxymethylethyl cellulose; or a combination of two or more thereof. In certain embodiments, the film-coated tablet core of the present invention contains the first diluent in an amount of 50% to 75% by weight, based on the total weight of the film-coated tablet core. In certain embodiments, the film-coated tablet core of the present invention contains 10% to 20% by weight, based on the total weight of the film-coated tablet core. A second diluent. The diluent may be selected from lactose, sucrose and calcium phosphate. The first diluent and the second diluent may be the same or different. In certain embodiments, the film-coated tablet core of the present invention further contains a disintegrant in an amount of 5% to 10% by weight based on the total weight of the film-coated tablet core. The disintegrant includes, but is not limited to, croscarmellose sodium, sodium starch glycolate, pregelatinized starch, sodium carboxymethyl cellulose, microcrystalline cellulose, cross-linked polyvinylpyrrolidone, sodium alginate, low substituted hydroxypropyl cellulose, and mixtures thereof. In one embodiment, the film-coated tablet core of the present invention contains a lubricant in the amount of 0.5% to 2% by weight, based on the total weight of the film-coated tablet core. Lubricant includes, but is not limited to, metallic stearates such as magnesium stearate, calcium stearate, zinc stearate; Contains stearic acid, hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmitostearate, glyceryl behenate, polyethylene glycols, corn starch, sodium stearyl fumarate, sodium benzoate, mineral oil, talc and mixtures thereof. The film-coated tablet core of the present invention can be obtained using known conventional methods, namely granulation or direct compression. The process of obtaining granules includes, but is not limited to, wet granulation, fluid bed granulation, spray drying or dry granulation. Suitable solvents used for wet granulation are selected from the group consisting of methyl alcohol, ethyl alcohol, isopropyl alcohol, n-butyl alcohol, acetone, acetonitrile, chloroform, methylene chloride, water, or mixtures thereof. The film-coated tablet composition of this invention is for oral use and is in film-coated tablet form. The tablet core of the present invention is coated with a film-forming polymer and one or more pharmaceutically acceptable excipients using techniques well known in the art, e.g., spray coating in a conventional coating pan or a fluidized bed processor or dip coating. Alternatively, coating can be achieved using the hot melt technique. The film coating may contain one or more film-forming polymers and optionally one or more pharmaceutically acceptable excipients. A suitable film-forming polymer is hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, sodium carboxymethyl cellulose, cellulose acetate, hydroxypropyl methyl cellulose phthalate, cellulose acetate trimellitate, methacrylic acid copolymers, e.g. Eudragit®, polyvinylpyrrolidone, poly vinyl alcohol , polyethylene glycol or mixtures thereof. The preferred film-forming polymer is hydroxypropyl methyl cellulose. Other suitable film-forming polymers known in the art may also be used. The film coating may also contain opacifiers such as titanium dioxide, flow aids such as talc, and pigment such as iron oxide yellow. According to the present invention, the film-coated tablet core can be used as a medicine. The pharmaceutical composition can typically be used in the treatment of hypertension. The present invention will be described in more detail by means of the following examples. The example is not intended to limit the scope of the invention and should be considered in the light of the description detailed above. Examples: Example 1: Benidipine Film-Coated Tablet containing Lactose in the outer phase Ingredients mg I tb Benidipine hydrochloride 8.00 Lactose monohydrate 173.23 Pregelatinized starch 23.0 Binding Solution Deionized water 33.00 Spray-dried lactose 40.73 Magnesium stearate 2.54 Deionized water 4 4.00 Manufacturing process: 1. Benidipine, Iactose monohydrate , pregelatinized starch and HPMC E5 were sieved through a suitable sieve to prevent agglomeration and mixed in a suitable drum mixer. 2. The binder solution was obtained by dissolving HPMC E5 in hot deionized water and mixing until a clear solution was obtained. 3. Wet granulation process was carried out using the binder solution obtained in the second step. 4. The granules obtained in the third step showed moisture (water content) % It was dried in a suitable oven at 50-60 °C until it was less than 2. The granules obtained in the fourth step were mixed with spray-dried lactose and magnesium stearate in a suitable mixer. 6. The resulting mixture was then pressed into tablets using an appropriate tablet pressing machine. 7. The obtained tablets were then coated with aqueous solution of Opadry ll Yellow 32K220070. Example-2: Benidipine Film-Coated Tablet without Lactose in the outer phase. Ingredients mg I tb Benidipine hydrochloride 8.00 Lactose monohydrate 173.23 Pregelatinized starch 23.0 Binding Solution Deionized water 33.00 Magne. zyum stearate 2.54 Deionized water 44.00 Production process: 1. Benidipine, Iactose monohydrate, pregelatinized starch and HPMC E5 were sieved through a suitable sieve to prevent agglomeration and mixed in a suitable drum mixer. . The binding solution was obtained by dissolving HPMC E5 in hot deionized water and mixing until a clear solution was obtained. . The wet granulation process was performed using the binder solution obtained in the second step. . The granules obtained in the third step were dried in a suitable oven at 50-60 °C until their moisture (water content) was less than 2%. . The granules obtained in the fourth step were mixed with magnesium stearate in a suitable mixer. . The resulting mixture was then pressed into tablets using the appropriate tablet pressing machine. The resulting tablets were then coated with an aqueous solution of Opadry II Yellow 32K220070. Testing Hardness and Disintegration Time of Tablets Parameters Example 1 Example 2 Punch system: 9.0 mm, Round 9.0 mm 9.0 mm Main compression force 23- 25 KN 23- 25 KN Pre-compression force 5- 6 KN 5- 6 KN Hardness (kp ) 8-9 kp 3-4 kp Disintegration time (min) 11-12min 5-6 min Observation: From the table above, the final tablet granules containing spray-dried lactose in the external phase (Example-1) are transformed into a lactose-free tablet spray-dried in the external phase (Example 2). It is clearly seen that it shows better printability compared to ) In detail, while the hardness value for the Sample-1 tablet is 8-9 kp, it can be said that it is 5-6 kp for the Sample 2 tablet under the same test parameter, which indicates the better printability of the mixture prepared with spray-dried lactose in the external phase. It was also observed that the disintegration time of Sample-1 tablet was 11-12 minutes, similar to Coniel®, while the disintegration time of Sample-2 tablet was 5-6 minutes, which may be due to the low hardness of the core tablet.TR TR TR
Claims (1)
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2021007428A2 true TR2021007428A2 (en) | 2023-07-21 |
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