CA2667039A1 - Multiple unit tablet compositions of benzimidazole compounds - Google Patents
Multiple unit tablet compositions of benzimidazole compounds Download PDFInfo
- Publication number
- CA2667039A1 CA2667039A1 CA002667039A CA2667039A CA2667039A1 CA 2667039 A1 CA2667039 A1 CA 2667039A1 CA 002667039 A CA002667039 A CA 002667039A CA 2667039 A CA2667039 A CA 2667039A CA 2667039 A1 CA2667039 A1 CA 2667039A1
- Authority
- CA
- Canada
- Prior art keywords
- enteric coating
- coating layer
- composition according
- core
- plasticizer
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Abandoned
Links
- 239000007916 tablet composition Substances 0.000 title claims abstract description 15
- 125000003785 benzimidazolyl group Chemical group N1=C(NC2=C1C=CC=C2)* 0.000 title abstract description 5
- 239000010410 layer Substances 0.000 claims abstract description 98
- 239000002702 enteric coating Substances 0.000 claims abstract description 84
- 238000009505 enteric coating Methods 0.000 claims abstract description 84
- 239000000203 mixture Substances 0.000 claims abstract description 54
- 239000004014 plasticizer Substances 0.000 claims abstract description 33
- 229920000642 polymer Polymers 0.000 claims abstract description 29
- 239000000546 pharmaceutical excipient Substances 0.000 claims abstract description 26
- -1 benzimidazole compound Chemical class 0.000 claims abstract description 23
- 238000000034 method Methods 0.000 claims abstract description 19
- 230000008569 process Effects 0.000 claims abstract description 15
- 238000002360 preparation method Methods 0.000 claims abstract description 12
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 28
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 28
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 28
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 26
- 235000000346 sugar Nutrition 0.000 claims description 21
- 229960000913 crospovidone Drugs 0.000 claims description 20
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 20
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 20
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 17
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 17
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 17
- 239000000454 talc Substances 0.000 claims description 17
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- 229940033134 talc Drugs 0.000 claims description 17
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- 238000000576 coating method Methods 0.000 claims description 14
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- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 13
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 12
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 11
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 11
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 11
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 11
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 10
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- 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 8
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- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 8
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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 claims description 7
- 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 7
- 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 7
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- 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 5
- HBAQYPYDRFILMT-UHFFFAOYSA-N 8-[3-(1-cyclopropylpyrazol-4-yl)-1H-pyrazolo[4,3-d]pyrimidin-5-yl]-3-methyl-3,8-diazabicyclo[3.2.1]octan-2-one Chemical class C1(CC1)N1N=CC(=C1)C1=NNC2=C1N=C(N=C2)N1C2C(N(CC1CC2)C)=O HBAQYPYDRFILMT-UHFFFAOYSA-N 0.000 claims description 5
- 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 5
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- 229960000381 omeprazole Drugs 0.000 claims description 5
- YREYEVIYCVEVJK-UHFFFAOYSA-N rabeprazole Chemical compound COCCCOC1=CC=NC(CS(=O)C=2NC3=CC=CC=C3N=2)=C1C YREYEVIYCVEVJK-UHFFFAOYSA-N 0.000 claims description 5
- 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 claims description 4
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- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 4
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- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 4
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- 239000008121 dextrose Substances 0.000 claims description 4
- 239000008103 glucose Substances 0.000 claims description 4
- BXWNKGSJHAJOGX-UHFFFAOYSA-N hexadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCO BXWNKGSJHAJOGX-UHFFFAOYSA-N 0.000 claims description 4
- 239000008101 lactose Substances 0.000 claims description 4
- 235000019359 magnesium stearate Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 4
- 235000019698 starch Nutrition 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
- 239000000811 xylitol Substances 0.000 claims description 4
- 235000010447 xylitol Nutrition 0.000 claims description 4
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 4
- 229960002675 xylitol Drugs 0.000 claims description 4
- 244000215068 Acacia senegal Species 0.000 claims description 3
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- 241000416162 Astragalus gummifer Species 0.000 claims description 3
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 3
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- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 3
- 235000019759 Maize starch Nutrition 0.000 claims description 3
- 229920000881 Modified starch Polymers 0.000 claims description 3
- 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 3
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- 229960001681 croscarmellose sodium Drugs 0.000 claims description 3
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 3
- 229960003174 lansoprazole Drugs 0.000 claims description 3
- 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 3
- 229940057948 magnesium stearate Drugs 0.000 claims description 3
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- 150000003839 salts Chemical class 0.000 claims description 3
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- 150000005846 sugar alcohols Chemical class 0.000 claims description 3
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- 229920001285 xanthan gum Polymers 0.000 claims description 3
- 229940082509 xanthan gum Drugs 0.000 claims description 3
- PSIREIZGKQBEEO-UHFFFAOYSA-N 2-(1h-benzimidazol-2-ylsulfinylmethyl)-n-methyl-n-(2-methylpropyl)aniline Chemical compound CC(C)CN(C)C1=CC=CC=C1CS(=O)C1=NC2=CC=CC=C2N1 PSIREIZGKQBEEO-UHFFFAOYSA-N 0.000 claims description 2
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- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 claims description 2
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- 229960000541 cetyl alcohol Drugs 0.000 claims description 2
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical class OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 2
- 229940031954 dibutyl sebacate Drugs 0.000 claims description 2
- 230000027119 gastric acid secretion Effects 0.000 claims description 2
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- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 159000000011 group IA salts Chemical class 0.000 claims description 2
- 230000002401 inhibitory effect Effects 0.000 claims description 2
- 229950007395 leminoprazole Drugs 0.000 claims description 2
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- HLKZFSVWBQSKKH-UHFFFAOYSA-N but-3-enoic acid;1-ethenylpyrrolidin-2-one Chemical compound OC(=O)CC=C.C=CN1CCCC1=O HLKZFSVWBQSKKH-UHFFFAOYSA-N 0.000 claims 1
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- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 8
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- WNROFYMDJYEPJX-UHFFFAOYSA-K aluminium hydroxide Chemical compound [OH-].[OH-].[OH-].[Al+3] WNROFYMDJYEPJX-UHFFFAOYSA-K 0.000 description 1
- 229910021502 aluminium hydroxide Inorganic materials 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- UTUUIUQHGDRVPU-UHFFFAOYSA-K aluminum;2-aminoacetate;dihydroxide;hydrate Chemical compound O.[OH-].[OH-].[Al+3].NCC([O-])=O UTUUIUQHGDRVPU-UHFFFAOYSA-K 0.000 description 1
- RJZNFXWQRHAVBP-UHFFFAOYSA-I aluminum;magnesium;pentahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Al+3] RJZNFXWQRHAVBP-UHFFFAOYSA-I 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 description 1
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 239000007891 compressed tablet Substances 0.000 description 1
- 238000005336 cracking Methods 0.000 description 1
- 238000006731 degradation reaction Methods 0.000 description 1
- GDVKFRBCXAPAQJ-UHFFFAOYSA-A dialuminum;hexamagnesium;carbonate;hexadecahydroxide Chemical compound [OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[OH-].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Mg+2].[Al+3].[Al+3].[O-]C([O-])=O GDVKFRBCXAPAQJ-UHFFFAOYSA-A 0.000 description 1
- 238000007865 diluting Methods 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 208000000718 duodenal ulcer Diseases 0.000 description 1
- 239000002662 enteric coated tablet Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 210000004051 gastric juice Anatomy 0.000 description 1
- 201000005917 gastric ulcer Diseases 0.000 description 1
- 208000021302 gastroesophageal reflux disease Diseases 0.000 description 1
- 229960001545 hydrotalcite Drugs 0.000 description 1
- 229910001701 hydrotalcite Inorganic materials 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 230000000670 limiting effect Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000010449 maltitol Nutrition 0.000 description 1
- 239000000845 maltitol Substances 0.000 description 1
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- 229940035436 maltitol Drugs 0.000 description 1
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 1
- 238000004806 packaging method and process Methods 0.000 description 1
- 230000036961 partial effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 150000003021 phthalic acid derivatives Chemical class 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 description 1
- 229940068968 polysorbate 80 Drugs 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
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- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
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- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
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- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
-
- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poly(lactide-co-glycolide)
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- 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
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
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- Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Chemical & Material Sciences (AREA)
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- Chemical Kinetics & Catalysis (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention relates to multiple unit tablet compositions of benzimidazole compounds and process of preparation thereof. The compositions are useful against various gastrointestinal disorders. The multiple unit tablet composition comprises: a) tablet excipients, and b) multiple enteric coated core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer.
Description
MULTIPLE UNIT TABLET COMPOSITIONS OF BENZIMIDAZOLE
COMPOUNDS
Field of the Invention The present invention relates to multiple unit tablet compositions of benzimidazole compounds and process of preparation thereof. The compositions are useful against various gastrointestinal disorders.
Backuound of the Invention Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and thus are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, gastro esophageal reflux disorders etc. by inhibiting gastric acid secretion.
The single isomers of corresponding benzimidazole compounds are reported to be more useful in therapy compared to the racemic benzimidazole compounds. U.S.
Patent No. 5,877,192 describes the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases.
Because of the instability of benzimidazole compounds under neutral and acidic environment, moisture, heat, organic solvents and to some degree by light, numerous approaches have been tried to form a stable pharmaceutical formulation comprising a benzimidazole compound. Most oral benzimidazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach.
This is most commonly achieved by formulating multiple unit formulations i.e. enteric-coated granules within capsules, enteric-coated granules compressed into tablets etc., and single unit enteric-coated tablets.
The pharmacokinetics of the two formulations differ considerably. The multiple unit formulation (capsules or tablets) is usually emptied gradually from the stomach into the intestine. In contrast to this, the single unit tablet will enter the intestine and dissolve as one unit. Further, the enteric- coated pellets of the multiple unit formulations disperse readily in contact with fluid, and are therefore suitable for patients with swallowing difficulties (can be dispersed in water or juice and the contents taken orally by the patient) or for patients with feeding tubes. Among the multiple unit formulations, tablets offer the advantage of good mechanical stability and being more tamper-resistant than capsules, which is an important consideration in OTC settings.
U.S. Patent Nos. 4,786,505 and 4,853,230 teach compositions of benzimidazole compounds having an alkaline core, separating layer and enteric coating.
When preparing multiple unit tablets, the application of compression forces to the tablet mixture comprising enteric-coated particles present a problem with respect to the strength of the coating and specifically the requirement to maintain the gastro-resistance and the integrity of the tablet and of the enteric- coated units after tableting.
It is known that the film-forming agents generally used to coat particles cannot under normal conditions absorb the mechanical stresses applied during tableting. Films composed of only enteric polymers or copolymers have very mediocre mechanical properties, such that they do not withstand tableting. The application of these compression forces can result in the appearance of cracks in the enteric coating film or by the splitting thereof, resulting in the partial or complete loss of the properties of the film coating.
The prior art provides solutions such as for example modifying the composition of the enteric coating films, so as to substantially improve its mechanical characteristics with regard to tableting properties, i.e. to withstand the application of compression forces.
Improvements in gastro-resistance and less film damage can also be achieved by using excipients that deform plastically during tableting. Alternative solutions consist of diluting/mixing the enteric-coated particles with auxiliary substances, which substances can absorb the physical stresses during tableting.
The document "Drugs made in Germany", 37(2) p. 53 (1994) teaches combination of Eudragit . L30D and Eudragit . NE30D to produce multiparticulate tablets comprising the enteric coated particles.
European Patent No. 0 723 436 B 1 teaches an oral pharmaceutical multiple unit tableted dosage form comprising tablet excipients and individually enteric coating layered units of a core material containing active substance in the form of omeprazole or one of its single enantiomers, the core material being covered with one or more layer(s), of which at least one is an enteric coating layer, characterized in that the enteric coating layer comprises a plasticizer in the amount of 20 - 50% by weight of the enteric coating layer polymer. This patent teaches that the enteric coating layer contains pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. The amount of the plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer, selected plasticizer and the applied amount of said polymer, in such a way that the mechanical properties, i.e. flexibility and hardness of the enteric coating layer are adjusted so that the acid resistance of the pellets covered with enteric coating layer does not decrease significantly during the compression of pellets into tablets.
European Patent No. 0 723 437 B 1 teaches an oral pharmaceutical multiple unit tableted dosage form of an acid labile H+K+-ATPase inhibitor or one of its single enantiomers, the core material being covered with one or more layer(s) of which at least one is an enteric coating layer, characterized in that the enteric coating layer has a thickness of at least 10 m and said layer comprises a plasticizer in an amount of 15 - 50 % by weight of the enteric coating layer polymer.
European Patent Application No. 0 723 777 Al teaches a tablet containing enteric granules prepared by tabletting a mixture of enteric granules with at least one member selected from the group consisting of synthetic hydrotalcite, dried aluminium hydroxide gel, a coprecipitate of aluminium hydroxide with sodium hydrogencarbonate, aluminium magnesium hydroxide, synthetic aluminium silicate and dihydroxyaluminium aminoacetate. The enteric-coated granules include a plasticizer, preferably added during formulation of the coating to be coated on the granules, at 15-40% w/w, and preferably 30-40 % w/w with respect to the total amount of the enteric coating.
PCT Application No. WO 02/19991 teaches a multiparticulate dosage form, produced from particles compressed with conventional binding agents. Said particles contain a pharmaceutical active ingredient and are covered with a gastric juice resistant coating consisting of a methacrylate copolymer and more than 15 and up to 50 wt % of the plasticizer propylene glycol in relation to the methacrylate copolymer.
U.S. Patent Application No. 2006/0018964 discloses a multiparticulate tablet comprising a pharmaceutically active substance in the form of enteric-coated particles, and a mixture of tableting excipients, wherein the mixture of excipients comprises: a first diluent selected from the group consisting of xylitol, maltitol, and mixtures thereof, wherein the first diluent is in a directly compressible form; a disintegrating agent; a lubricant; and at least one other diluent, and wherein the ratio of a) the first diluent to b) the other diluent(s) is less than 5/95 (weight/weight). The enteric coating composition can also comprise a plasticizer. The plasticizer is usually used in a total proportion of at most 40%, preferably between 10% and 30%, expressed by weight with respect to the dry weight of polymer. However, the examples disclosed in this patent application state that the enteric coated microgranules are manufactured according to the teaching of the prior art WO 96/01623 (PCT application corresponding to EP 0 723 436 BI).
However, there is still a need for development of new enteric coating layered multiple unit preparations with good mechanical and chemical stability. We have surprisingly found that multiple unit tablets of benzimidazole compounds having desired mechanical properties and good acid resistance can be prepared by using a plasticizer in the enteric coating layer in an amount lower than that disclosed in the prior art.
Summary of the Invention Multiple unit tablet compositions of benzimidazole compounds are disclosed.
According to one embodiment the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer.
According to another embodiment the multiple unit tablet composition comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer.
According to still another embodiment the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer.
According to further embodiment the multiple unit tablet composition comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered core units 5 containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer comprising a plasticizer in an amount ranging from 0-30% by weight of the enteric coating layer polymer.
According to further embodiment the process of preparation of multiple unit tablet composition of the present invention is disclosed.
Detailed Description of the Invention The term benzimidazole compound used herein refers to any of the compounds belonging to the category of benzimidazole used for gastrointestinal disorders and may be selected from omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and pariprazole, including their single enantiomers, pharmaceutically accepted salts, solvates and mixtures. For example, the benzimidazole compound may be esomeprazole in the form of a pharmaceutically acceptable alkaline salt such as esomeprazole calcium or esomeprazole magnesium. The benzimidazole compound may be either in the crystalline or amorphous form.
The core may be in the form of pellets, granules or beads. The core may be acidic, alkaline or neutral depending on the type of formulation. The core may contain one or more pharmaceutically acceptable excipients selected from the group consisting of inert carriers, binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof. The inert carrier may be coated with the benzimidazole compound and one or more of the binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
The inert carrier may comprise starch, microcrystalline cellulose or sugar sphere such as nonpareil sugar seeds.
COMPOUNDS
Field of the Invention The present invention relates to multiple unit tablet compositions of benzimidazole compounds and process of preparation thereof. The compositions are useful against various gastrointestinal disorders.
Backuound of the Invention Benzimidazole compounds such as omeprazole, lansoprazole, pantoprazole, rabeprazole or single enantiomers thereof are strong inhibitors of proton pump and thus are widely used as therapeutic agents for stomach ulcer, duodenal ulcer, gastro esophageal reflux disorders etc. by inhibiting gastric acid secretion.
The single isomers of corresponding benzimidazole compounds are reported to be more useful in therapy compared to the racemic benzimidazole compounds. U.S.
Patent No. 5,877,192 describes the use of the (-)-enantiomer of omeprazole (esomeprazole), or a pharmaceutically acceptable salt thereof, in the treatment of gastric acid related diseases.
Because of the instability of benzimidazole compounds under neutral and acidic environment, moisture, heat, organic solvents and to some degree by light, numerous approaches have been tried to form a stable pharmaceutical formulation comprising a benzimidazole compound. Most oral benzimidazole preparations are enteric-coated, due to the rapid degradation of the drug in the acidic conditions of the stomach.
This is most commonly achieved by formulating multiple unit formulations i.e. enteric-coated granules within capsules, enteric-coated granules compressed into tablets etc., and single unit enteric-coated tablets.
The pharmacokinetics of the two formulations differ considerably. The multiple unit formulation (capsules or tablets) is usually emptied gradually from the stomach into the intestine. In contrast to this, the single unit tablet will enter the intestine and dissolve as one unit. Further, the enteric- coated pellets of the multiple unit formulations disperse readily in contact with fluid, and are therefore suitable for patients with swallowing difficulties (can be dispersed in water or juice and the contents taken orally by the patient) or for patients with feeding tubes. Among the multiple unit formulations, tablets offer the advantage of good mechanical stability and being more tamper-resistant than capsules, which is an important consideration in OTC settings.
U.S. Patent Nos. 4,786,505 and 4,853,230 teach compositions of benzimidazole compounds having an alkaline core, separating layer and enteric coating.
When preparing multiple unit tablets, the application of compression forces to the tablet mixture comprising enteric-coated particles present a problem with respect to the strength of the coating and specifically the requirement to maintain the gastro-resistance and the integrity of the tablet and of the enteric- coated units after tableting.
It is known that the film-forming agents generally used to coat particles cannot under normal conditions absorb the mechanical stresses applied during tableting. Films composed of only enteric polymers or copolymers have very mediocre mechanical properties, such that they do not withstand tableting. The application of these compression forces can result in the appearance of cracks in the enteric coating film or by the splitting thereof, resulting in the partial or complete loss of the properties of the film coating.
The prior art provides solutions such as for example modifying the composition of the enteric coating films, so as to substantially improve its mechanical characteristics with regard to tableting properties, i.e. to withstand the application of compression forces.
Improvements in gastro-resistance and less film damage can also be achieved by using excipients that deform plastically during tableting. Alternative solutions consist of diluting/mixing the enteric-coated particles with auxiliary substances, which substances can absorb the physical stresses during tableting.
The document "Drugs made in Germany", 37(2) p. 53 (1994) teaches combination of Eudragit . L30D and Eudragit . NE30D to produce multiparticulate tablets comprising the enteric coated particles.
European Patent No. 0 723 436 B 1 teaches an oral pharmaceutical multiple unit tableted dosage form comprising tablet excipients and individually enteric coating layered units of a core material containing active substance in the form of omeprazole or one of its single enantiomers, the core material being covered with one or more layer(s), of which at least one is an enteric coating layer, characterized in that the enteric coating layer comprises a plasticizer in the amount of 20 - 50% by weight of the enteric coating layer polymer. This patent teaches that the enteric coating layer contains pharmaceutically acceptable plasticizers to obtain the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. The amount of the plasticizer is optimized for each enteric coating layer formula, in relation to selected enteric coating layer polymer, selected plasticizer and the applied amount of said polymer, in such a way that the mechanical properties, i.e. flexibility and hardness of the enteric coating layer are adjusted so that the acid resistance of the pellets covered with enteric coating layer does not decrease significantly during the compression of pellets into tablets.
European Patent No. 0 723 437 B 1 teaches an oral pharmaceutical multiple unit tableted dosage form of an acid labile H+K+-ATPase inhibitor or one of its single enantiomers, the core material being covered with one or more layer(s) of which at least one is an enteric coating layer, characterized in that the enteric coating layer has a thickness of at least 10 m and said layer comprises a plasticizer in an amount of 15 - 50 % by weight of the enteric coating layer polymer.
European Patent Application No. 0 723 777 Al teaches a tablet containing enteric granules prepared by tabletting a mixture of enteric granules with at least one member selected from the group consisting of synthetic hydrotalcite, dried aluminium hydroxide gel, a coprecipitate of aluminium hydroxide with sodium hydrogencarbonate, aluminium magnesium hydroxide, synthetic aluminium silicate and dihydroxyaluminium aminoacetate. The enteric-coated granules include a plasticizer, preferably added during formulation of the coating to be coated on the granules, at 15-40% w/w, and preferably 30-40 % w/w with respect to the total amount of the enteric coating.
PCT Application No. WO 02/19991 teaches a multiparticulate dosage form, produced from particles compressed with conventional binding agents. Said particles contain a pharmaceutical active ingredient and are covered with a gastric juice resistant coating consisting of a methacrylate copolymer and more than 15 and up to 50 wt % of the plasticizer propylene glycol in relation to the methacrylate copolymer.
U.S. Patent Application No. 2006/0018964 discloses a multiparticulate tablet comprising a pharmaceutically active substance in the form of enteric-coated particles, and a mixture of tableting excipients, wherein the mixture of excipients comprises: a first diluent selected from the group consisting of xylitol, maltitol, and mixtures thereof, wherein the first diluent is in a directly compressible form; a disintegrating agent; a lubricant; and at least one other diluent, and wherein the ratio of a) the first diluent to b) the other diluent(s) is less than 5/95 (weight/weight). The enteric coating composition can also comprise a plasticizer. The plasticizer is usually used in a total proportion of at most 40%, preferably between 10% and 30%, expressed by weight with respect to the dry weight of polymer. However, the examples disclosed in this patent application state that the enteric coated microgranules are manufactured according to the teaching of the prior art WO 96/01623 (PCT application corresponding to EP 0 723 436 BI).
However, there is still a need for development of new enteric coating layered multiple unit preparations with good mechanical and chemical stability. We have surprisingly found that multiple unit tablets of benzimidazole compounds having desired mechanical properties and good acid resistance can be prepared by using a plasticizer in the enteric coating layer in an amount lower than that disclosed in the prior art.
Summary of the Invention Multiple unit tablet compositions of benzimidazole compounds are disclosed.
According to one embodiment the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer.
According to another embodiment the multiple unit tablet composition comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer.
According to still another embodiment the multiple unit tablet composition comprises: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer.
According to further embodiment the multiple unit tablet composition comprises:
a) one or more tablet excipients, and b) a multiple of enteric coating layered core units 5 containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount ranging from 8% to 14% by weight of the enteric coating layer polymer and the enteric coating layer is further covered by an over-coating layer comprising a plasticizer in an amount ranging from 0-30% by weight of the enteric coating layer polymer.
According to further embodiment the process of preparation of multiple unit tablet composition of the present invention is disclosed.
Detailed Description of the Invention The term benzimidazole compound used herein refers to any of the compounds belonging to the category of benzimidazole used for gastrointestinal disorders and may be selected from omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole and pariprazole, including their single enantiomers, pharmaceutically accepted salts, solvates and mixtures. For example, the benzimidazole compound may be esomeprazole in the form of a pharmaceutically acceptable alkaline salt such as esomeprazole calcium or esomeprazole magnesium. The benzimidazole compound may be either in the crystalline or amorphous form.
The core may be in the form of pellets, granules or beads. The core may be acidic, alkaline or neutral depending on the type of formulation. The core may contain one or more pharmaceutically acceptable excipients selected from the group consisting of inert carriers, binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof. The inert carrier may be coated with the benzimidazole compound and one or more of the binders, diluents, disintegrants, lubricants/glidants, solubilizers/wetting agents and mixtures thereof.
The inert carrier may comprise starch, microcrystalline cellulose or sugar sphere such as nonpareil sugar seeds.
Generally the diluents may be selected from one or more of sugars like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starches like corn starch, pregelatinized starch, maize starch and mixtures thereof.
Generally the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
The solubilizers/wetting agents may be selected from one or more of sodium lauryl sulphate, polysorbate 80 and mixtures thereof. The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
The core may be coated with a separating layer prior to the enteric coating layer.
The separating layer is made up of substantially water-soluble material, which is capable of dissolving or forming a gel in contact with water. Such material may include substantially water-soluble polymer and/or substantially water-soluble excipients. The substantially water-soluble excipients may be selected from glucose, lactose, mannitol, sorbitol, sucrose, dextrose and mixtures thereof. The substantially water-soluble polymers may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate.
An enteric coating layer is applied onto the core coated with the separating layer by using suitable coating techniques. The enteric coating layer may include polymers such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid copolymers, for example, compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L 100 55 or mixtures thereof. The enteric coating layer contains plasticizers and may also include inert excipients such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose and crospovidone. The plasticizer is used in an amount of less than 15% by weight of the enteric coating layer polymer. For example, the amount of the plasticizer may range from 8% to 14% by weight of the enteric coating layer polymer.
For example, the amount of plasticizer is 13% by weight of the enteric coating layer polymer. These amounts of the plasticizer in the enteric coating layer provide the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. The acid resistance of the core covered with enteric coating layer does not decrease significantly during the compression of core into tablets. The plasticizers may be selected from one or more of triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and mixtures thereof.
The core covered with enteric coating layer may further be covered with one or more over-coating layers. The materials for over-coating layers are pharmaceutically acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and carboxymethylcellulose sodium, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as magnesium stearate, titanium dioxide and talc may also be included into the over-coating layer. The over coating layer may contain plasticizers in an amount ranging from 0-30 % by weight of the enteric coating layer polymer. For example, the amount of the plasticizer may range from 5-20 % by weight of the enteric coating layer polymer. Said over-coating layer may further prevent potential agglomeration of enteric coating layered core, protect the enteric coating layer towards cracking during the compaction process and enhance the tableting process.
The separating layer, enteric coating layer and the over-coating layer can be applied to the core by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the layering process.
The multiple enteric-coating layered core units are mixed with one or more tablet excipients and compressed into a multiple unit tablet dosage form. The enteric coating layered core units, with or without an over-coating layer, are mixed with tablet excipients such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives and compressed into tablets.
Generally the fillers may be selected from one or more of sugars like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starches like corn starch, pregelatinized starch, maize starch and mixtures thereof.
Generally the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
According to one embodiment the process for the preparation of the multiple unit tablet composition comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) mixing the multiple of enteric coating layered core units of step (c) with one or more tablet excipients, and e) compressing the mixture of step (d) into tablets.
According to another embodiment the process for the preparation of the multiple unit tablet composition comprises the steps of:
Generally the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
The solubilizers/wetting agents may be selected from one or more of sodium lauryl sulphate, polysorbate 80 and mixtures thereof. The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
The core may be coated with a separating layer prior to the enteric coating layer.
The separating layer is made up of substantially water-soluble material, which is capable of dissolving or forming a gel in contact with water. Such material may include substantially water-soluble polymer and/or substantially water-soluble excipients. The substantially water-soluble excipients may be selected from glucose, lactose, mannitol, sorbitol, sucrose, dextrose and mixtures thereof. The substantially water-soluble polymers may be selected from hydroxypropylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone, sodium alginate, sodium carboxymethyl cellulose, copolymer of vinylpyrrolidone and vinyl acetate.
An enteric coating layer is applied onto the core coated with the separating layer by using suitable coating techniques. The enteric coating layer may include polymers such as cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose, methacrylic acid copolymers, for example, compounds known under the trademarks of Eudragit NE30D, Eudragit L, Eudragit S, Eudragit L 100 55 or mixtures thereof. The enteric coating layer contains plasticizers and may also include inert excipients such as talc, titanium dioxide, colloidal silicon dioxide, hydroxypropyl methylcellulose and crospovidone. The plasticizer is used in an amount of less than 15% by weight of the enteric coating layer polymer. For example, the amount of the plasticizer may range from 8% to 14% by weight of the enteric coating layer polymer.
For example, the amount of plasticizer is 13% by weight of the enteric coating layer polymer. These amounts of the plasticizer in the enteric coating layer provide the desired mechanical properties, such as flexibility and hardness of the enteric coating layers. The acid resistance of the core covered with enteric coating layer does not decrease significantly during the compression of core into tablets. The plasticizers may be selected from one or more of triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols, polysorbates and mixtures thereof.
The core covered with enteric coating layer may further be covered with one or more over-coating layers. The materials for over-coating layers are pharmaceutically acceptable compounds such as sugar, polyethylene glycol, polyvinylpyrrolidone, polyvinyl alcohol, polyvinyl acetate, hydroxypropyl cellulose, methylcellulose, ethylcellulose, hydroxypropyl methylcellulose and carboxymethylcellulose sodium, used alone or in mixtures. Additives such as plasticizers, colorants, pigments, fillers, anti-tacking and anti-static agents, such as magnesium stearate, titanium dioxide and talc may also be included into the over-coating layer. The over coating layer may contain plasticizers in an amount ranging from 0-30 % by weight of the enteric coating layer polymer. For example, the amount of the plasticizer may range from 5-20 % by weight of the enteric coating layer polymer. Said over-coating layer may further prevent potential agglomeration of enteric coating layered core, protect the enteric coating layer towards cracking during the compaction process and enhance the tableting process.
The separating layer, enteric coating layer and the over-coating layer can be applied to the core by coating or layering procedures in suitable equipments such as coating pan, coating granulator or in a fluidized bed apparatus using water and/or organic solvents for the layering process.
The multiple enteric-coating layered core units are mixed with one or more tablet excipients and compressed into a multiple unit tablet dosage form. The enteric coating layered core units, with or without an over-coating layer, are mixed with tablet excipients such as fillers, binders, disintegrants, lubricants and other pharmaceutically acceptable additives and compressed into tablets.
Generally the fillers may be selected from one or more of sugars like dextrose, glucose, lactose; sugar alcohols like sorbitol, xylitol, mannitol; cellulose derivatives like powdered cellulose, microcrystalline cellulose; starches like corn starch, pregelatinized starch, maize starch and mixtures thereof.
Generally the binders are selected from one or more of cellulose derivatives like hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methylcellulose; gums like xanthan gum, gum acacia, tragacanth; water-soluble vinylpyrrolidone polymers like polyvinylpyrrolidone, copolymer of vinylpyrrolidone and vinyl acetate; sugars like sorbitol, mannitol and mixtures thereof.
Generally the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone, cornstarch and mixtures thereof.
The lubricant/glidants may be selected from one or more of magnesium stearate, talc, sodium stearyl fumarate, colloidal silicon dioxide and mixtures thereof.
According to one embodiment the process for the preparation of the multiple unit tablet composition comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) mixing the multiple of enteric coating layered core units of step (c) with one or more tablet excipients, and e) compressing the mixture of step (d) into tablets.
According to another embodiment the process for the preparation of the multiple unit tablet composition comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) covering the enteric coating layered core units of step (c) with an over-coating layer, e) mixing the multiple of over coating layered core units of step (d) with one or more tablet excipients, and f) compressing the mixture of step (e) into tablets.
The compressed tablet is optionally coated with a non-functional film coating to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport.
The following non-limiting examples describe the various embodiments:
Example 1 Qty (mg/unit) Ingredients Strength (40mg) Strength (20mg) 40 mg 20 mg Sugar spheres 60 30 Drug Layer Esomeprazole Magnesium eqv. to 44.5 22.25 Esomeprazole Hydroxypropylcellulose 16.0 8.0 Crospovidone 5.0 2.5 Purified water q. s. q.s.
Total 125.5 62.75 Separating layer Polyvinyl pyrrolidone 14.5 7.25 Polyethylene G1yco1400 1.0 0.5 Talc 4.0 2.0 Purified water/Isopropyl alcohol q. s. q.s.
Total 145.0 72.5 Enteric Coating layer Hydroxypropylmethyl cellulose phthalate 98.77 49.39 HPMCP (HP-55S) Hydroxypropylmethyl cellulose phthalate 42.33 21.17 Diethyl phthalate 18.4 9.2 Acetone q.s. q.s.
Purified water q.s. q.s.
Total 304.5 152.25 Overcoating layer Hydroxypropylcellulose 6.0 3.0 Polyethylene glycol (PEG 6000) 9.0 4.5 Isopropyl alcohol/Dichloromethane q. s. q.s.
Total 319.5 159.75 Compression Crospovidone 58 29 Cellulose microcrystalline PH 101 502.5 251.25 Cellulose microcrystalline PH 112 211 105.5 Polyvinylpyrrolidone/Hydroxypropylcellulose 105 52.5 Sodium stearyl Fumarate 4.0 2.0 Total 1200 600 Film Coating Opadry pink 30 15 Isopropyl alcohol q.s. q.s.
Dichloromethane q.s. q.s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the 10 dispersion of step 3 to obtain drug layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) covering the enteric coating layered core units of step (c) with an over-coating layer, e) mixing the multiple of over coating layered core units of step (d) with one or more tablet excipients, and f) compressing the mixture of step (e) into tablets.
The compressed tablet is optionally coated with a non-functional film coating to obtain a smooth surface of the tablet and further enhance the stability of the tablet during packaging and transport.
The following non-limiting examples describe the various embodiments:
Example 1 Qty (mg/unit) Ingredients Strength (40mg) Strength (20mg) 40 mg 20 mg Sugar spheres 60 30 Drug Layer Esomeprazole Magnesium eqv. to 44.5 22.25 Esomeprazole Hydroxypropylcellulose 16.0 8.0 Crospovidone 5.0 2.5 Purified water q. s. q.s.
Total 125.5 62.75 Separating layer Polyvinyl pyrrolidone 14.5 7.25 Polyethylene G1yco1400 1.0 0.5 Talc 4.0 2.0 Purified water/Isopropyl alcohol q. s. q.s.
Total 145.0 72.5 Enteric Coating layer Hydroxypropylmethyl cellulose phthalate 98.77 49.39 HPMCP (HP-55S) Hydroxypropylmethyl cellulose phthalate 42.33 21.17 Diethyl phthalate 18.4 9.2 Acetone q.s. q.s.
Purified water q.s. q.s.
Total 304.5 152.25 Overcoating layer Hydroxypropylcellulose 6.0 3.0 Polyethylene glycol (PEG 6000) 9.0 4.5 Isopropyl alcohol/Dichloromethane q. s. q.s.
Total 319.5 159.75 Compression Crospovidone 58 29 Cellulose microcrystalline PH 101 502.5 251.25 Cellulose microcrystalline PH 112 211 105.5 Polyvinylpyrrolidone/Hydroxypropylcellulose 105 52.5 Sodium stearyl Fumarate 4.0 2.0 Total 1200 600 Film Coating Opadry pink 30 15 Isopropyl alcohol q.s. q.s.
Dichloromethane q.s. q.s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the 10 dispersion of step 3 to obtain drug layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of polyethylene glycol (PEG 400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Diethylpthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Diethylpthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring.
12. The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Overcoating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
Overcoating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 22 BSS.
Compression 17. The overcoated beads of step 16 were sifted through # 22 BSS.
18. Microcrystalline cellulose, polyvinylpyrrolidone/Hydroxypropylcellulose-L
and crospovidone was sifted through # 30 BSS.
and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 2 Qty (mg/unit) Ingredients Strength (40mg) 40 mg Sugar spheres (#40-60) 60 Drug Layer Esomeprazole Magnesium eqv. to Esomeprazole 45.44 Hydroxypropylcellulose 16.0 Crospovidone 8.0 Purified water q. s.
Total 131.44 Separating layer Polyvinyl pyrrolidone 8.5 Polyethylene G1yco1400 0.8 Talc 14.5 Purified water/Isopropyl alcohol q. s.
Total 155.24 Enteric Coating layer Methacrylic acid copolymer (Eudragit L100D 55) 121 Hydroxypropylmethyl cellulose phthalate HPMCP 30 Triethyl citrate 19.63 Talc 15.8 Acetone q.s.
Purified water q.s.
Total 341.67 Overcoating layer Hydroxypropylcellulose 5.6 Polyethylene glycol (PEG 6000) 8.4 Isopropyl alcohol/Dichloromethane q. s.
Total 355.67 Compression Crospovidone 60 Cellulose microcrystalline PH 101 478 Cellulose microcrystalline PH 112 189 Hydroxypropylcellulose 110 Sodium stearyl Fumarate 18 Total 1200 Film Coating Opadry pink 27 Isopropyl alcohol q.s.
Dichloromethane q. s.
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads obtained in step 8 were dried at product temperature of 35 5 C
for 15-30 minutes.
Enteric Coating 10. Triethylcitrate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate and Eudragit L 100D 55 under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Overcoating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- Hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
5 Acid resistance test of the multiple unit tablet was performed in 0.1N HC1 at 75 rpm paddle for 120min (at initial time point and after 3 months storage at accelerated conditions). The result is given in the following table 1 below:
Table 1: Acid resistance test of Example 2 Initial After 3M storage at 40 C/75% RH
Acid resistance (%) 101 96 Dissolution of the multiple unit tablet was carried out in 0.1N HC1 (300m1) at 75rpm paddle for 2hrs followed by pH 6.8 (700m1) at 75rpm paddle for 45 minutes (at initial time point and after 3 months storage at accelerated conditions). The result for Example 2 is given in Table 2 given below:
Table 2: Dissolution test of Example 2 Initial After 3M storage at 40 C/75% RH
% Drug release Further, it was observed that the multiple unit tablet dosage form according to the present invention has good stability. The assay values and the amount of impurities (at initial time point and after 3 months storage at accelerated conditions) for Example 2 is provided in Table 3 below:
Table 3: Stability data for Example 2 Initial 3M (40 / 75 % RH) Assay (%) 98 94.5 Impurity 1 0.077 0.130 Impurity 2 0.018 0.015 Impurity 3 0.145 0.157 Impurity 4 0.047 0.100 Impurity 5 0.062 0.197 Totallmpurity 0.753 1.481 The above results show that composition of the present invention is stable even after storage for 3 months at 40 C and 75% RH.
Example 3 Qty (mg/unit) S. No Ingredients Strength (40mg) 40 mg Sugar spheres 60 A Drug Layer Esomeprazole calcium eqv. to Esomeprazole 45.44 Hydroxypropylcellulose 16.0 Crospovidone 8.0 Purified water q. s.
Total 131.44 B Separating layer Polyvinyl pyrrolidone 8.5 Polyethylene G1yco1400 0.8 Talc 14.5 Purified water/Isopropyl alcohol q. s.
Total 155.24 C Enteric Coating layer Hydroxypropylmethyl cellulose phthalate 119 HPMCP (HP-55) Hydroxypropylmethyl cellulose phthalate 29.66 Diethyl phthalate 19.1 Talc 3 Acetone q.s.
Purified water q.s.
Total 326 D Overcoating layer Hydroxypropylcellulose 5.6 Polyethylene glycol (PEG 6000) 8.4 Isopropyl alcohol/Dichloromethane q. s.
Total 341.23 E Compression Crospovidone 60 Cellulose microcrystalline PH 101 478 Cellulose microcrystalline PH 112 189 Hydroxypropylcellulose (L-HPC) 110 Sodium stearyl Fumarate 18 Total 1200 F Film Coating Opadry pink 27 Isopropyl alcohol q.s.
Dichloromethane q.s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose (HPC-L) and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole calcium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to obtain a dispersion.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Diethyl phthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Over coating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 4 Qty (mg/unit) S. No Ingredients Strength (40mg) 40 mg Sugar spheres 60 A Drug Layer Esomeprazole magnesium e v. to Esomeprazole 44.5 Hydroxypropylcellulose 18.0 Crospovidone 8.0 Purified water q. s.
Total 130.5 B Separating layer Polyvinyl pyrrolidone 15.0 Polyethylene G1yco1400 1.0 Talc 3.2 Purified water/Isopropyl alcohol q. s.
Total 150.0 C Enteric Coating layer Eudragit L30D55 96.51 Triethyl citrate 12.53 Talc 23.67 Acetone q.s.
Purified water q.s.
Total 282.72 D Overcoating layer Hydroxypropylmethylcellulose (HPMC-E5) 12.0 Polyethylene glycol (PEG 6000) 16.0 Isopropyl alcohol/Dichloromethane q.s.
Total 310.72 E Compression Crospovidone 58 Cellulose microcrystalline PH 101 511.28 Cellulose microcrystalline PH 112 211 Polyvinylpyrrolidone /Hydroxypropylcellulose / low 105 substituted hydroxypropylcellulose (L-HPC) Sodium stearyl Fumarate 4.0 Total 1200 F Film Coating Opadry pink 30 Isopropyl alcohol q.s.
Dichloromethane q. s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the 10 dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified 15 water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG
400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to obtain a dispersion.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to 20 obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Triethylcitrate was dissolved in purified water followed by addition of talc under continuous stirring.
11. Eudragit dispersion was added to step 10 under continuous stirring.
12. The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Overcoating 14. Hydroxypropylmethylcellulose (HPMC-E5) was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, Polyvinylpyrrolidone /Hydroxypropylcellulose /
low substituted hydroxypropylcellulose (L-HPC) and crospovidone were sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 2 Qty (mg/unit) Ingredients Strength (40mg) 40 mg Sugar spheres (#40-60) 60 Drug Layer Esomeprazole Magnesium eqv. to Esomeprazole 45.44 Hydroxypropylcellulose 16.0 Crospovidone 8.0 Purified water q. s.
Total 131.44 Separating layer Polyvinyl pyrrolidone 8.5 Polyethylene G1yco1400 0.8 Talc 14.5 Purified water/Isopropyl alcohol q. s.
Total 155.24 Enteric Coating layer Methacrylic acid copolymer (Eudragit L100D 55) 121 Hydroxypropylmethyl cellulose phthalate HPMCP 30 Triethyl citrate 19.63 Talc 15.8 Acetone q.s.
Purified water q.s.
Total 341.67 Overcoating layer Hydroxypropylcellulose 5.6 Polyethylene glycol (PEG 6000) 8.4 Isopropyl alcohol/Dichloromethane q. s.
Total 355.67 Compression Crospovidone 60 Cellulose microcrystalline PH 101 478 Cellulose microcrystalline PH 112 189 Hydroxypropylcellulose 110 Sodium stearyl Fumarate 18 Total 1200 Film Coating Opadry pink 27 Isopropyl alcohol q.s.
Dichloromethane q. s.
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring to obtain a dispersion.
3. Esomeprazole Magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads obtained in step 8 were dried at product temperature of 35 5 C
for 15-30 minutes.
Enteric Coating 10. Triethylcitrate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate and Eudragit L 100D 55 under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Overcoating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- Hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
5 Acid resistance test of the multiple unit tablet was performed in 0.1N HC1 at 75 rpm paddle for 120min (at initial time point and after 3 months storage at accelerated conditions). The result is given in the following table 1 below:
Table 1: Acid resistance test of Example 2 Initial After 3M storage at 40 C/75% RH
Acid resistance (%) 101 96 Dissolution of the multiple unit tablet was carried out in 0.1N HC1 (300m1) at 75rpm paddle for 2hrs followed by pH 6.8 (700m1) at 75rpm paddle for 45 minutes (at initial time point and after 3 months storage at accelerated conditions). The result for Example 2 is given in Table 2 given below:
Table 2: Dissolution test of Example 2 Initial After 3M storage at 40 C/75% RH
% Drug release Further, it was observed that the multiple unit tablet dosage form according to the present invention has good stability. The assay values and the amount of impurities (at initial time point and after 3 months storage at accelerated conditions) for Example 2 is provided in Table 3 below:
Table 3: Stability data for Example 2 Initial 3M (40 / 75 % RH) Assay (%) 98 94.5 Impurity 1 0.077 0.130 Impurity 2 0.018 0.015 Impurity 3 0.145 0.157 Impurity 4 0.047 0.100 Impurity 5 0.062 0.197 Totallmpurity 0.753 1.481 The above results show that composition of the present invention is stable even after storage for 3 months at 40 C and 75% RH.
Example 3 Qty (mg/unit) S. No Ingredients Strength (40mg) 40 mg Sugar spheres 60 A Drug Layer Esomeprazole calcium eqv. to Esomeprazole 45.44 Hydroxypropylcellulose 16.0 Crospovidone 8.0 Purified water q. s.
Total 131.44 B Separating layer Polyvinyl pyrrolidone 8.5 Polyethylene G1yco1400 0.8 Talc 14.5 Purified water/Isopropyl alcohol q. s.
Total 155.24 C Enteric Coating layer Hydroxypropylmethyl cellulose phthalate 119 HPMCP (HP-55) Hydroxypropylmethyl cellulose phthalate 29.66 Diethyl phthalate 19.1 Talc 3 Acetone q.s.
Purified water q.s.
Total 326 D Overcoating layer Hydroxypropylcellulose 5.6 Polyethylene glycol (PEG 6000) 8.4 Isopropyl alcohol/Dichloromethane q. s.
Total 341.23 E Compression Crospovidone 60 Cellulose microcrystalline PH 101 478 Cellulose microcrystalline PH 112 189 Hydroxypropylcellulose (L-HPC) 110 Sodium stearyl Fumarate 18 Total 1200 F Film Coating Opadry pink 27 Isopropyl alcohol q.s.
Dichloromethane q.s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
2. Hydroxypropylcellulose (HPC-L) and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole calcium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG 400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to obtain a dispersion.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Diethyl phthalate was dissolved in acetone followed by hydroxypropylmethylcellulose phthalate under continuous stirring.
11. Purified water was added in the dispersion of step 10 under stirring to obtain a dispersion.
12. The separating layer coated beads of step 9 was coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Over coating 14. Hydroxypropylcellulose was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution to obtain a dispersion.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, L- hydroxypropylcellulose and crospovidone was sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Example 4 Qty (mg/unit) S. No Ingredients Strength (40mg) 40 mg Sugar spheres 60 A Drug Layer Esomeprazole magnesium e v. to Esomeprazole 44.5 Hydroxypropylcellulose 18.0 Crospovidone 8.0 Purified water q. s.
Total 130.5 B Separating layer Polyvinyl pyrrolidone 15.0 Polyethylene G1yco1400 1.0 Talc 3.2 Purified water/Isopropyl alcohol q. s.
Total 150.0 C Enteric Coating layer Eudragit L30D55 96.51 Triethyl citrate 12.53 Talc 23.67 Acetone q.s.
Purified water q.s.
Total 282.72 D Overcoating layer Hydroxypropylmethylcellulose (HPMC-E5) 12.0 Polyethylene glycol (PEG 6000) 16.0 Isopropyl alcohol/Dichloromethane q.s.
Total 310.72 E Compression Crospovidone 58 Cellulose microcrystalline PH 101 511.28 Cellulose microcrystalline PH 112 211 Polyvinylpyrrolidone /Hydroxypropylcellulose / low 105 substituted hydroxypropylcellulose (L-HPC) Sodium stearyl Fumarate 4.0 Total 1200 F Film Coating Opadry pink 30 Isopropyl alcohol q.s.
Dichloromethane q. s.
Process of preparation:
Drug Layering 1. Sugar spheres were sifted through # 36 BSS and # 60 BSS and the fraction retained between # 36-60 BSS was collected.
5 2. Hydroxypropylcellulose and Crospovidone was sifted through # 30 BSS
followed by dispersing in purified water under mechanical stirring.
3. Esomeprazole magnesium was sifted through # 30 BSS followed by dispersing in step 2 dispersion.
4. The sugar spheres of step 1 were loaded into Wurster coater and coated with the 10 dispersion of step 3 to obtain drug-layered beads.
5. The beads obtained in step 4 were dried at product temperature of 35 5 C
for 15-30 minutes.
Separating layer 6. Polyvinylpyrrolidone was sifted through # 30 BSS and dissolved in purified 15 water/Isopropyl alcohol followed by addition of Polyethylene glycol (PEG
400) in the solution.
7. Talc was sifted through # 30 BSS and dispersed in solution of step 6 to obtain a dispersion.
8. The drug-layered beads of step 5 were coated with the dispersion of step 7 to 20 obtain separating layer coated beads.
9. The beads were dried at product temperature of 35 5 C for 15-30 minutes.
Enteric Coating 10. Triethylcitrate was dissolved in purified water followed by addition of talc under continuous stirring.
11. Eudragit dispersion was added to step 10 under continuous stirring.
12. The separating layer coated beads of step 9 were coated with dispersion of step 11 to obtain enteric-coated beads.
13. The beads obtained in step 12 were dried at product temperature of 35 5 C for 12 hrs in vacuum tray drier.
Overcoating 14. Hydroxypropylmethylcellulose (HPMC-E5) was sifted through # 30 BSS and dissolved in Isopropyl alcohol/Dichloromethane followed by addition of Polyethylene glycol (PEG 400) in the solution.
15. The enteric-coated beads of step 13 were coated with the dispersion of step 14 to obtain overcoated coated beads.
16. The beads obtained in step 15 were dried at product temperature of 35 5 C for 15-30 minutes.
Compression 17. The overcoated beads of step 16 were sifted through # 18 BSS.
18. Microcrystalline cellulose, Polyvinylpyrrolidone /Hydroxypropylcellulose /
low substituted hydroxypropylcellulose (L-HPC) and crospovidone were sifted through # 30 BSS.
19. The material of step 17 & 18 were blended in a blender.
20. Sodium stearyl fumarate was sifted through # 30 BSS and added to the material of step 19 and blended further.
21. The material of step 20 was compressed using approved tooling.
Film Coating 22. Opadry pink was dispersed in isopropyl alcohol/dichloromethane.
23. The tablets of step 21 were coated with the dispersion of step 22.
Claims (17)
1. A multiple unit tablet composition comprising: a) one or more tablet excipients, and b) a multiple of enteric coating layered core units containing a benzimidazole compound, wherein each core unit is covered with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer.
2. The composition according to claim 1, wherein the enteric coating layered core units comprise: a) a core comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients, and b) a separating layer surrounding the core, and c) an enteric coating layer surrounding the separating layer.
3. The composition according to claim 1, wherein the benzimidazole compound is selected from one or more of omeprazole, lansoprazole, rabeprazole, pantoprazole, leminoprazole, pariprazole and their single enantiomers, pharmaceutically accepted salts, solvates and their mixtures.
4. The composition according to claim 3, wherein the benzimidazole compound is in the form of a pharmaceutically acceptable alkaline salt.
5. The composition according to claim 1, wherein the enteric coating layer polymer is selected from one or more of cellulose acetate phthalate, hydroxypropylmethyl cellulose phthalate, polyvinyl acetate phthalate, carboxymethylethylcellulose and methacrylic acid copolymers.
6. The composition according to claim 1, wherein the plasticizer is selected from one or more of triacetin, citric acid esters, phthalic acid esters, dibutyl sebacate, cetyl alcohol, polyethylene glycols and polysorbates.
7. The composition according to claim 1, wherein the amount of the plasticizer ranges from 8% to 14% by weight of the enteric coating layer polymer.
8. The composition according to claim 1, wherein the tablet excipients are selected from one or more of binders, fillers, disintegrants and lubricants.
9. The composition according to claim 8, wherein the binders are selected from one or more of cellulose derivatives selected from hydroxypropylmethyl cellulose, hydroxypropyl cellulose and methylcellulose; gums selected from xanthan gum, gum acacia and tragacanth; water-soluble vinylpyrrolidone polymers selected from polyvinylpyrrolidone and copolymer of vinylpyrrolidone vinyl acetate; and sugars selected from sorbitol and mannitol.
10. The composition according to claim 8, wherein the fillers are selected from one or more of sugars selected from dextrose, glucose and lactose; sugar alcohols selected from sorbitol, xylitol and mannitol; cellulose derivatives selected from powdered cellulose and microcrystalline cellulose and starches selected from corn starch, pregelatinized starch and maize starch.
11. The composition according to claim 8, wherein the disintegrants are selected from one or more of sodium starch glycolate, croscarmellose sodium, crospovidone and corn starch.
12. The composition according to claim 8, wherein the lubricants are selected from one or more of magnesium stearate, talc, sodium stearyl fumarate and colloidal silicon dioxide.
13. The composition according to claim 2, wherein the enteric coating layer is further covered by an over-coating layer.
14. The composition according to claim 13, wherein the over-coating layer comprises a plasticizer in an amount ranging from 0-30% by weight of the enteric coating layer polymer.
15. The process for the preparation of composition of any of claims 2-12, wherein the process comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) mixing the multiple of enteric coating layered core units of step (c) with one or more tablet excipients, and e) compressing the mixture of step (d) into tablets.
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) mixing the multiple of enteric coating layered core units of step (c) with one or more tablet excipients, and e) compressing the mixture of step (d) into tablets.
16. The process for the preparation of composition of any of claims 13 or 14, wherein the process comprises the steps of:
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) covering the enteric coating layered core units of step (c) with an over-coating layer, e) mixing the multiple of over coating layered core units of step (d) with one or more tablet excipients, and f) compressing the mixture of step (e) into tablets.
a) preparing a multiple of core units comprising the benzimidazole compound and one or more pharmaceutically acceptable excipients.
b) coating the core of step (a) with a separating layer, c) covering the core of step (b) with an enteric coating layer comprising a plasticizer in an amount of less than 15% by weight of the enteric coating layer polymer, d) covering the enteric coating layered core units of step (c) with an over-coating layer, e) mixing the multiple of over coating layered core units of step (d) with one or more tablet excipients, and f) compressing the mixture of step (e) into tablets.
17. A method of inhibiting gastric acid secretion, the method comprising administering to a patient in need thereof a multiple unit tablet composition according to claim 1.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| IN2279DE2006 | 2006-10-17 | ||
| IN2279/DEL/2006 | 2006-10-17 | ||
| PCT/IB2007/054233 WO2008047320A2 (en) | 2006-10-17 | 2007-10-17 | Multiple unit tablet compositions of benzimidazole compounds |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA2667039A1 true CA2667039A1 (en) | 2008-04-24 |
Family
ID=39271195
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA002667039A Abandoned CA2667039A1 (en) | 2006-10-17 | 2007-10-17 | Multiple unit tablet compositions of benzimidazole compounds |
Country Status (5)
| Country | Link |
|---|---|
| EP (1) | EP2081546A2 (en) |
| AU (1) | AU2007311493B2 (en) |
| BR (1) | BRPI0717613A2 (en) |
| CA (1) | CA2667039A1 (en) |
| WO (1) | WO2008047320A2 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ607225A (en) | 2010-07-22 | 2015-02-27 | Lupin Ltd | Multiple unit tablet composition |
| US20170042806A1 (en) | 2015-04-29 | 2017-02-16 | Dexcel Pharma Technologies Ltd. | Orally disintegrating compositions |
| US10076494B2 (en) | 2016-06-16 | 2018-09-18 | Dexcel Pharma Technologies Ltd. | Stable orally disintegrating pharmaceutical compositions |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| GB2189698A (en) * | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
| DE29522419U1 (en) * | 1994-07-08 | 2003-07-03 | AstraZeneca AB, Södertälje | Multiple unit tabletted dosage form contg omeprazole - comprising enteric coated layered units of core material contg omeprazole compressed with excipients into tablets |
| WO1996007421A2 (en) * | 1994-09-09 | 1996-03-14 | Takeda Chemical Industries, Ltd. | An antiulcer medicine comprising a protein possessing all growth factor activity and a proton pump inhibitor |
| FR2774288B1 (en) * | 1998-01-30 | 2001-09-07 | Ethypharm Sa | GASTROPROTEGED OMEPRAZOLE MICROGRANULES, PROCESS FOR OBTAINING AND PHARMACEUTICAL PREPARATIONS |
| US6228400B1 (en) * | 1999-09-28 | 2001-05-08 | Carlsbad Technology, Inc. | Orally administered pharmaceutical formulations of benzimidazole derivatives and the method of preparing the same |
| PE20050150A1 (en) * | 2003-05-08 | 2005-03-22 | Altana Pharma Ag | A DOSAGE FORM CONTAINING (S) -PANTOPRAZOLE AS AN ACTIVE INGREDIENT |
-
2007
- 2007-10-17 AU AU2007311493A patent/AU2007311493B2/en not_active Withdrawn - After Issue
- 2007-10-17 CA CA002667039A patent/CA2667039A1/en not_active Abandoned
- 2007-10-17 WO PCT/IB2007/054233 patent/WO2008047320A2/en active Application Filing
- 2007-10-17 BR BRPI0717613-9A2A patent/BRPI0717613A2/en not_active IP Right Cessation
- 2007-10-17 EP EP07826778A patent/EP2081546A2/en not_active Withdrawn
Also Published As
| Publication number | Publication date |
|---|---|
| WO2008047320A2 (en) | 2008-04-24 |
| WO2008047320A3 (en) | 2008-06-19 |
| EP2081546A2 (en) | 2009-07-29 |
| AU2007311493A1 (en) | 2008-04-24 |
| BRPI0717613A2 (en) | 2013-10-22 |
| AU2007311493B2 (en) | 2013-01-31 |
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