ZA200600432B - Pharmaceutical compositions having a swellable coating - Google Patents
Pharmaceutical compositions having a swellable coating Download PDFInfo
- Publication number
- ZA200600432B ZA200600432B ZA200600432A ZA200600432A ZA200600432B ZA 200600432 B ZA200600432 B ZA 200600432B ZA 200600432 A ZA200600432 A ZA 200600432A ZA 200600432 A ZA200600432 A ZA 200600432A ZA 200600432 B ZA200600432 B ZA 200600432B
- Authority
- ZA
- South Africa
- Prior art keywords
- dosage form
- coating
- core
- pharmaceutical
- swellable
- Prior art date
Links
- 238000000576 coating method Methods 0.000 title claims description 141
- 239000011248 coating agent Substances 0.000 title claims description 130
- 239000008194 pharmaceutical composition Substances 0.000 title description 5
- 239000002552 dosage form Substances 0.000 claims description 106
- 238000009505 enteric coating Methods 0.000 claims description 73
- 239000002702 enteric coating Substances 0.000 claims description 73
- 229920002494 Zein Polymers 0.000 claims description 54
- 239000005019 zein Substances 0.000 claims description 54
- 229940093612 zein Drugs 0.000 claims description 54
- 238000000034 method Methods 0.000 claims description 45
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 37
- 239000007884 disintegrant Substances 0.000 claims description 35
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 34
- 239000012530 fluid Substances 0.000 claims description 33
- 229960000913 crospovidone Drugs 0.000 claims description 27
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 27
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 27
- 239000000416 hydrocolloid Substances 0.000 claims description 23
- 239000002253 acid Substances 0.000 claims description 21
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 18
- 235000010980 cellulose Nutrition 0.000 claims description 17
- 229920002678 cellulose Polymers 0.000 claims description 17
- 239000007787 solid Substances 0.000 claims description 17
- 239000000126 substance Substances 0.000 claims description 17
- 239000000463 material Substances 0.000 claims description 16
- 239000001913 cellulose Substances 0.000 claims description 14
- 229920002472 Starch Polymers 0.000 claims description 13
- 239000004014 plasticizer Substances 0.000 claims description 13
- 235000019698 starch Nutrition 0.000 claims description 13
- 210000002784 stomach Anatomy 0.000 claims description 13
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 12
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 12
- 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 12
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 12
- 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 claims description 11
- 229960000381 omeprazole Drugs 0.000 claims description 11
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 10
- 235000010443 alginic acid Nutrition 0.000 claims description 10
- 229920000615 alginic acid Polymers 0.000 claims description 10
- 239000002775 capsule Substances 0.000 claims description 10
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 10
- HYZJCKYKOHLVJF-UHFFFAOYSA-N 1H-benzimidazole Chemical compound C1=CC=C2NC=NC2=C1 HYZJCKYKOHLVJF-UHFFFAOYSA-N 0.000 claims description 9
- 229920001817 Agar Polymers 0.000 claims description 9
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 9
- 235000010419 agar Nutrition 0.000 claims description 9
- 229920000642 polymer Polymers 0.000 claims description 9
- 229920001577 copolymer Polymers 0.000 claims description 8
- 210000002249 digestive system Anatomy 0.000 claims description 8
- 229960005019 pantoprazole Drugs 0.000 claims description 8
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 8
- JIGUQPWFLRLWPJ-UHFFFAOYSA-N Ethyl acrylate Chemical compound CCOC(=O)C=C JIGUQPWFLRLWPJ-UHFFFAOYSA-N 0.000 claims description 7
- 230000015572 biosynthetic process Effects 0.000 claims description 7
- -1 hydroxypropyl Chemical group 0.000 claims description 7
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 7
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 7
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 7
- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 claims description 6
- 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 claims description 6
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 229960004770 esomeprazole Drugs 0.000 claims description 6
- SUBDBMMJDZJVOS-DEOSSOPVSA-N esomeprazole Chemical compound C([S@](=O)C1=NC2=CC=C(C=C2N1)OC)C1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-DEOSSOPVSA-N 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 239000004094 surface-active agent Substances 0.000 claims description 6
- 241000206672 Gelidium Species 0.000 claims description 5
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 5
- 229920002125 Sokalan® Polymers 0.000 claims description 5
- 239000000783 alginic acid Substances 0.000 claims description 5
- 229960001126 alginic acid Drugs 0.000 claims description 5
- 150000004781 alginic acids Chemical class 0.000 claims description 5
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 5
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 5
- 235000011010 calcium phosphates Nutrition 0.000 claims description 5
- 235000010987 pectin Nutrition 0.000 claims description 5
- 239000001814 pectin Substances 0.000 claims description 5
- 229920001277 pectin Polymers 0.000 claims description 5
- 235000020712 soy bean extract Nutrition 0.000 claims description 5
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 claims description 5
- 229920001800 Shellac Polymers 0.000 claims description 4
- 239000008272 agar Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 4
- 229920000058 polyacrylate Polymers 0.000 claims description 4
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 claims description 4
- 239000011347 resin Substances 0.000 claims description 4
- 229920005989 resin Polymers 0.000 claims description 4
- 239000004208 shellac Substances 0.000 claims description 4
- 229940113147 shellac Drugs 0.000 claims description 4
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 claims description 4
- 235000013874 shellac Nutrition 0.000 claims description 4
- 230000000717 retained effect Effects 0.000 claims description 3
- 238000011049 filling Methods 0.000 claims description 2
- 230000036571 hydration Effects 0.000 claims description 2
- 238000006703 hydration reaction Methods 0.000 claims description 2
- 229960003174 lansoprazole Drugs 0.000 claims description 2
- MJIHNNLFOKEZEW-UHFFFAOYSA-N lansoprazole Chemical compound CC1=C(OCC(F)(F)F)C=CN=C1CS(=O)C1=NC2=CC=CC=C2N1 MJIHNNLFOKEZEW-UHFFFAOYSA-N 0.000 claims description 2
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims 1
- 229960004157 rabeprazole Drugs 0.000 claims 1
- 229920002554 vinyl polymer Polymers 0.000 claims 1
- 239000003826 tablet Substances 0.000 description 69
- 108010055615 Zein Proteins 0.000 description 50
- 239000000203 mixture Substances 0.000 description 39
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 30
- 229940079593 drug Drugs 0.000 description 30
- 239000003814 drug Substances 0.000 description 30
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 25
- 229930195725 Mannitol Natural products 0.000 description 25
- 239000000594 mannitol Substances 0.000 description 25
- 235000010355 mannitol Nutrition 0.000 description 25
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 18
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 16
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 16
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 16
- 239000008188 pellet Substances 0.000 description 16
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 16
- 239000000243 solution Substances 0.000 description 16
- 239000001069 triethyl citrate Substances 0.000 description 16
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 16
- 235000013769 triethyl citrate Nutrition 0.000 description 16
- 239000008187 granular material Substances 0.000 description 15
- 239000004615 ingredient Substances 0.000 description 15
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 14
- 239000012634 fragment Substances 0.000 description 13
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- 239000000454 talc Substances 0.000 description 12
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- 235000012222 talc Nutrition 0.000 description 12
- 238000001035 drying Methods 0.000 description 11
- 230000000968 intestinal effect Effects 0.000 description 11
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- 238000009472 formulation Methods 0.000 description 10
- 238000013467 fragmentation Methods 0.000 description 10
- 238000006062 fragmentation reaction Methods 0.000 description 10
- 239000000047 product Substances 0.000 description 10
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 9
- 239000004408 titanium dioxide Substances 0.000 description 9
- ZGDLVKWIZHHWIR-UHFFFAOYSA-N 4-[5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl]morpholine Chemical compound O1C(C)(C)C(C)(C)OB1C1=CC=C(N2CCOCC2)N=C1 ZGDLVKWIZHHWIR-UHFFFAOYSA-N 0.000 description 8
- RWRDLPDLKQPQOW-UHFFFAOYSA-N Pyrrolidine Chemical compound C1CCNC1 RWRDLPDLKQPQOW-UHFFFAOYSA-N 0.000 description 8
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- 230000002378 acidificating effect Effects 0.000 description 8
- 239000010408 film Substances 0.000 description 8
- 239000000976 ink Substances 0.000 description 8
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 8
- 229960001778 rabeprazole sodium Drugs 0.000 description 8
- 230000008961 swelling Effects 0.000 description 8
- 229920003134 Eudragit® polymer Polymers 0.000 description 7
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 7
- 235000019359 magnesium stearate Nutrition 0.000 description 7
- 229940057948 magnesium stearate Drugs 0.000 description 7
- 239000002245 particle Substances 0.000 description 7
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- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229920003072 Plasdone™ povidone Polymers 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 6
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- KWORUUGOSLYAGD-YPPDDXJESA-N esomeprazole magnesium Chemical compound [Mg+2].C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C.C([S@](=O)C=1[N-]C2=CC=C(C=C2N=1)OC)C1=NC=C(C)C(OC)=C1C KWORUUGOSLYAGD-YPPDDXJESA-N 0.000 description 6
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- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 6
- 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 6
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- 238000004090 dissolution Methods 0.000 description 4
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- PCYQQSKDZQTOQG-NXEZZACHSA-N dibutyl (2r,3r)-2,3-dihydroxybutanedioate Chemical compound CCCCOC(=O)[C@H](O)[C@@H](O)C(=O)OCCCC PCYQQSKDZQTOQG-NXEZZACHSA-N 0.000 description 3
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- UHVMMEOXYDMDKI-JKYCWFKZSA-L zinc;1-(5-cyanopyridin-2-yl)-3-[(1s,2s)-2-(6-fluoro-2-hydroxy-3-propanoylphenyl)cyclopropyl]urea;diacetate Chemical compound [Zn+2].CC([O-])=O.CC([O-])=O.CCC(=O)C1=CC=C(F)C([C@H]2[C@H](C2)NC(=O)NC=2N=CC(=CC=2)C#N)=C1O UHVMMEOXYDMDKI-JKYCWFKZSA-L 0.000 description 3
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- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
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- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 2
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- 235000021314 Palmitic acid Nutrition 0.000 description 2
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- WVWZXTJUCNEUAE-UHFFFAOYSA-M potassium;1,2-bis(ethenyl)benzene;2-methylprop-2-enoate Chemical compound [K+].CC(=C)C([O-])=O.C=CC1=CC=CC=C1C=C WVWZXTJUCNEUAE-UHFFFAOYSA-M 0.000 description 1
- 230000002035 prolonged effect Effects 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 150000003856 quaternary ammonium compounds Chemical class 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 235000015424 sodium Nutrition 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical compound O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 239000001488 sodium phosphate Substances 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
- JGMJQSFLQWGYMQ-UHFFFAOYSA-M sodium;2,6-dichloro-n-phenylaniline;acetate Chemical compound [Na+].CC([O-])=O.ClC1=CC=CC(Cl)=C1NC1=CC=CC=C1 JGMJQSFLQWGYMQ-UHFFFAOYSA-M 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000010902 straw Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 239000007885 tablet disintegrant Substances 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 235000010487 tragacanth Nutrition 0.000 description 1
- 239000000196 tragacanth Substances 0.000 description 1
- 229940116362 tragacanth Drugs 0.000 description 1
- KBPHJBAIARWVSC-XQIHNALSSA-N trans-lutein Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C(=CC(O)CC2(C)C)C KBPHJBAIARWVSC-XQIHNALSSA-N 0.000 description 1
- VLPFTAMPNXLGLX-UHFFFAOYSA-N trioctanoin Chemical compound CCCCCCCC(=O)OCC(OC(=O)CCCCCCC)COC(=O)CCCCCCC VLPFTAMPNXLGLX-UHFFFAOYSA-N 0.000 description 1
- 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
- OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 description 1
- 210000002438 upper gastrointestinal tract Anatomy 0.000 description 1
- 239000001993 wax Substances 0.000 description 1
- 230000003313 weakening effect Effects 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- FJHBOVDFOQMZRV-XQIHNALSSA-N xanthophyll Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)CC(O)CC1(C)C)C=CC=C(/C)C=CC2C=C(C)C(O)CC2(C)C FJHBOVDFOQMZRV-XQIHNALSSA-N 0.000 description 1
- 235000008210 xanthophylls Nutrition 0.000 description 1
Description
PHARMACEUTICAL COMPOSITIONS HAVING A SWELLABLE COATING
Throughout this application, several patent and other documents are mentioned. The contents of these documents are hereby incorporated by reference.
The invention relates to solid pharmaceutical dosage forms having coatings that protect contained pharmaceutical active ingredients against degradation by acidic gastric fluid. In particular, the dosage forms have coatings comprising substances that swell upon contact with aqueous fluids.
A number of pharmaceutical active ingredients are not chemically stable in acidic environments. For this reason, oral administration cannot be effective without some means for protecting the substances against contact with gastric ‘ fluid. This, however, also has the generally undesired effect of delaying availability of the substance to the body, since systemic absorption will not commence until the substance has been released from its dosage form.
Approaches have been devised to protect pharmaceutical dosage forms from being affected by the acidic stomach contents, and permitting active ingredients to be made available only after the dosage form enters a more alkaline environment, such as in the duodenum, jejunum, or ileum. This typically involves coating the dosage form or particles containing an active pharmaceutical agent with a material that resists acid attack, but dissolves or becomes permeable in a more alkaline environment.
Lovgren et al., in U.S. Patent 4,786,505, describe a stable pharmaceutical preparation of omeprazole that resists acid attack, but dissolves rapidly in neutral or alkaline media. Particles of omeprazole are mixed with a water-soluble alkaline-reacting substance and the particles are coated with a “separating layer that acts as a pH buffering zone to prevent contact of the drug and acidic groups that are present in the final coating material. Finally, the bi-layered composition is coated with an enteric polymer coating that does not react with acids.
U.S. Patent 5,035,899 to Saeki et al. relates to compositions of acid- unstable drugs, which are protected against contact with gastric acid. A core that contains the drug is coated first with fine particles of a material having a low water solubility, then are coated with an enteric fiim-forming material such as ethylcellulose.
Mazer et al., in U.S. Patent 5,160,742, discloses a sustained release system for an acid-sensitive drug such as a g-lactam antibiotic. Coated drug particles, suitable for inclusion in syrups or other formulations are prepared by forming a core that contains the drug, coating the core with a prolamine, and applying a final exterior coating of an enteric substance such as a methacrylic acid copolymer. Optionally, an additional coating of prolamine can be applied onto the : enteric coating layer. The drug is released over a prolonged time, beginning after the coated particles enter a high-pH environment.
U.S. Patent 5472,712 to Oshlack et al. teaches controlled release formulations having drug-containing core and a controlled release hydrophobic coating of ethylcellulose, optionally containing a hydrophilic pore forming substance such as hydroxypropyl methylcellulose. Optionally, the cores can have an intermediate ‘bamier’ coating of a substance such ‘as hydroxypropyl methylcellulose, which preferably does not affect the dissolution rate of the final product.
In U.S. Patent 5,609,909 to Meyer et al., oral formulations in which the unpleasant taste of a drug substance is masked, but in which the drug is immediately bioavailable upon exposure to acidic fluid in the stomach, are prepared by coating a drug-containing core particle with a mixture of a prolamine and a nonpolymeric plasticizer.
U.S. Patent 5,811,388 to Friend et al. teachés the preparation of a dosage form in which drug is not released to the upper gastrointestinal tract, but is released in the lower gastrointestinal tract for directly treating diseases of the colon. The dosage form includes a core tablet containing the drug and a large amount of a plant-derived hydrocolloid, optionally coated with a film of an enteric substance.
Lemer et al. describe, in U.S. Patent 5,840,332, a composition that delivers a drug to a particular portion of the gastrointestinal tract, wherein a drug- containing core is coated with a water-insoluble material having embedded particles of water-insoluble hydrophilic matter. The coated core can optionally be further coated with an enteric polymer.
U.S. Patent 6,346,269 to Hsiao et al. teaches 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, then an enteric coating is applied over the drug substance layer.
Methods for the production of films, sheets, and articles from zein are taught in U.S. Patent 6,635,206 to Padua et al.
A need exists for a drug-containing dosage form in which drug substances - will not be exposed to acid in the stomach, but will be rapidly released when the dosage form enters a more alkaline environment.
In one embodiment, the invention includes a pharmaceutical dosage form comprising: a solid core comprising a pharmaceutical active and a disintegrant; a swellable coating surrounding the core; and an enteric coating surrounding the swellable coating. The dosage form can have different embodiments, including coated tablets or capsules containing coated pellets or coated minitablets.
A preferred aspect of the invention is a dosage form in which the pharmaceutical active is substantially retained while the dosage form is present in the stomach, but where the pharmaceutical active is rapidly released after the dosage form enters an environment having a pH value at least about 5.
Also included in the invention is a pharmaceutical dosage form comprising: a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant; a swellable coating comprising a hydrocolloid-forming component, surrounding the core; and an enteric coating surrounding the swellable coating.
The invention further includes a pharmaceutical dosage form comprising: a solid core comprising a benzimidazole and a disintegrant; a swellable coating comprising one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl celiulose, surrounding the core: and an enteric coating comprising a copolymer of methacrylic acid and ethyl acrylate, surrounding the swellable coating.
Another aspect of the invention is a method of treating a medical condition comprising orally administering a pharmaceutical dosage form according to any of the preceding aspects and embodiments, in which method: the dosage form remains substantially intact during stomach transit; the enteric coating is removed in digestive system environments having pH values above about 5; aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; aqueous fluids pass through the hydrocolloid to hydrate the core; and the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form.
Further, the invention includes a method of preparing a pharmaceutical dosage form, comprising the steps of: combining components comprising a phamaceutical active and a disintegrant, and forming a solid core; coating the core with a swellable coating comprising a hydrocollioid-forming component; and applying an outer coating comprising an acid-resistant enteric substance.
Preferred swelling agents in the swellable coating include prolamines; vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar; and gums. Zein, crospovidone, or a hydroxypropyi cellulose are more preferred for use as the swelling agent.
The subject invention provides a pharmaceutical dosage form comprising a core that comprises a pharmaceutical active ingredient, and a swellable coating surrounding the core. The core comprises at least 50%, at least 60%, at least 70%, preferably at least 80%, preferably at least 82.5%, preferably at least 85%, preferably at least 87%, preferably at least 88%, preferably at least 89% of the total pharmaceutical composition. The core may also comprise at least 90%, at least 91%, at least 92% or at least 93% of the total pharmaceutical composition.
In this application, the terms “pharmaceutical active ingredient” “pharmaceutical active” and “active” are used interchangeably to refer to a component of a pharmaceutical dosage form that provides a therapeutic effect upon administration to a subject. This invention is particularly applicable to acid- sensitive pharmaceutical actives, which exhibit instability in a low-pH environment, such as the benzimidazole derivatives, including their optically active isomers.
Specific examples of useful benzimidazole compounds include rabeprazoie, omeprazole, esomeprazole, lansoprazole, and pantoprazole. Other drugs for which the invention will be useful include, without limitation thereto:
pharmaceutical actives that react with enteric coating components, examples being drugs that form insoluble complexes with the enteric coatings, such as fluoxetine and duloxetine; and highly alkaline drugs that can react with acidic groups to reduce the acid-insolubility of the coating, such as diclofenac sodium and piroxicam.
As contemplated herein, a “swellable coating” is a coating that increases in volume upon contact with aqueous fluids. This swelling usually occurs through imbibition of water. The swellable coating adds 0.1-10%, 0.5-8%, 0.7-7%, 1-5%, 1.3-3%, 1.5-2%, about 2%, or about 1.5% to the weight of the core. In another embodiment, the sweliable coating adds 0.1- 5%, 0.1- 4%, 0.1- 3%, 0.1-2%, or 0.1-1% to the weight of the core.
Generally, the swellable coating, upon wetting, becomes a hydrocolloid, which is a gelatinous suspension of microscopic particles in water. Preferably, the hydrocolloid is formed from a prolamine, such as gliadan, hordein, or, more preferably, zein. Zein is extracted from com as a granular, straw to pale yellow colored amorphous powder or fine flakes and various commercial extracts have molecular weights in the range of 25,000-35,000. Zein is insoluble in water and insoluble in alcohols, but soluble in aqueous alcohol solutions. Chemically, zein is fairly abundant in glutamine and devoid of lysine and tryptophan. Zein comprises about 20-22% glutamic acid and glutamine, 17-20% leucine, 5-9% proline, 8-10% alanine, 4-7% phenylalanine, 3-7% isoleucine, 4-6% serine, 4-5% asparginine and 3-6% tyrosine. All of the other amino acids in zein each comprise less than 3%.
Zein has been generally recognized as safe (GRAS) by the United States Food and Drug Administration since March, 1985 for use in food and pharmaceutical products. Zein is available commercially from several sources, including Freeman
Industries LLC, Tuckahoe, New York USA; among the commercial zein products sold by this company are those designated Zein F4000, Zein 4400, Zein F6000,
Zein G-10, Aqua Zein, and Aqua Zein Neutral.
A presently preferred zein for the present invention is the Zein F6000, which has been re-extracted to reduce its color (from xanthophyll) level. Zein
F6000 is a very light yellow granular powder with an approximate molecular weight of 35,000 and a bulk density of 0.125-0.21 g/ml. It contains 90-96% zein protein, calculated on a dry basis.
The hydrocolloid can also be formed from a hydroxypropyl methylcellulose.
The viscosity of a 2 weight percent aqueous solution of various hydroxypropyl methylcellulose products ranges from about 4,000 mPa-s to about 100,000 mPa:-s.
In one embodiment, the hydroxypropyl methylcellulose is United States
Pharmacopeia Substitution Type 2208, also called hypromellose 2208, with a viscosity of about 15,000 mPa-s, which is commercially available as Methocel
K15M. In another embodiment, the hydroxypropyl methylcellulose is United
States Pharmacopeia Substitution Type 2910, also known as hypermeliose 2910, with a viscosity of about 4,000 mPa-s, which is marketed as Methocel E4M.
METHOCEL is a trademark of Dow Chemical Company, Midland, Michigan U.S.A.
Other useful substances for forming a hydrocolloid include, without limitation, crospovidone; croscammellose sodium; cellulose derivatives such as hydroxyethyicellulose, hydroxypropyl cellulose, or methylceliulose; gums such as seaweed extracts, plant extracts, plant exudates, plant seed extracts, and 1S microbial fermentation products; starches including pregelatinized and modified starches; and synthetics such as carboxyvinyl polymers, including carbopols.
Additional specific examples include alginates, pectins, low methoxy pectins, agar, carrageenan, plus arabic, tragacanth, karaya, ghatti, locust bean (carob), guar, dextran, xanthan, carrageenan, tara, Khaya grandfolia, gellan, Konjac mannan, galactomannan, funoran, acetan, welan, rhamsan, furcelleran, succinoglycan, scieroglycan, schizophylan, curdlan, pullulan, karaya and tamarind gums.
In addition to the pharmaceutical active, the core further comprises a disintegrant that, in an aqueous environment, assists in the physical fragmentation of any material with which is it combined. A disintegrant does not promote dissolution or a chemical change in the material being fragmented. The following are examples of useful disintegrants: starches such as potato or tapioca starch, modified starches (such as sodium starch glycolate) and partially pregelatinized starches (such as Starch 1500); polyvinylpyrrolidones, including modified polyvinylpyrrolidones (such as crospovidone, polymerized under conditions that promote crosslinking); celluloses such as microcrystalline cellulose, modified celluloses (such as low substituted hydroxypropyl cellulose, croscarmellose sodium and calcium carboxymethyl cellulose); formaldehyde-casein compounds (such as Esma-Spreng.RTM); resins, such as the polacrilin potassium sold by
Rohm and Haas Company, Philadelphia, Pennsylvania U.S.A., using the trademark AMBERLITE IRP88; defatted soybean extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; and sodium carbonate. U.S. Patent 6,696,085 to Rault et al. teaches that acrylic polymers are useful as tablet disintegrants.
In addition to the foregoing, the core can contain any desired components such as binders, lubricants, antioxidants, etc., as are well known in the art and further discussed below.
The pharmaceutical dosage form further comprises an enteric coating surrounding the swellable coating. An “enteric coating” is a coating that is substantially insoluble at the acidic pH conditions of the stomach but is substantially soluble or water-pemmeable at the higher pH conditions of the intestines. In this invention, the enteric coating protects the swellable coating against contact with the acidic stomach environment but permits contact of the swellable coating with the more alkaline intestinal fluid. The enteric coating can be chosen to provide targeted release to a particular section of the intestine. For instance, an enteric coating can provide delivery to the duodenum (pH > 5.5), to the jejunum (pH 6-7), or to the ileum (pH up to 7.5). Intermediate delivery points can be achieved by combining different coating materials or varying the thickness of the coating. Enteric coating materials include cellulose-based coatings, such as cellulose acetate phthalate and hydroxypropylmethyl cellulose phthalate, methacrylate-based coatings, polyvinyl acetate phthalate-based coatings, and shellac-based coatings.
In the present invention, methacrylate-based coatings are preferred and several useful products are commercially available from R8hm GmbH & Co.,
Darmstadt, Germany under the trademark EUDRAGIT. Eudragit L100-55 is especially preferred. Eudragit L 100-55 is a powder, spray-dried Eudragit L 30 D- 55 which can be reconstituted. Eudragit L 30 D-55 is an aqueous dispersion of a pH dependent polymer soluble at or above pH 5.5 for targeted delivery in the duodenum. Eudragit L 100-55 retains the pH dependency of Eudragit L. 30 D-55 and thus, is soluble at or above pH 5.5 and provides delivery to the duodenum.
Eudragit L 100-55 and Eudragit L 30 D-55 are copolymers of methacrylic acid and ethyl acrylate in a 1:1 rato. They have the molecular formula: (CsH202-C4HeOz2) and have been assigned the Chemical Abstracts Registry No.
25212-88-8. Eudragit L100-55 also meets the United States Pharmacopeia specificiation for Methacrylic Acid Copolymer Type C.
In one embodiment, the enteric coating comprises 1-40%, 3-35%, 5-30%, 6-20%, or 7-10% or 8% of the total composition. In another embodiment, the enteric coating comprises at most 20%, at most 17.5%, at most 15%, at most 12.5%, at most 10%, at most 9%, at most 8%, at most 7%, at most 6%, at most 5%, or at most 4% of the total composition.
Optionally, an excipient that modulates the release of the pharmaceutical active is added to the swellable coating. Modulation may be achieved by facilitating or impeding the access of water to the core. Useful excipients include plasticizers such as lactic acid, lactic acid acetamide, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, dibutyl tartrate, ethylene glycol monooleate, palmitic acid, stearic acid, oleic acid, dibutyl sebacate, aceylated monoglycerides, and other oils and waxes, as well as polyethylene glycol 300, 400, 600, 1450, 3350 and 8000. Additional excipients that modulate the rate of release of the active include water soluble surfactants, such as sodium lauryl sulfate and docusate sodium, and enteric coating materials, such as Eudragit L 100-55, which are mixed into the swellable coating.
Without being limited to any single theory of operation, it is believed that enteric coating material incorporated in the swellable coating dissolves upon contact with the intestinal fluid and forms channels in the swellable coating, which facilitate the entry of the intestinal fluids into the core. In one embodiment, the enteric coating material constitutes about 0.1-30%, 0.5-20%, 1-17.5%, preferably 5-15%, or more preferably 5-10% of the swellable coating. In another embodiment, the enteric coating material comprises 10-50%, 15-40%, preferably 20-30% of the swellable coating.
Again, without being limited to any theory, it is postulated that the water soluble surfactant causes rapid wetting of the swellable coating upon exposure to the intestinal fluids, thereby assisting entry of fluid into the core. When the water soluble surfactant is present, it constitutes about 0.001-30%, 0.005-20%, 0.01- 10%, 0.03-8%, 0.05-6%, 0.074%, 0.09-2%, or 0.1-1% by weight of the swellable coating. A preferred range is 0.01-10%.
For instance, where zein is present in the swellable coating, the extent of the swelling controls its permeability and the greatest permeation is achieved at the largest swelling volume. See Y. K. Oh et al, “Swelling and Permeability
Characteristics of Zein Membranes,” PDA Joumal of Pharmaceutical Science and
Technology, Vol. 57, pages 208-217 (2003) for additional information concerning diffusion through hydrated zein films.
The addition of plasticizers to zein affects its permeability to water. The combination of zein with hygroscopic plasticizers such as glycerol, triethyelene glycol, and levulinic acid produces more water absorption than in unplasticized zein. However, incorporating into zein hydrophobic plasticizers such as dibutyl tartrate and oleic acid results in less water absorption than unplasticized zein.
The greater the degree of water permeation, the weaker the tensile strength and the coating can simply give way to provide full release of the pharmaceutical active. See J. W. Lawton, “Plasticizers for Zein: Their Effect on Tensile
Properties and Water Absorption of Zein Films,” Cereal Chemistry, Vol. 81, pages 1-5 (2004) for a discussion of the water absorption characteristics of cast plasticized zein films.
The modulation of the release profile of the pharmaceutical active by an excipient, such as a plasticizer, is not limited to zein. In general, varying the amount and type of plasticizer affects the tensile strength of coatings. The use of hygroscopic versus hydrophobic excipients also affects the release profile in the same manner as discussed regarding zein.
To form the cores of the invention, the pharmaceutical active is blended with one or more pharmaceutically acceptable carriers, such as water, saline, sodium citrate or dicalcium phosphate, and/or any of the following: fillers or extenders, such as starch, lactose, sucrose, glucose, mannitol, or silicic acid; binders, such as carboxymethyiceliulose, alginates, gelatin, copolyvidonum (such as the PLASDONE™ S-630 copolymer of N-vinyl-2-pyrrolidone and vinyl acetate, sold by Intemational Specialty Products, Wayne, New Jersey U.S.A,), copolymers of ethylene oxide and propylene oxide such as Poloxamer 407, sucrose, or acacia; humectants, such as glycerol; disintegrants, such as starch, polyvinyl pyrrolidones, celluloses, formaldehyde-casein compounds, defatted soybean extracts, alginic acid, agar-agar, calcium carbonate, calcium phosphate, potato or tapioca starch or sodium carbonate; lubricants such as talc, calcium stearate,
magnesium stearate or solid polyethylene glycol; solution retarding agents, such as paraffin; absorption accelerators, such as quaternary ammonium compounds; wetting agents, such as cetyl alcohol and glycerol monostearate; surfactants, such as sodium lauryl sulfate or docusate sodium; absorbents, such as kaolin or bentonite clay; and stabilizing agents. The phamaceutical active may also be blended with buffering agents such as alkali metal carbonates and alkaline earth metal oxides. This listing is not exhaustive, many other functional components that are known in the art will also be useful in the present invention. © The cores of the invention may be in the form of tablets, minitablets, granules, particulates or pellets. The tablets and minitablets can be manufactured by direct compression or any other process known to those of skill in the art. Dry granulation, wet granulation, melt granulation, or any other process known to those of skill in the art may be used to form granules. The particulates and pellets may be manufactured by any method known to those of skill in the art, such as extrusion or spheronization. Pellets may also be made by melt pelletization or by coating non-pareil seeds. Wet cores are dried by conventional drying procedures such as air drying, or drying under heated and/or low pressure conditions.
The cores of invention are coated with a swellable coating, followed by the application of an outer enteric coating. In general, coatings may be applied by any techniques known in the art, such as pan coating (including perforated closed system pan coating), coacervation, or fluidized bed coating. The fluidized bed may contain a rotor insert and/or a Wurster column insert. The coatings can be generally classified according to their polymer base, such as: cellulose-based, including cellulose acetate phthalate, hydroxypropylimethyi cellulose phthalate, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydroxypropylethyl cellulose, ethyl cellulose, methyl cellulose, microcrystalline cellulose; carrageenan; methacrylate- or methacrylic acid-based, such as methacrylic acid, methacrylate, acrylate, methacrylate, ethacrylate, methyimethacrylate, or copolymers thereof; or polyvinyl acetate phthalate-based. Typically, the polymer is combined with a solvent, such as water, and a plasticizer, such as polyethylene glycol, lactic acid, lactic acid, acetamide, glycerin, glyceryl monostearate, triacetin, sorbitol, triethyl citrate, polyvinylpyrrolidone, triethylene glycol, tricresyl phosphate, dibutyl tartrate, ethylene glycol monooleate, palmitic acid, stearic acid, oleic acid, or dibutyl sebacate. Optionally, one may also add any of the following elements:
an anti-tack agent, an anti-foam agent, a filler, a surfactant, a colorant, a flavoring agent, and combinations of any two or more thereof.
Following application of the enteric coating, the pharmaceutical composition may have identifying information printed thereon using inks and procedures known in the art, such as offset gravure printing. Pharmaceutically acceptable inks that may be used with offset gravure printing include Markem™ 2200, 2202, 2212 and 2222, from Markem Corporation, Keene, New Hampshire
USA. These inks are typically shellac-based and contain pigments. Thinners may be added to any of these inks to increase or decrease the drying rate and/or modify the viscosity. Following application, these inks are nomally air dried.
Other pharmaceutically acceptable inks include those products sold as
Opacode™ and Opacode™ WB, both of which contain pigments, titanium dioxide, and a solvent and are sold by Colorcon, West Point, Pennsylvania USA. Many other printing inks are known to those skilled in the art, and any of these will be useful for the dosage forms of the invention.
Optionally, the enteric-coated dosage forms can be further coated with a thin film. Frequently, the film will be colored to facilitate product identification and for esthetic purposes; in this instance, any desired printing of information will be done after the film coating has been applied. Many suitable film coating products are commercially available, including those sold by Colorcon, West Point,
Pennsylvania USA using the OPADRY and OPAGLOS trademarks. These products from Colorcon are dry powders, containing a polymer, plasticizer, and pigment, that are mixed with water or a solvent such as alcohol, and sprayed onto tablets or other solid dosage forms. This film coating procedure, and alternative film coating products, are well known in the art.
The coated tablets, pellets, granules, or particulates may be encased in capsules for ease of administration. The encasement may be accomplished by any method known in the art, such as filling a pre-formed capsule. Such capsules may be comprised of gelatin or any other material known to those of skill in the art.
Without being limited to any theory, it is postulated that after an enteric coating dissolves in the intestine, the swellable coating imbibes intestinal fluids and expands outwardly. Thus, initially, the swellable coating expands like a balloon being inflated and does not burst. As the coating swells, its permeability to water increases. It is hypothesized that the swellable coating contains microchannels, through which water enters by diffusion and reaches the core.
The water causes the core to begin to fragment. Some of these fragments can puncture the swellable coating, leading to the ingress of more water. The additional water produces even more fragmentation of the core, which is thought to cause more fragments to puncture the swellable coating. This cycle is believed to continue until the pharmaceutical active is fully released or until the swellable coating is so weakened by the imbibition that the coating ruptures.
Further without being limited to any theory, it is believed that the release of the active may be modulated by several factors other than the presence of an enteric coating. One such factor is the selection of a hydrocolioid-forming substance in the swellable coating. Hydrocolloids vary in their swelling ability and hence their permeability to intestinal fiuid. The permeability of the hydrocolloid is postulated to affect the hydration rate of the core and the resultant fragmentation of the core. Hydrocolloids also differ in tensile strength, which is thought to affect the percentage of core fragments that are able to puncture the swellable coating upon fragmentation. The number of fragments that are able to achieve egress directly affects the release of the pharmaceutical active. It is also believed that the number of openings created in the swellable coating further affects the release of the active by permitting more intestinal fluid into the core, producing more fragmentation. Tensile strength additionally affects whether and when a swellable coating ruptures due to the weakening caused by the imbibition of water, resulting in complete release of the active. Furthermore, some hydrocolloids erode upon swelling, which affects the ease with which core fragments are able to puncture the swaellable coating.
Another factor can be the optional addition of an excipient to the swellable coating that modulates the release of the pharmaceutical active. Such agents can increase or decrease the permeability of the hydrocolloid to the intestinal fluid.
This permeability affects the amount of intestinal fluid that contacts the core and leads to fragmentation. It is hypothesized that the fragments puncture the swellable coating upon fragmentation, thereby affecting the release of the pharmaceutical active. It is further believed that the openings created in the swellable coating provide conduits for the entry of additional intestinal fluid into the core, further accelerating fragmentation.
A third factor is the use of a disintegrant in the core. The employment of a disintegrant increases the rate of fragmentation of the core, which is thought to raise the frequency with which fragments create voids in the swellable coating.
The sheer increase in fragments exiting through the swellable coating raises the rate of release of the pharmaceutical active. Additionally, the higher number of voids created in the swellable coating is believed to allow more water to enter the core, causing an even greater fragmentation of the active. Furthermore, the disintegrant may augment the force at which the core fragments impact the swellable coating, which may result in more fragments successfully creating voids in the swellable coating. These more forceful disintegrations further raise the rate of release of the pharmaceutical active by allowing a greater number of core fragments to pass through the swellable coating. Such disintegrants also produce additional openings for the intestinal fluid to hydrate and fragment the active, leading to additional release of the active
Although the rate of release of the pharmaceutical active can be modulated as set forth above, this invention does not have an objective of producing sustained release formulations whereby the pharmaceutical active is released at a controlled rate over an extended period of time, such as 12 or 24 hours. Rather, a feature of this invention is a delayed release of ingested pharmaceutical active until the dosage form has reached the intestinal tract, where the alkaline pH conditions will not affect an acid-sensitive pharmaceutical active, then facilitation of a rapid, essentially complete release of the pharmaceutical active for systemic absorption.
The following examples are provided to aid in understanding the invention, and are not intended, and should not be construed, to limit in any manner the invention as defined in the appended claims. In the examples, ingredients that are volatile during drying and therefore not present in the final product are not included in the tabular listings of ingredients; such ingredients, however, are mentioned as solvents, etc. in the preparation procedure discussions. Further, the weight added by printing information on a finished dosage form is insignificant and therefore is not included in the final cumulative weights. Percentages are expressed on a weight basis, unless the context clearly indicates otherwise.
EXAMPLE 1
Tablets containing either 20 or 40 mg of pantoprazole were prepared using the following components and procedure:
Quantity (mg) per | Quantity (mg) per
Ingredients 20 mg Tablet 40 mg Tablet
Core Tablet I __DryMiing 1
Pantoprazole sodium 2255 [ 454
Mannitol (Pearitol SD-200 110.95 221.9 [Crospovidone | 825 | "165 __ Granulation ~~ —
Sodium carbonate anhydrous
Hydroxypropyi cellulose (Klucel LF) | 4 ~~ | =~ 8 = __Lubrication ~~
Crospovidone ~~ | 825 | 165 (Tale ~~ 4s 3
Calcium stearate 2 4 ___ Total [165 | 330
Swellable Coating I
Zein F6000 | 207 | 413
Methacryiic acid copolymer (Eudragit 0.41
L 100-55
Cum. Total 167.48 | 33495
Enteric Coating I
Methacrytic acid copolymer (Eudragit 18.49
L 100-55
Triethyl citrate | 093 | 18
Titanium dioxide | 183 | 365
Tale ~~ 0 A441 281
Cum. Total 180.83 | 36165 (FimCoating ~~ | F/————
Opadry Yellow OY-52945 | 452 | 004
Cum.Total | 185.42 370.79
Printing ~~
Opacode Black 5-1-8152 HV gas. [gs]
Tablet cores were prepared by granulating a dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropyt cellulose (Klucel LF) and sodium carbonate anhydrous. The granulates were dried using conventional drying techniques. The dried granules were then lubricated with crospovidone, talc and calcium stearate. The lubricated granules were compressed into cores. The cores were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol, and dried. Enteric coating on top of the subcoat was performed using Eudragit L 100-55 with isopropyl alcohol as the solvent and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opaquent, respectively. After drying, the enteric coated tablet was film-coated using Opadry Yellow OY-52945 and printed with Opacode Black S-1-8152 HV.
EXAMPLE 2
Tablets containing either 20 or 40 mg of pantoprazole were prepared using the following components and procedure.
Quantity (mg) per | Quantity (mg) per
Ingredients 20 mg Tablet 40 mg Tablet [CoreTablet ~~ [7 __DryMiing
Pantoprazole potassium | 2255 | 454
Mannitol (Pearitol SD-200 110.95 [2219 [Crospovidone | 826 | 165
Granulation ~~ | 1
Sodium carbonate anhydrous
Hydroxypropyl cellulose (Klucel LF) | 4 ~~ | 8 [Lubrication [Crospovidone ~~ | "825 | 165 (Talc ~~ [45 3
Calcium stearate I EA EY SE ___ Total |" 166 | 330
Swellable Coating I ER
Zein F6000
Methacrylic acid copolymer (Eudragit 0.41
L 100-55
Cum. Total | 167.48 | 33495
Enteric Coating I
Methacrylic acid copolymer (Eudragit 18.49
L 100-55
Triethy citrate | 083 [185
Titanium dioxide 18 | "365 [Tale ~~~ = 14 281 ____ Cum.Total | 180.83 361.65 [FilmCoating ~~ — | — 1
Opadry Yellow OY-52945
CumToal | 18542 | 37079
(PAnting | 0 T]
Opacode Black S-1-8152 HV as. [ qs.
Tablet cores were prepared by granulating a dry mix of pantoprazole sodium, mannitol, crospovidone and sodium carbonate with an aqueous solution of hydroxypropyl cellulose (Klucel LF) and sodium carbonate anhydrous. The granulates were dried using conventional drying techniques. The dried granules were lubricated with crospovidone, talc and calcium stearate. The lubricated granules were then compressed into cores. The cores were subcoated with a mixture of zein, Eudragit L 100-55, water, and isopropyl alcohol. After drying, an enteric coating on top of the subcoat was performed using Eudragit L 100-55 with isopropyi alcohol as the solvent and triethyl citrate as the plasticizer. Talc and titanium dioxide were used as the lubricant and the opaquent, respectively.
Then, the dried enteric coated tablet was film-coated using Opadry Yellow OY- 52945 and printed upon with Opacode Black S-1-8152 HV.
EXAMPLE 3
Capsules containing 40 mg of omeprazole were prepared using the following components and procedure:
Ingredients Quantity/Capsule (mg
Core Pellets I (Mannitol ~~ © 53
Crospovidone [4g
Hydroxypropyl methylcellulose, 5¢cps | 8
Poloxamer 407 5 ______ Total [30
Swellable Coating oT
Zein F 6000 62
Enteric Coating ES 1 M—
Hydroxypropyl methylcellulose phthalate (HP 55
Triethylcitrate | gar
Omeprazole core pellets were prepared by mixing omeprazole, mannitol, crospovidone, meglumine and polaxomer and granulating this mixture with hydroxypropyl methylceliulose as a binder. The granules thus obtained were subjected to extrusion and spheronization to produce spherical pellets. The pellets were then dried by conventional drying techniques. The pellets were coated with a swellable coating containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried. The enteric coat was prepared by dissolving hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which was then layered upon the intermediate coating.
The coated pellets were measured into a gelatin capsule.
EXAMPLE 4
Tablets containing 40 mg of omeprazole were prepared using the following ingredients and procedure:
Quantity/Tablet (mg
Core Tablet oT
Omeprazole [40
Mannitol (Pearfitol SD-200 | 2313 [Crospovidone | §
Poloxamer 407 5
Hydroxypropyl methylcellulose, 5 mPa-s
Magnesiumstearate ~~ | 38
Tale ~~ 0000 0 3 __ Total 30
Swellable Coating 7
Zein F 6000 I<
Sodium lauryl sulphate 027 _______ CumTotal | 33
Enteric Coating —
Hydroxypropyl methylcellulose phthalate (HP 55
Triethyi citrate 24
Omeprazole core tablets were prepared by mixing omeprazole, mannitol, crospovidone, meglumine and poloxmer and granulating the mixture with hydroxypropyl methylcellulose as a binder. The granules were dried in fiuid bed drier and the dried granules were compressed into tablets or minitablets. These core tablets or minitablets were coated with intermediate coating solution containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried. The enteric coat was prepared by dissolving hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which was then layered upon intermediate coating.
EXAMPLE 5
Tablets containing 40 mg of pantoprazole were prepared using the following components and procedure:
Quantity/ Tablet (mg
Core Tablet OT
Pantoprazole sodium sesquihydrate 4]
Mannitol (Pearlitol SD-200 143.18
Mannitol (Pearlitol DC-400 47.72
Crospovidone ~~ "465
Plasdone S-630 30 0]
Sodium lauryl sulfate 0 25
Calcium stearate 6
Tale ~~~ 0%
Total 130
Swellable Coating
Zein 00000 3%
Enteric Coating TT
Methacrylic acid copolymer (Eudragit 16.81
L100-55
Triethyl citrate
Titanium dioxide ss ___ Cum.Total | 328.89
Core tablets were prepared by blending pantoprazole sodium sesquihydrate with mannitol, crospovidone, Plasdone S630, talc, and magnesium stearate, and direct compressing into tablets. These core tablets were coated with a swellable coating solution containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl! alcohol and water, then dried. The enteric coat was prepared by dissolving hydroxypropyl methylcellulose phthalate and triethyl citrate in a mixture of isopropyl alcohol and acetone and dispersing talc in this solution, which was then layered upon intermediate coating.
EXAMPLE 6
Capsules containing esomeprazole were prepared using the following components and procedure:
Ingredients Guantity(g)
Pellets ]
Esomeprazole magnesium trihydrate (Mannitol ~~ ~~ | gs
Sodium lauryl sulphate 20 0 [Copovidone ~~ [3p _ Total | T1240
Swellable Coating TT (Zein 0 0000 462
Sodium lauryl sulphate 0 162
Cum To | 1257 82
Enteric Coating 1]
Methacrylic acid copolymer Type C
Triethyl citrate I
Titanium dioxide 15.29 (Tale ~~ 45 __ CumTotal | 1410.61
The core was prepared by mixing esomeprazole magnesium trihydrate, mannitol, crospovidone and sodium lauryl sulphate and granulating this mixture with an aqueous solution of copovidone. The granules were then subjected to extrusion and spheronization to obtain spherical pellets. The pellets were dried by conventional drying techniques. The dried pellets were coated with intermediate coating solution containing zein and sodium lauryl sulphate dissolved in a mixture of isopropyl alcohol and water, then dried. The enteric coat was prepared by dissolving Methacrylic Acid Copolymer Type C and triethyl citrate in isopropyl alcohol and dispersing talc and titanium dioxide in this solution.
0
Coated pellets are filled into gelatin capsules, giving 4000 capsules that each contain 40 mg of esomeprazole.
EXAMPLE 7 5 .
Esomeprazole tablets were prepared, using the following ingredients and procedure.
Ingredients Quantity (mg/tablet
Core Tablet ]
Esomeprazole magnesium trihydrate
Magnesiumoxide ~~ [20
Plasdone S-630
Mannitol (Peariitol SD 200
Colloidal silicon dioxide 35
Sodium stearyl fumarate
Swellable Coating 1]
Zein F6000 68 0]
Cum. Total
Enteric Coating oo ]
Eudragit L100-55
Triethyl citrate
Titanium dioxide 38
Cum. Total 374.5
Esomeprazole magnesium trihydrate, magnesium oxide, copovidone, crospovidone, mannitol, and silicon dioxide were blended, then sodium stearyl fumarate was added with further blending. This mixture was compressed into core tablets. The tablets were coated with an aqueous alcohol solution of zein, then dried. Finally, the enteric coating ingredients were dispersed in water and coated onto the zein-coated tablets, followed by a final drying.
EXAMPLE 8
Tablets containing rabeprazole sodium were prepared using the following components and procedure:
PCT/US2004/022910
Quantity/Tablet (mg
Core Tablet TT
Rabeprazole sodium 20
Mannitol (Peariitol SD 200 972
Mannitol (Peariitol DC 400 28 [Crospovidone ~~ [34
Plasdone S-630 | 105
Tale ~~ 34
Magnesiumstearate ~~ | 24
Swellable Coating SO A—
Zein F6000 | 425
Triethyicitrate | 93
Enteric Coating TT
Methacrylic acid copolymer (Eudragit 12.26
L 100-55
Triethyl citrate | 1224 [Tale ~~ 068 ___ Cum.Total | 188.614
Rabeprazole sodium, crospovidone, Plasdone S630 and mannitol (Pearitol
SD 200) were mixed with mannitol (Peariitol DC 400) for 20 minutes. Talc and magnesium stearate were then added to the mixture and mixed for 5 minutes.
This lubricated blend was then compressed into tablets. The core tablets were subcoated with a water-alcohol solution of zein (weight increase 2.5+0.5%) and dried. The subcoated tablets were coated with enteric coating solution (weight increase 8-9%).
EXAMPLE 9
Rabeprazole sodium tablets were prepared using the following components and procedure:
Ingredients Quantity/Tablet (mg
Core Tablet TT
Rabeprazole sodium 20
Mannitol (Peariitol SD-200 | 9701
Low substituted hydroxypropyl cellulose,
LH21 (“L-HPC* Magnesiumoxide | 5
Sodium lauryl sulfate ds]
Hydroxypropyl methylcellulose, 5mPas | 3 1]
BE -~ SE
Magnesiumstearate ~~ [225
Swellable Coating 0
Zein 6000 49
Triethyl citrate 049 1] _____ CumTotal | 18539
Enteric Coating I
Eudragit L100-55 | 1446
Triethyl citrate | 144 ___ Cum.Total | 202.08
FilmCoating | ————
Opadry Yellow OY-52945 | 505
Printing ~~
Opacode Black qs.
Magnesium oxide was sifted through a 60 mesh sieve. Rabeprazole sodium, L-HPC, mannitol (SD 200) and the sifted magnesium oxide were sifted through a 40 mesh sieve. The materials were then mixed for 30 minutes in a
Rapid mixer granulator. Sodium lauryl sulfate (SLS) was dissolved in purified water and hydroxypropyimethyicsllulose (HPMC) was dissolved in warm purified water. The rabeprazole sodium mixture was mixed with the SLS and HPMC solutions. The wet mass was dried in a fluid bed drier and the dried granules were sifted through a 20 mesh sieve. The sifted granules were blended with L-
HPC in a double cone blender for 5 minutes. Magnesium stearate (sifted through a 60 mesh sieve) was added to the blend and mixed for 5 minutes. The lubricated blend was then compressed into core tablets. The core tablets were coated with a water-alcohol zein coating solution (weight increase 2.5 + 0.5%) and dried. The coated tablets were further coated with enteric coating solution (weight increase 8.0 + 1.0%). The enteric coated tablets were additionally coated with Opadry solution until the weight increase was 2.0 + 0.5%. Then, the film coated tablets were imprinted with Opacode black ink.
EXAMPLE 10
Pantoprazole sodium tablets, prepared according to Example 5, were tested according to Method 724 ‘Drug Release” of The United Stafes
Pharmacopeia 24, United States Pharmacopeial Convention, Inc., Rockville,
Maryland U.S.A., pp. 1944-1947, 2000, using Method B and Apparatus 1 (described in Method 711 “Dissolution,” on page 1942). A tablet was first immersed in 0.1 N hydrochloric acid, with stirring, for two hours at 37°C. The tablet was then immersed in the pH 6.8 phosphate buffer, with stirring, and samples of the buffer solution were taken at intervals for analysis to determine the amount of drug released from the tablet.
Following are the data obtained from testing six tablets. The amount of drug released into the acid is not shown, but was small. in general, release of up to 10% of the drug into the acid is considered acceptable for enteric coated dosage forms. For purposes of this invention, a phamaceutical active is considered to be substantially retained within the dosage form if less than about ten percent by weight is released into 0.1 N hydrochloric acid, under the conditions of the USP test.
Tablet | Tablet | Tablet | Tablet | Tablet | Tablet | Mean = TE
EJ
IC 0 a A CO BI
IC EC I I I A IC
0 [ee [ea [or | | 8 [a [er
These results show that the drug was substantially completely released within sixty minutes at pH 6.8.
EXAMPLE 11
As in Example 10, tablets of rabeprazole sodium prepared according to
Example 9 were tested by USP Drug Release Method 724. However, the alkaline solution for the second part of the test was a phosphate buffer adjusted to pH 8.0 and also containing 0.5 weight percent of sodium lauryl sulfate. Results were obtained, as follows.
Time Percent Drug Released (min.) Tablet | Tablet | Tablet | Tablet | Tablet | Tablet | Mean 1 2 3 4 5 6 0 [8 ¥ [12] 4 [To "2% |B [2 [ [7 [ees |e | 8s
SEC I I CC
5 These results show that the drug was substantially completely released within sixty minutes at pH 6.8.
EXAMPLE 12
Esomeprazole tablets were prepared using the following ingredients and the procedure described below.
Ingredients Quantity/Tablet (mg)
Esomeprazole magnesium trihydrate
Mannitol (Peariitol SD 200)
Colloidal silicon dioxide 35]
Esomeprazole magnesium trihydrate, magnesium oxide, Plasdone S-630, silicon dioxide, and mannitol were sieved and blended, then sodium stearyl fumarate was added and the mixture blended, and finally tablets were formed by direct compression of the mixture. Zein was dissolved in aqueous alcohol and coated onto the tablets. The coated tablets were then dried.
Additional tablets were similarly prepared, further including either 7 mg or mg of the disintegrant ingredient crospovidone in the core composition, with corresponding decreases in the amount of mannitol to maintain constant tablet weights. The tablets were tested for dissolution characteristics at pH 6.8, using 10 the procedure of Example 10 (except that the acid contact step was omitted) and giving the following results,
Time in) ee
I A J EE A
EE EL I
ICH EL RE
IEC I RR A
J 0° TT wm
ICE EE EE BE
For this particular formulation, 10 mg of disintegrant produced the desired rapid release of drug at pH 6.8. However, other formulations could exhibit the desired drug release with different disintegrant concentrations, depending on the identity of the various formulation components, the physical methods used to prepare cores (such as compression pressure for tablets), and the presence of additional coatings. Therefore, each proposed formulation should be tested using varying amounts of the selected disintegrant components, to identify the exact formulation that gives desired drug release characteristics.
Claims (46)
1. A pharmaceutical dosage form comprising:
a. a solid core comprising a pharmaceutical active and a disintegrant;
b. a swellable coating surrounding the core; and
Cc. an enteric coating surrounding the swellable coating.
2. The pharmaceutical dosage form of claim 1, wherein the core is a tablet.
3. The pharmaceutical dosage form of claim 1, comprising multiple coated cores contained in a capsule.
4. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical active is unstable in the presence of acid.
5. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical active is reactive with a component of the enteric coating.
6. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical active comprises a benzimidazole.
7. The pharmaceutical dosage form of claim 6, wherein the benzimidazole is one or more members selected from the group consisting of omeprazole, esomeprazole, lansoprazole, rabeprazole and pantoprazole.
8. The pharmaceutical dosage form of claim 1, wherein the disintegrant comprises one or more members selected from the group consisting of: starches; polyvinyl pymolidones; formaldehyde-casein compounds; resins; defatted soybean extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate; and acrylic polymers.
9. The pharmaceutical dosage form of claim 1, wherein the swellable coating comprises one or more hydrocolloid-forming members selected from the group consisting of: prolamines; vinylpyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates; pectins; agar; and gums.
10. The pharmaceutical dosage form of claim 1, wherein the swellable coating comprises zein.
11. The pharmaceutical dosage form of claim 1, wherein the swellable coating comprises a hydroxypropylmethyl cellulose.
12. The pharmaceutical dosage form of claim 1, wherein the swellable coating comprises an excipient that modulates release of pharmaceutical active from the core upon hydration.
13. The phamaceutical dosage form of claim 12, wherein the excipient comprises one or more members selected from the group consisting of: plasticizers; water soluble surfactants; and enteric coating materials.
14. The pharmaceutical dosage form of claim 1, wherein the enteric coating comprises a component that is cellulose-based, methacrylate-based, polyvinyl acetate phthalate-based, or shellac-based.
156. The pharmaceutical dosage form of claim 1, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate.
16. The pharmaceutical dosage form of claim 1, wherein the core comprises at least about 50 percent of the weight of the dosage form.
17. The pharmaceutical dosage form of claim 1, wherein the swellable coating comprises about 0.1 to 10 percent of the weight of the dosage form.
18. The pharmaceutical dosage form of claim 1, wherein the enteric coating comprises about 0.1 to 30 percent of the weight of the dosage form.
$2004/022910
19. The pharmaceutical dosage form of claim 1, wherein the pharmaceutical active is substantially retained in the dosage form while the dosage form is present in the stomach, but is rapidly released after the dosage form enters a digestive system environment having a pH value at least about 5.
20. A pharmaceutical dosage form comprising:
a. a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant;
b. a swellable coating comprising a hydrocolloid-forming component, surrounding the core; and
Cc. an enteric coating surrounding the swellable coating.
21. The pharmaceutical dosage form of claim 20, wherein the acid-sensitive pharmaceutical active comprises a benzimidazole.
22. The pharmaceutical dosage form of claim 20, wherein the disintegrant comprises one or more members selected from the group consisting of: starches; polyvinyl pyrrolidones; formaldehyde-casein compounds; resins; defatted soybean extracts; alginic acid; agar-agar; calcium carbonate: calcium phosphate; sodium carbonate; and acrylic polymers.
23. The pharmaceutical dosage form of claim 20, wherein the hydrocolloid- forming component comprises one or more members’ selected from the group consisting of: prolamines; vinyl pyrrolidone polymers; cellulose derivatives; starches; carboxyvinyl polymers; alginates:; pectins; agar; and gums.
24. The pharmaceutical dosage form of claim 20, wherein the enteric coating comprises a component that is cellulose-based, methacrylate-based, polyvinyl acetate phthalate-based, or shellac-based.
25. The phamaceutical dosage form of claim 20, wherein the enteric coating comprises a copolymer of methacrylic acid and ethyl acrylate.
: PCT/US2004/022910
26. A pharmaceutical dosage form comprising:
a. a solid core comprising a benzimidazole and a disintegrant;
b. a swellable coating comprising one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl cellulose, surrounding the core; and
C. an enteric coating comprising a copolymer or methacrylic acid and ethyl acrylate, surrounding the swellable coating.
27. The pharmaceutical dosage form of claim 26, wherein the disintegrant comprises one or more members selected from the group consisting of: starches; polyvinyl pyrrolidones; formaldehyde-casein compounds; resins; defatted soybean extracts; alginic acid; agar-agar; calcium carbonate; calcium phosphate; sodium carbonate; and acrylic polymers. 16
28. The pharmaceutical dosage form of claim 26, wherein the swellable coating comprises zein.
29. The pharmaceutical dosage form of claim 26, wherein the swellabie coating comprises crospovidone.
30. The pharmaceutical dosage form of claim 26, wherein the swellable coating comprises a hydroxypropyl celiulose.
31. Use of a. solid core comprising a pharmaceutical active and a disintegrant;
b. a swellable coating surrounding the core; and
Cc. an enteric coating surrounding the swellable coating in the manufacture of an orally administrable pharmaceutical dosage form for treating a medical condition, wherein said pharmaceutical active is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating and the enteric coating are characterised in that: (i) the dosage form remains substantially intact during stomach transit; AMENDED SHEET
: PCT/US2004/022910 (i) the enteric coating is removed in digestive system environments having pH values above about 5; (if) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolloid to hydrate the core; and (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form.
32. Use of a. a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant;
b. a swellable coating comprising a hydrocolloid-forming component, surrounding the core; and c. an enteric coating surrounding the swellable coating in the manufacture of an orally administrable pharmaceutical dosage form for treating a medical condition, wherein said acid sensitive pharmaceutical active is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating and the enteric coating are characterised in that: (i) the dosage form remains substantially intact during stomach transit; (i) the enteric coating is removed in digestive system areas having pH values above about 5; (iii) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolloid to hydrate the core; and (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form.
33. Use of a. a solid core comprising a benzimidazole and a disintegrant;
b. a swellable coating comprising one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl cellulose, surrounding the core; and AMENDED SHEET
. PCT/US2004/022910
C. an enteric coating comprising a copolymer or methacrylic acid and ethyl acrylate, surrounding the swellable coating in the manufacture of an orally administrable pharmaceutical dosage form for treating a medical condition, wherein said benzimidazole is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating, and the enteric coating are characterised in that: (1) the dosage form remains substantially intact during stomach transit; (ii) the enteric coating is removed in digestive system areas having pH values above about 5; (iii) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolioid to hydrate the core; and (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form.
34. Use of claim 33, wherein at least about 80 percent of the pharmaceutical active is released within about one hour after the dosage form is contacted with an aqueous fluid having a pH about 6.8.
35. A method of preparing a pharmaceutical dosage form, comprising the steps of:
a. combining components comprising a pharmaceutical active and a disintegrant, and forming a solid core,
b. coating the core with a swellable coating comprising a hydrocolloid- forming component; and
C. applying an outer coating comprising an acid-resistant enteric substance.
36. The method of claim 35, wherein the solid core is formed as a tablet.
37. The method of claim 35, further comprising the step of filling multiple coated cores into a capsule. AMENDED SHEET
) PCT/US2004/022910
38. A pharmaceutical dosage form for use in a method of treating a medical condition, said pharmaceutical dosage form comprising a. a solid core comprising a pharmaceutical active and a disintegrant;
b. a swellable coating surrounding the core; and
C. an enteric coating surrounding the swellable coating, wherein said pharmaceutical active is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating and the enteric coating are characterised in that: 0 the dosage form remains substantially intact during stomach transit; (ii) the enteric coating is removed in digestive system environments having pH values above about 5; (iii) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolloid to hydrate the core; and (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form, and said method comprising orally administering said pharmaceutical dosage form.
39. A pharmaceutical dosage form for use in a method of treating a medical condition, said pharmaceutical dosage form comprising a. a solid core comprising an acid-sensitive pharmaceutical active and a disintegrant;
b. a swellable coating comprising a hydrocolloid-forming component surrounding the core; and
Cc. an enteric coating surrounding the swellable coating wherein said acid sensitive pharmaceutical active is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating and the enteric coating are characterised in that: (i) the dosage form remains substantially intact during stomach transit: (ii) the enteric coating is removed in digestive system areas having pH values above about 5; (iii) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolloid to hydrate the core; and AMENDED SHEET
. PCT/US2004/022910 (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form and said method comprising orally administering said pharmaceutical dosage form.
40. A pharmaceutical dosage form for use in a method of treating a medical condition, said pharmaceutical dosage form comprising a. a solid core comprising a benzimidazole and a disintegrant;
b. a swellable coating comprising one or more hydrocolloid-formers selected from zein, crospovidone, and a hydroxypropyl! cellulose, surrounding the core; and
Cc. an enteric coating comprising a copolymer or methacrylic acid and ethyl acrylate, surrounding the swellable coating, wherein said benzimidazole is selected according to its efficacy in treating said condition, and other component(s) of the core, the disintegrant, the swellable coating 16 and the enteric coating are characterised in that: (i) the dosage form remains substantially intact during stomach transit; (if) the enteric coating is removed in digestive system areas having pH values above about 5; (iii) aqueous fluids penetrate areas of the dosage form where the enteric coating has been removed, causing hydrocolloid formation in the swellable coating; (iv) aqueous fluids pass through the hydrocolloid to hydrate the core; and (v) the hydrated core becomes fragmented, releasing the pharmaceutical active from the dosage form and said method comprising orally administering said pharmaceutical dosage form.
41. A pharmaceutical dosage form for use in a method of treatment of claim 40, wherein at least about 80 percent of the pharmaceutical active is released within about one hour after the dosage form is contacted with an aqueous fluid having a pH about 6.8.
42. A dosage form according to any one of claims 1 to 30, substantially as herein described and illustrated. AMENDED SHEET
) PCT/US2004/022910
43. Use according to any one of claims 31 to 34, substantially as herein described and illustrated.
44, A method according to any one of claims 35 to 37, substantially as herein described and illustrated.
45. A pharmaceutical dosage form for use in a method of treatment according to any one of claims 38 to 41, substantially as herein described and illustrated.
46. A new dosage form, a new use of a substance substantially as defined herein, a new method of preparing a dosage form, or a pharmaceutical dosage form for a new use in a method of treatment, substantially as herein described. AMENDED SHEET
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
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IN580CH2003 | 2003-07-17 |
Publications (1)
Publication Number | Publication Date |
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ZA200600432B true ZA200600432B (en) | 2007-01-31 |
Family
ID=37003245
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
ZA200600432A ZA200600432B (en) | 2003-07-17 | 2006-01-16 | Pharmaceutical compositions having a swellable coating |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN1835738A (en) |
ZA (1) | ZA200600432B (en) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115887396A (en) * | 2023-01-06 | 2023-04-04 | 北京中科利华医药研究院有限公司 | Methazolamide orally disintegrating tablet and preparation method and application thereof |
-
2004
- 2004-07-16 CN CNA2004800229087A patent/CN1835738A/en active Pending
-
2006
- 2006-01-16 ZA ZA200600432A patent/ZA200600432B/en unknown
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115887396A (en) * | 2023-01-06 | 2023-04-04 | 北京中科利华医药研究院有限公司 | Methazolamide orally disintegrating tablet and preparation method and application thereof |
Also Published As
Publication number | Publication date |
---|---|
CN1835738A (en) | 2006-09-20 |
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