WO2008015530A2 - Stable solid oral formulation of pantoprazole - Google Patents
Stable solid oral formulation of pantoprazole Download PDFInfo
- Publication number
- WO2008015530A2 WO2008015530A2 PCT/IB2007/002176 IB2007002176W WO2008015530A2 WO 2008015530 A2 WO2008015530 A2 WO 2008015530A2 IB 2007002176 W IB2007002176 W IB 2007002176W WO 2008015530 A2 WO2008015530 A2 WO 2008015530A2
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- stable formulation
- coating
- water soluble
- pantoprazole
- core
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 55
- 238000009472 formulation Methods 0.000 title claims abstract description 30
- IQPSEEYGBUAQFF-UHFFFAOYSA-N Pantoprazole Chemical compound COC1=CC=NC(CS(=O)C=2NC3=CC=C(OC(F)F)C=C3N=2)=C1OC IQPSEEYGBUAQFF-UHFFFAOYSA-N 0.000 title claims abstract description 24
- 229960005019 pantoprazole Drugs 0.000 title claims abstract description 24
- 239000007787 solid Substances 0.000 title description 2
- 150000003839 salts Chemical class 0.000 claims abstract description 12
- -1 benzimidazole compound Chemical class 0.000 claims abstract description 9
- 238000000034 method Methods 0.000 claims abstract description 7
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 24
- 239000002702 enteric coating Substances 0.000 claims description 22
- 238000009505 enteric coating Methods 0.000 claims description 22
- 238000009498 subcoating Methods 0.000 claims description 18
- 150000001875 compounds Chemical class 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 15
- 239000011248 coating agent Substances 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 13
- 239000007884 disintegrant Substances 0.000 claims description 12
- 239000001856 Ethyl cellulose Substances 0.000 claims description 11
- 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 claims description 11
- 229920001249 ethyl cellulose Polymers 0.000 claims description 11
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 11
- 239000010419 fine particle Substances 0.000 claims description 11
- DNIAPMSPPWPWGF-UHFFFAOYSA-N propylene glycol Substances CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 10
- 239000011230 binding agent Substances 0.000 claims description 10
- 239000003085 diluting agent Substances 0.000 claims description 9
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 8
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
- 239000000725 suspension Substances 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 7
- 239000002270 dispersing agent Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 4
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 4
- 229930006000 Sucrose Natural products 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 229920001577 copolymer Polymers 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical group CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000000395 magnesium oxide Substances 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 229920000642 polymer Polymers 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000011734 sodium Substances 0.000 claims description 4
- 229910052708 sodium Inorganic materials 0.000 claims description 4
- 239000005720 sucrose Substances 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical group O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 3
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 3
- 239000008116 calcium stearate Substances 0.000 claims description 3
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- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 3
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- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 3
- 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 3
- GUBGYTABKSRVRQ-QKKXKWKRSA-N lactose group Chemical group OC1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@@H](O)[C@H](O2)CO)[C@H](O1)CO GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims description 3
- 239000004014 plasticizer Substances 0.000 claims description 3
- 229920000136 polysorbate Polymers 0.000 claims description 3
- 229940068965 polysorbates Drugs 0.000 claims description 3
- 239000002904 solvent Substances 0.000 claims description 3
- 239000004094 surface-active agent Substances 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000013769 triethyl citrate 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
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 claims description 2
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 239000002202 Polyethylene glycol Substances 0.000 claims description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 2
- 229920002472 Starch Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 2
- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 claims description 2
- 229910021502 aluminium hydroxide Inorganic materials 0.000 claims description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000000378 calcium silicate Substances 0.000 claims description 2
- 229910052918 calcium silicate Inorganic materials 0.000 claims description 2
- OYACROKNLOSFPA-UHFFFAOYSA-N calcium;dioxido(oxo)silane Chemical compound [Ca+2].[O-][Si]([O-])=O OYACROKNLOSFPA-UHFFFAOYSA-N 0.000 claims description 2
- 239000001768 carboxy methyl cellulose Substances 0.000 claims description 2
- 229920006217 cellulose acetate butyrate Polymers 0.000 claims description 2
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 2
- 229960000541 cetyl alcohol Drugs 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical group CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 229940049654 glyceryl behenate Drugs 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 230000001050 lubricating effect Effects 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 claims description 2
- 239000000347 magnesium hydroxide Substances 0.000 claims description 2
- 229910001862 magnesium hydroxide Inorganic materials 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 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
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 2
- 229920001223 polyethylene glycol Polymers 0.000 claims description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 claims description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 2
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 2
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 2
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 claims description 2
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 239000008107 starch Substances 0.000 claims description 2
- 235000019698 starch Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960002622 triacetin Drugs 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
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims 1
- 239000010410 layer Substances 0.000 description 24
- 239000003814 drug Substances 0.000 description 12
- 239000003826 tablet Substances 0.000 description 12
- 229940079593 drug Drugs 0.000 description 11
- 239000002253 acid Substances 0.000 description 8
- YNWDKZIIWCEDEE-UHFFFAOYSA-N pantoprazole sodium Chemical compound [Na+].COC1=CC=NC(CS(=O)C=2[N-]C3=CC=C(OC(F)F)C=C3N=2)=C1OC YNWDKZIIWCEDEE-UHFFFAOYSA-N 0.000 description 8
- 230000002378 acidificating effect Effects 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229960004048 pantoprazole sodium Drugs 0.000 description 6
- 150000001556 benzimidazoles Chemical class 0.000 description 4
- 229920001688 coating polymer Polymers 0.000 description 4
- 238000004519 manufacturing process Methods 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- 239000008188 pellet Substances 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 239000011247 coating layer Substances 0.000 description 3
- 239000012055 enteric layer Substances 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 210000004051 gastric juice Anatomy 0.000 description 3
- 159000000011 group IA salts Chemical class 0.000 description 3
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 2
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 2
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- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 2
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- 230000015556 catabolic process Effects 0.000 description 2
- 238000006731 degradation reaction Methods 0.000 description 2
- 239000007950 delayed release tablet Substances 0.000 description 2
- 238000004090 dissolution Methods 0.000 description 2
- 229960000381 omeprazole Drugs 0.000 description 2
- 229940126409 proton pump inhibitor Drugs 0.000 description 2
- 239000000612 proton pump inhibitor Substances 0.000 description 2
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 description 1
- 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 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 230000003113 alkalizing effect Effects 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000008199 coating composition Substances 0.000 description 1
- 238000013270 controlled release Methods 0.000 description 1
- 230000001934 delay Effects 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
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- 230000007935 neutral effect Effects 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 230000035515 penetration Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920006254 polymer film Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
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- 229940001593 sodium carbonate Drugs 0.000 description 1
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- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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- 125000000475 sulfinyl group Chemical group [*:2]S([*:1])=O 0.000 description 1
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- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 1
- 229910000406 trisodium phosphate Inorganic materials 0.000 description 1
- 235000019801 trisodium phosphate Nutrition 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
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—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
- A61K9/28—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
Definitions
- the present invention relates to stable formulations comprising an acid-labile benzimidazole compound. More particularly, the present invention relates to stable formulations comprising pantoprazole or its pharmaceutically acceptable salts.
- the present invention also relates to a process for the preparation of stable formulations containing pantoprazole or its pharmaceutically acceptable salts.
- Pantoprazole sodium is a substituted benzimidazole that inhibits gastric acid secretion and is chemically known as sodium 5-(difluoromethoxy)-2-[[3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole.
- Pantoprazole sodium is marketed under trade name PROTONIX® as a delayed release tablet and PROTONIX IV® as an injectable infusion in US.
- Pantoprazole being a benzimidazole proton pump inhibitor is very much susceptible to degradation/transformation in an acidic and neutral medium. So in order to avoid contact between the pantoprazole and the acidic gastric juice it is formulated as a capsule or tablet, which contains a core and a gastro-resistant coating that is entero-soluble. As most of the enteric coating polymer comprises acidic groups, benzimidazole compounds may rapidly decompose by direct or indirect contact with the acidic group of the coating polymer. To avoid the contact between the core and the enteric coating, a subcoating layer is established between the acidic drugs and enteric coating.
- compositions that are suitable for oral administration of acid-labile benzimidazole derivative.
- 4,853,230 discloses a pharmaceutical preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region and (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.
- compositions which consist essentially of: a core containing an acid-unstable benzimidazole compound; a slightly water- soluble first coating layer coated on the core, comprising a slightly water-soluble, film- forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substances and a second coating layer, coated on the first layer, of an enteric polymer film.
- U.S. Patent No. 5,232,706 discloses compositions comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating.
- U.S. Patent No. 5,997,903 discloses orally administrable medicament in pellet or tablet form which is resistant to gastric juice and in which each pellet or tablet consists of: a) a core comprising pantoprazole in admixture with binder, filler b) an inert water-soluble intermediate layer surrounding the core and c) an outer layer which is resistant to gastric juice wherein the binder is polyvinylpyrrolidone and/or hydroxypropylmethylcellulose and optionally, the filler is mannitol.
- U.S. Patent No. 6,013,281 discloses in situ formation of separating layer as a water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer.
- U.S. Patent No. 6,068,856 discloses a delayed and controlled release oral composition comprising pantoprazole, an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient and an outer enteric layer.
- U.S. Patent No. 6,207,198 discloses compositions that are exempt of alkaline-reacting compounds comprising: a core containing an acid-labile benzimidazole, and said active principle not being in the form of an alkaline salt; an intermediate layer and an enteric layer.
- U.S. Patent No. 6,346,269 discloses oral formulations for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, and an enteric coating.
- an alkaline material such as trisodium phosphate
- U.S. Patent No. 6,479,075 discloses a method for producing a composition, comprising combining proton pump inhibitor compound and disintegrant to form a core; coating said core with at least one protector coat layer comprising from about
- compositions comprising a core containing an active ingredient unstable to acid, an intermediate film enveloping the core, and an enteric film further enveloping the intermediate film, and the intermediate film comprises a matrix sparsely soluble in water and water-soluble fine particles dispersed therein.
- US 2005/042277 discloses compositions comprising a core containing the active ingredient and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.
- WO 03/077829 discloses a process for preparation of a pharmaceutical composition comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials c) second coat, termed as a seal coat, comprising of a mixture of polymers over the subcoat, d) an enteric coating layer surrounding said seal coat layer.
- WO 07/014928 discloses a composition comprising a core comprising pantoprazole having particle size in the range of 60-25 O ⁇ m, an alkalizing substance, filler and a disintegrant, an optional water-soluble separating layer and finally coated by enteric coating layer.
- WO 07/029124 discloses a composition comprising a core of pantoprazole, an inert intermediate layer surrounding said core, wherein said intermediate layer insulates said core; and finally an outer layer.
- the prior art patents disclose stable dosage forms for acid labile drugs containing core with or without alkaline reactive compound, an intermediate layer and an enteric coating.
- the inventors of the present invention during their efforts to develop stable and bioequivalent formulation found that the presence of subcoating comprising the dispersion of fine particles of slightly water soluble substance in ethylcellulose stabilizes the release of the drug from core. Objective of the invention
- the main objective of the present invention is to provide a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.
- Yet another objective of the present invention is to provide a stable formulation of pantoprazole in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration etc.
- Yet another objective of the present invention is to provide process for the preparation of a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.
- the main embodiment of the present invention is to provide a stable formulation comprising: i. a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating.
- a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating.
- the core may be in the form of spheroid, pellets, tablets or mini tablets.
- the core composition further comprises one or more excipients selected from lubricants, binder and surfactants.
- Suitable binders used in accordance with the present invention are selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or starch and the like or a combination thereof.
- Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like. The lubricant may be used in the range of 0.5- 5% of the total weight of the core.
- Suitable surfactants in accordance with the present invention are selected from sodium lauryl sulfate, polysorbates and the like or a combination thereof.
- Suitable disintegrant used in accordance with the present invention are selected from low substituted hydroxypropylcelluloses, microcrystalline cellulose, sodium carboxymethyl cellulose, crosscarmellose sodium, crospovidone and the like.
- the disintegrant may be used in the range of 10-70 % of the total weight of the core.
- Suitable water soluble diluents of the present invention include lactose, sucrose, dextrose, mannitol, sorbitol or a combination thereof.
- the diluent may be used in the range of 2-50% of the total weight of the core.
- Suitable alkaline reacting compounds of the present invention include calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate and the like or a combination thereof.
- the pharmaceutically acceptable salts include its sodium, potassium and magnesium.
- the amount of pantoprazole sodium used may be in the range of 20 to 70% of the total weight of the core.
- the sub coating composition comprises ethylcellulose, slightly water-soluble substance and a dispersing agent.
- the subcoating comprises a dispersion of fine particles of slightly water-soluble substance in ethyl cellulose. The presence of subcoating enhances the penetration of water through the pores, which enables the core to disintegrate rapidly thereby releasing the drug.
- Suitable slightly water soluble substances of the present invention include fine particles of colloidal silicon dioxide, magnesium oxide, calcium silicate, magnesium hydroxide, aluminium hydroxide, sucrose fatty acid esters, sodium carbonate and the like or a combination thereof.
- the content of the slightly water- soluble fine particles may be in the range of 30 to 70 % by weight of the sub coating dispersion.
- the presence of an insufficient amount of slightly water-soluble fine particles in the intermediate film often results in extension of disintegration time of the intermediate film, which delays release of pantoprazole.
- Suitable dispersing agent of the present invention may be selected from polyethylene-propylene glycol copolymer, polyoxyethylene stearates, poly sorbates, propylene glycol, polyvinyl alcohol and the like and a mixture thereof.
- the subcoated core is further coated with enteric coating composition comprising enteric coating polymer, plasticizer and anti-sticking agent.
- Suitable enteric polymers used according to the present invention are selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate and hydroxypropylmethylcellulose phthalate, methacrylic acid and ethyl acrylate copolymer such as eudragit or a combination thereof.
- the enteric coating has a thickness not less than 0.1% and preferably 1 to 50%, most preferably 2 to 25% by weight of the final dosage form.
- Suitable plasticizers used according to the present invention are selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin and the like.
- Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture, thereof.
- the coating according to the present invention is applied by dissolving / dispersing the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylene dichloride and the like or a mixture thereof.
- solvents such as isopropyl alcohol, water, acetone, ethanol, methylene dichloride and the like or a mixture thereof.
- the present invention also provides a process for the preparation of a stable formulation comprising : i) a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii) an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii) an enteric coating over the sub coating, which comprises the following steps:
- pantoprazole sodium pantoprazole sodium, mannitol, sodium carbonate and crospovidone were blended, ii) binder solution of polyvinylpyrrolidone in water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii) and dried the granulated mass at 40 0 C, iv) dried granules were blended with crospovidone, v) lubricated the blended granules of step (iv) with calcium stearate vi) compressed the lubricated blend of step (v) into tablets, vii) a suspension of ethylcellulose, colloidal silicon dioxide, iron oxide yellow and propylene glycol in ethanol was prepared, viii) tablets of step (vi) were coated with the coating suspension of step (vii), ix) a suspension of eudragit, triethylcitrate and tal
- compositions given in examples 2, 3 and 4 were prepared using similar procedure described in example 1.
- pantoprazole sodium prepared according to the present invention were tested for drug release in 0. IN HCl for 2hours followed by phosphate buffer having pH 6.8 using USP apparatus 2 with paddle speed at 75 rpm.
- the samples of the media were periodically withdrawn and spectrophotometrically analyzed for pantoprazole content.
- the dissolution profile is given in Table 1 below:
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Abstract
The present invention relates to a stable formulation comprising an acid-labile benzimidazole compound. More particularly, the present invention relates to a stable formulation comprising pantoprazole or its pharmaceutically acceptable salts. The present invention also relates to a process for the preparation of a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.
Description
STABLE SOLID ORAL FORMULATION OF AN ACID LABILE DRUG
Field of the invention The present invention relates to stable formulations comprising an acid-labile benzimidazole compound. More particularly, the present invention relates to stable formulations comprising pantoprazole or its pharmaceutically acceptable salts.
The present invention also relates to a process for the preparation of stable formulations containing pantoprazole or its pharmaceutically acceptable salts. Background of the invention
Pantoprazole sodium is a substituted benzimidazole that inhibits gastric acid secretion and is chemically known as sodium 5-(difluoromethoxy)-2-[[3,4- dimethoxy-2-pyridinyl)methyl]sulfinyl]-lH-benzimidazole. Pantoprazole sodium is marketed under trade name PROTONIX® as a delayed release tablet and PROTONIX IV® as an injectable infusion in US.
Pantoprazole, being a benzimidazole proton pump inhibitor is very much susceptible to degradation/transformation in an acidic and neutral medium. So in order to avoid contact between the pantoprazole and the acidic gastric juice it is formulated as a capsule or tablet, which contains a core and a gastro-resistant coating that is entero-soluble. As most of the enteric coating polymer comprises acidic groups, benzimidazole compounds may rapidly decompose by direct or indirect contact with the acidic group of the coating polymer. To avoid the contact between the core and the enteric coating, a subcoating layer is established between the acidic drugs and enteric coating.
Further, it is necessary to add an inert substance to the composition, which provide an alkaline environment aimed at improving stability of the active substance during manufacturing and storage of the dosage form.
Several prior art references describe compositions that are suitable for oral administration of acid-labile benzimidazole derivative. Some of the patents/ patent publications, which disclose compositions of acid labile benzimidazoles, are given below. U.S. Patent No. 4,853,230 discloses a pharmaceutical preparation comprising: (a) an alkaline reacting core comprising an acid-labile pharmaceutically active substance and an alkaline reacting compound different from said active substance (b) an inert subcoating which rapidly dissolves or disintegrates in water disposed on said core region and (c) an enteric coating layer surrounding said subcoating layer, wherein the subcoating layer isolates the alkaline reacting core from the enteric coating layer such that the stability of the preparation is enhanced.
U.S. Patent No. 5,035,899 discloses compositions which consists essentially of: a core containing an acid-unstable benzimidazole compound; a slightly water- soluble first coating layer coated on the core, comprising a slightly water-soluble, film- forming material selected from the group consisting of ethyl cellulose and polyvinyl acetate and fine particles of a slightly water-soluble substances and a second coating layer, coated on the first layer, of an enteric polymer film.
U.S. Patent No. 5,232,706 discloses compositions comprising: (a) a core containing omeprazole and an alkaline salt of omeprazole mixed with a first alkaline-reacting compound; (b) at least one intermediate layer formed by an excipient and a second alkaline-reacting compound and (c) an outer layer formed by an enteric coating.
U.S. Patent No. 5,997,903 discloses orally administrable medicament in pellet or tablet form which is resistant to gastric juice and in which each pellet or tablet consists of: a) a core comprising pantoprazole in admixture with binder, filler b) an inert water-soluble intermediate layer surrounding the core and c) an outer
layer which is resistant to gastric juice wherein the binder is polyvinylpyrrolidone and/or hydroxypropylmethylcellulose and optionally, the filler is mannitol.
U.S. Patent No. 6,013,281 discloses in situ formation of separating layer as a water soluble salt layer between the alkaline reacting compound(s) and the enteric coating polymer.
U.S. Patent No. 6,068,856 discloses a delayed and controlled release oral composition comprising pantoprazole, an alkaline pellet or tablet core, at least one intermediate layer controlling release of active ingredient and an outer enteric layer.
U.S. Patent No. 6,207,198 discloses compositions that are exempt of alkaline-reacting compounds comprising: a core containing an acid-labile benzimidazole, and said active principle not being in the form of an alkaline salt; an intermediate layer and an enteric layer.
U.S. Patent No. 6,346,269 discloses oral formulations for acid-sensitive drugs, where the drug substance is mixed with an alkaline material such as trisodium phosphate and coated onto a core, such as a tablet, and an enteric coating.
U.S. Patent No. 6,479,075 discloses a method for producing a composition, comprising combining proton pump inhibitor compound and disintegrant to form a core; coating said core with at least one protector coat layer comprising from about
0.1% to about 10% aminoalkyl methacrylate copolymers and providing at least one enteric layer.
US 2004/0146558 discloses compositions comprising a core containing an active ingredient unstable to acid, an intermediate film enveloping the core, and an enteric film further enveloping the intermediate film, and the intermediate film comprises a matrix sparsely soluble in water and water-soluble fine particles dispersed therein.
US 2005/042277 discloses compositions comprising a core containing the active ingredient and a disintegrant, a swellable coating surrounding the core, and an enteric coating surrounding the swellable coating.
WO 03/077829 discloses a process for preparation of a pharmaceutical composition comprises steps of manufacturing a) a core containing a pharmacologically effective acid labile compounds, and/or its alkaline salts, optionally with alkaline reacting substance, b) an inert subcoating layer which is a first coating layer, coated on the core, comprising film forming materials c) second coat, termed as a seal coat, comprising of a mixture of polymers over the subcoat, d) an enteric coating layer surrounding said seal coat layer.
WO 07/014928 discloses a composition comprising a core comprising pantoprazole having particle size in the range of 60-25 Oμm, an alkalizing substance, filler and a disintegrant, an optional water-soluble separating layer and finally coated by enteric coating layer. WO 07/029124 discloses a composition comprising a core of pantoprazole, an inert intermediate layer surrounding said core, wherein said intermediate layer insulates said core; and finally an outer layer.
Even though many patents disclose stable formulations of acid labile drugs, still there is need to develop dosage forms of acid labile drugs in which the drug will not be exposed to acidic media in the stomach and release the drug rapidly once the dosage form enters more alkaline environment.
The prior art patents disclose stable dosage forms for acid labile drugs containing core with or without alkaline reactive compound, an intermediate layer and an enteric coating. The inventors of the present invention during their efforts to develop stable and bioequivalent formulation found that the presence of subcoating comprising the dispersion of fine particles of slightly water soluble substance in ethylcellulose stabilizes the release of the drug from core.
Objective of the invention
Accordingly, the main objective of the present invention is to provide a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.
Yet another objective of the present invention is to provide a stable formulation of pantoprazole in such a way that it will comply with the reference product in terms of in vivo parameters like bioequivalence and in vitro parameters like dissolution, disintegration etc.
Yet another objective of the present invention is to provide process for the preparation of a stable formulation containing pantoprazole or its pharmaceutically acceptable salts.
Summary of the invention
Accordingly, the main embodiment of the present invention is to provide a stable formulation comprising: i. a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating. Detailed description of the invention
In an embodiment of the present invention, the core may be in the form of spheroid, pellets, tablets or mini tablets.
In one embodiment of the present invention, the core composition further comprises one or more excipients selected from lubricants, binder and surfactants. Suitable binders used in accordance with the present invention are selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone or starch and the like or a combination thereof.
Suitable lubricants of the present invention include sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate, talc and the like. The lubricant may be used in the range of 0.5- 5% of the total weight of the core. Suitable surfactants in accordance with the present invention are selected from sodium lauryl sulfate, polysorbates and the like or a combination thereof.
Suitable disintegrant used in accordance with the present invention are selected from low substituted hydroxypropylcelluloses, microcrystalline cellulose, sodium carboxymethyl cellulose, crosscarmellose sodium, crospovidone and the like. The disintegrant may be used in the range of 10-70 % of the total weight of the core.
Suitable water soluble diluents of the present invention include lactose, sucrose, dextrose, mannitol, sorbitol or a combination thereof. The diluent may be used in the range of 2-50% of the total weight of the core. Suitable alkaline reacting compounds of the present invention include calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate and the like or a combination thereof.
The presence of alkaline reacting compound in the core is favorable since it prevents degradation of pantoprazole, which is unstable in acidic medium. In another embodiment, the pharmaceutically acceptable salts include its sodium, potassium and magnesium.
In yet another embodiment of the present invention, the amount of pantoprazole sodium used may be in the range of 20 to 70% of the total weight of the core. In another embodiment of the present invention, the sub coating composition comprises ethylcellulose, slightly water-soluble substance and a dispersing agent.
In another embodiment of the present invention, the subcoating comprises a dispersion of fine particles of slightly water-soluble substance in ethyl cellulose. The presence of subcoating enhances the penetration of water through the pores, which enables the core to disintegrate rapidly thereby releasing the drug. Suitable slightly water soluble substances of the present invention include fine particles of colloidal silicon dioxide, magnesium oxide, calcium silicate, magnesium hydroxide, aluminium hydroxide, sucrose fatty acid esters, sodium carbonate and the like or a combination thereof. The content of the slightly water- soluble fine particles may be in the range of 30 to 70 % by weight of the sub coating dispersion. The presence of an insufficient amount of slightly water-soluble fine particles in the intermediate film often results in extension of disintegration time of the intermediate film, which delays release of pantoprazole.
Suitable dispersing agent of the present invention may be selected from polyethylene-propylene glycol copolymer, polyoxyethylene stearates, poly sorbates, propylene glycol, polyvinyl alcohol and the like and a mixture thereof.
In yet another embodiment of the present invention, the subcoated core is further coated with enteric coating composition comprising enteric coating polymer, plasticizer and anti-sticking agent.
Suitable enteric polymers used according to the present invention are selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate and hydroxypropylmethylcellulose phthalate, methacrylic acid and ethyl acrylate copolymer such as eudragit or a combination thereof. In a preferred embodiment, the enteric coating has a thickness not less than 0.1% and preferably 1 to 50%, most preferably 2 to 25% by weight of the final dosage form.
Suitable plasticizers used according to the present invention are selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate, triacetin and the like.
Suitable anti-sticking agents used according to the present invention are selected from talc, magnesium stearate and the like or a mixture, thereof.
The coating according to the present invention is applied by dissolving / dispersing the excipients in solvents such as isopropyl alcohol, water, acetone, ethanol, methylene dichloride and the like or a mixture thereof.
The present invention also provides a process for the preparation of a stable formulation comprising : i) a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii) an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii) an enteric coating over the sub coating, which comprises the following steps:
1) blending pantoprazole, disintegrant, water soluble diluent, alkaline reacting compound and other excipients, 2) granulating the blend with binder solution,
3) drying the granules and then blending the dried granules with extra granular excipients,
4) lubricating the blended granules of step (3) and then compressing it to obtained tablets, 5) coating the tablets of step (4) with the coating suspension of ethylcellulose, slightly water soluble substance and dispersing agent in a solvent and finally 6) coating the sub coated tablets of step (5) with the enteric coating suspension.
The following examples further exemplify the invention and are not intended to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry. Example 1
The processing steps involved in manufacturing enteric coated tablet dosage form of pantoprazole sodium are given below: i) pantoprazole sodium, mannitol, sodium carbonate and crospovidone were blended, ii) binder solution of polyvinylpyrrolidone in water was prepared, iii) granulated the blended material of step (i) with binder solution of step (ii) and dried the granulated mass at 400C, iv) dried granules were blended with crospovidone,
v) lubricated the blended granules of step (iv) with calcium stearate vi) compressed the lubricated blend of step (v) into tablets, vii) a suspension of ethylcellulose, colloidal silicon dioxide, iron oxide yellow and propylene glycol in ethanol was prepared, viii) tablets of step (vi) were coated with the coating suspension of step (vii), ix) a suspension of eudragit, triethylcitrate and talc in water was prepared and x) the coated tablets of step (viii) were coated with the coating suspension prepared in step (ix) to obtain delayed release tablets of pantoprazole.
The compositions given in examples 2, 3 and 4 were prepared using similar procedure described in example 1.
Example 2
Example 4
The stable solid dosage forms of pantoprazole sodium prepared according to the present invention were tested for drug release in 0. IN HCl for 2hours followed by phosphate buffer having pH 6.8 using USP apparatus 2 with paddle speed at 75 rpm. The samples of the media were periodically withdrawn and spectrophotometrically analyzed for pantoprazole content. The dissolution profile is given in Table 1 below:
Table-l
Claims
1. A stable formulation comprising: i. a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii. an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii. an enteric coating over the sub coating.
2. A stable formulation as claimed in claim 1, wherein core composition further comprises one or more excipients selected from lubricants, binder and surfactants.
3. A stable formulation as claimed in claim 1, wherein the disintegrant is selected from low substituted hydroxypropyl cellulose, microcrystalline cellulose, sodium carboxymethyl cellulose, crosscarmellose sodium, crospovidone or a combination thereof.
4. A stable formulation as claimed in claim 1, wherein the water soluble diluent is selected from lactose, sucrose, dextrose, mannitol, sorbitol or a combination thereof.
5. A stable formulation as claimed in claim 1, wherein the alkaline reacting compound is selected from calcium carbonate, magnesium carbonate, magnesium oxide, sodium carbonate, sodium bicarbonate or a combination thereof.
6. A stable formulation as claimed in claim 2, wherein the binder is selected from hydroxypropylcellulose, hydroxypropylmethylcellulose, polyvinylpyrrolidone starch or a combination thereof.
7. A stable formulation as claimed in claim 2, wherein the lubricant is selected from sodium stearyl fumarate, magnesium stearate, calcium stearate, hydrogenated vegetable oil, stearic acid, glyceryl behenate or talc.
8. A stable formulation as claimed in claim 1, wherein the slightly water soluble substance is selected from colloidal silicon dioxide, magnesium oxide, calcium silicate, magnesium hydroxide, aluminium hydroxide, sucrose fatty acid esters, sodium carbonate or a combination thereof.
9. A stable formulation as claimed in claim 1, wherein the dispersing agent is selected from polyethylene-propylene glycol copolymer, polyoxyethylene stearates, poly sorbates, propylene glycol or polyvinyl alcohol.
10. A stable formulation as claimed in claim 1, wherein the enteric coating composition comprises of enteric polymer, plastisizer and anti-sticking agent.
11. A stable formulation as claimed in claim 10, wherein the enteric polymer is selected from cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose acetate succinate, cellulose acetate butyrate, hydroxypropylmethylcellulose phthalate, methacrylic acid and ethyl acrylate copolymer or a combination thereof.
12. A stable formulation as claimed in claim 10, wherein the plasticizer is selected from diethyl phthalate, dibutyl phthalate, cetyl alcohol, polyethylene glycol, triethyl citrate or triacetin.
13. A stable formulation as claimed in claim 10, wherein the anti-sticking agent is selected from talc or magnesium stearate.
14. A process for the preparation of a stable formulation comprising: i) a core comprising pantoprazole or its pharmaceutically acceptable salts, at least one disintegrant, one water soluble diluent and an alkaline reacting compound, ii) an inert sub coating comprising a dispersion of fine particles of slightly water soluble substance over ethylcellulose and iii) an enteric coating over the sub coating, which comprises the following steps: 1) blending pantoprazole, disintegrant, water soluble diluent, alkaline reacting compound and other excipients,
2) granulating the blend with binder solution,
3) drying the granules and then blending the dried granules with extra granular excipients,
4) lubricating the blended granules of step (3) and then compressing it to obtain tablets,
5) coating the tablets of step (4) with the coating suspension of ethylcellulose, slightly water soluble substance and dispersing agent in a solvent and finally 6) coating the sub coated tablets of step (5) with the enteric coating suspension.
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| IN1380/CHE/2006 | 2006-08-03 | ||
| IN1380CH2006 | 2006-08-03 |
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric-coated tablet and preparation method thereof |
| CN105380919A (en) * | 2015-11-20 | 2016-03-09 | 世贸天阶制药（江苏）有限责任公司 | Pantoprazole sodium enteric-coated tablet and preparation method thereof |
| CN112020370A (en) * | 2018-03-22 | 2020-12-01 | Bcm特别有限公司 | preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5945124A (en) * | 1995-07-05 | 1999-08-31 | Byk Gulden Chemische Fabrik Gmbh | Oral pharmaceutical composition with delayed release of active ingredient for pantoprazole |
| US20040146558A1 (en) * | 2003-01-28 | 2004-07-29 | Kyowa Pharmaceutical Co., Ltd. | Oral enteric-coated preparation |
| AU2005225283B2 (en) * | 2004-03-26 | 2008-09-18 | Eisai R&D Management Co., Ltd. | Controlled-release pharmaceutical composition and method for producing the same |
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2007
- 2007-07-30 WO PCT/IB2007/002176 patent/WO2008015530A2/en active Application Filing
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102406656A (en) * | 2011-11-21 | 2012-04-11 | 南开大学 | Sodium bicarbonate enteric-coated tablet and preparation method thereof |
| CN105380919A (en) * | 2015-11-20 | 2016-03-09 | 世贸天阶制药（江苏）有限责任公司 | Pantoprazole sodium enteric-coated tablet and preparation method thereof |
| CN112020370A (en) * | 2018-03-22 | 2020-12-01 | Bcm特别有限公司 | preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008015530A3 (en) | 2009-02-26 |
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