CN1747723B - 含活性成分混合物的组合物及其制备方法 - Google Patents
含活性成分混合物的组合物及其制备方法 Download PDFInfo
- Publication number
- CN1747723B CN1747723B CN200480003558XA CN200480003558A CN1747723B CN 1747723 B CN1747723 B CN 1747723B CN 200480003558X A CN200480003558X A CN 200480003558XA CN 200480003558 A CN200480003558 A CN 200480003558A CN 1747723 B CN1747723 B CN 1747723B
- Authority
- CN
- China
- Prior art keywords
- active component
- coating
- core
- granule
- weight
- 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.)
- Expired - Fee Related
Links
- 239000000203 mixture Substances 0.000 title claims description 58
- 238000000034 method Methods 0.000 title claims description 21
- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000000576 coating method Methods 0.000 claims abstract description 59
- 239000011248 coating agent Substances 0.000 claims abstract description 56
- 239000007931 coated granule Substances 0.000 claims description 30
- 239000008187 granular material Substances 0.000 claims description 27
- 239000011230 binding agent Substances 0.000 claims description 26
- 229920000642 polymer Polymers 0.000 claims description 19
- 239000000654 additive Substances 0.000 claims description 12
- 230000000996 additive effect Effects 0.000 claims description 12
- 239000002346 layers by function Substances 0.000 claims description 12
- 229920001577 copolymer Polymers 0.000 claims description 11
- 239000000725 suspension Substances 0.000 claims description 10
- 239000000243 solution Substances 0.000 claims description 9
- 238000005507 spraying Methods 0.000 claims description 9
- 235000019640 taste Nutrition 0.000 claims description 9
- 239000010410 layer Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 229920001688 coating polymer Polymers 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 238000001035 drying Methods 0.000 claims description 5
- 229920000881 Modified starch Polymers 0.000 claims description 4
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000004480 active ingredient Substances 0.000 claims description 4
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 4
- 239000011877 solvent mixture Substances 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims description 3
- 229920002907 Guar gum Polymers 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 229930006000 Sucrose Natural products 0.000 claims description 3
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
- 235000010443 alginic acid Nutrition 0.000 claims description 3
- 239000000783 alginic acid Substances 0.000 claims description 3
- 229920000615 alginic acid Polymers 0.000 claims description 3
- 229960001126 alginic acid Drugs 0.000 claims description 3
- 150000004781 alginic acids Chemical class 0.000 claims description 3
- 239000000665 guar gum Substances 0.000 claims description 3
- 235000010417 guar gum Nutrition 0.000 claims description 3
- 229960002154 guar gum Drugs 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229940068984 polyvinyl alcohol Drugs 0.000 claims description 3
- 235000019422 polyvinyl alcohol Nutrition 0.000 claims description 3
- 235000010413 sodium alginate Nutrition 0.000 claims description 3
- 239000000661 sodium alginate Substances 0.000 claims description 3
- 229940005550 sodium alginate Drugs 0.000 claims description 3
- 229940032147 starch Drugs 0.000 claims description 3
- 239000005720 sucrose Substances 0.000 claims description 3
- 239000002152 aqueous-organic solution Substances 0.000 claims description 2
- 239000008194 pharmaceutical composition Substances 0.000 claims 2
- 238000005469 granulation Methods 0.000 claims 1
- 230000003179 granulation Effects 0.000 claims 1
- 239000002245 particle Substances 0.000 abstract description 5
- 239000003826 tablet Substances 0.000 description 34
- RZVAJINKPMORJF-UHFFFAOYSA-N Acetaminophen Chemical compound CC(=O)NC1=CC=C(O)C=C1 RZVAJINKPMORJF-UHFFFAOYSA-N 0.000 description 26
- 239000011162 core material Substances 0.000 description 24
- 239000003814 drug Substances 0.000 description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 16
- 229960005489 paracetamol Drugs 0.000 description 13
- 239000000546 pharmaceutical excipient Substances 0.000 description 10
- 239000003795 chemical substances by application Substances 0.000 description 9
- 238000005243 fluidization Methods 0.000 description 9
- 210000000214 mouth Anatomy 0.000 description 9
- 239000007921 spray Substances 0.000 description 9
- 239000000377 silicon dioxide Substances 0.000 description 8
- 150000005846 sugar alcohols Polymers 0.000 description 8
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 239000003085 diluting agent Substances 0.000 description 7
- BQNSLJQRJAJITR-UHFFFAOYSA-N 1,1,2-trichloro-1,2-difluoroethane Chemical compound FC(Cl)C(F)(Cl)Cl BQNSLJQRJAJITR-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- -1 anticholesteremic Substances 0.000 description 6
- 239000000314 lubricant Substances 0.000 description 6
- 229960003617 oxycodone hydrochloride Drugs 0.000 description 6
- 210000003296 saliva Anatomy 0.000 description 6
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 6
- OJHZNMVJJKMFGX-BWCYBWMMSA-N (4r,4ar,7ar,12bs)-9-methoxy-3-methyl-1,2,4,4a,5,6,7a,13-octahydro-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;(2r,3r)-2,3-dihydroxybutanedioic acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O.C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC OJHZNMVJJKMFGX-BWCYBWMMSA-N 0.000 description 5
- 239000001828 Gelatine Substances 0.000 description 5
- 239000002775 capsule Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 229920000159 gelatin Polymers 0.000 description 5
- 235000019322 gelatine Nutrition 0.000 description 5
- 239000002904 solvent Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical class [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 4
- BRUQQQPBMZOVGD-XFKAJCMBSA-N Oxycodone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C BRUQQQPBMZOVGD-XFKAJCMBSA-N 0.000 description 4
- 229940069428 antacid Drugs 0.000 description 4
- 239000003159 antacid agent Substances 0.000 description 4
- 230000001458 anti-acid effect Effects 0.000 description 4
- 239000004148 curcumin Substances 0.000 description 4
- XYYVYLMBEZUESM-UHFFFAOYSA-N dihydrocodeine Natural products C1C(N(CCC234)C)C2C=CC(=O)C3OC2=C4C1=CC=C2OC XYYVYLMBEZUESM-UHFFFAOYSA-N 0.000 description 4
- 239000007919 dispersible tablet Substances 0.000 description 4
- LLPOLZWFYMWNKH-CMKMFDCUSA-N hydrocodone Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)CC(=O)[C@@H]1OC1=C2C3=CC=C1OC LLPOLZWFYMWNKH-CMKMFDCUSA-N 0.000 description 4
- 229960000240 hydrocodone Drugs 0.000 description 4
- OROGSEYTTFOCAN-UHFFFAOYSA-N hydrocodone Natural products C1C(N(CCC234)C)C2C=CC(O)C3OC2=C4C1=CC=C2OC OROGSEYTTFOCAN-UHFFFAOYSA-N 0.000 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 229960002085 oxycodone Drugs 0.000 description 4
- 235000012239 silicon dioxide Nutrition 0.000 description 4
- LLPOLZWFYMWNKH-UHFFFAOYSA-N trans-dihydrocodeinone Natural products C1C(N(CCC234)C)C2CCC(=O)C3OC2=C4C1=CC=C2OC LLPOLZWFYMWNKH-UHFFFAOYSA-N 0.000 description 4
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 3
- IAOZJIPTCAWIRG-QWRGUYRKSA-N aspartame Chemical compound OC(=O)C[C@H](N)C(=O)N[C@H](C(=O)OC)CC1=CC=CC=C1 IAOZJIPTCAWIRG-QWRGUYRKSA-N 0.000 description 3
- 239000000796 flavoring agent Substances 0.000 description 3
- 235000013355 food flavoring agent Nutrition 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 229940016286 microcrystalline cellulose Drugs 0.000 description 3
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 3
- 239000008108 microcrystalline cellulose Substances 0.000 description 3
- 238000002156 mixing Methods 0.000 description 3
- 230000000149 penetrating effect Effects 0.000 description 3
- 239000000825 pharmaceutical preparation Substances 0.000 description 3
- 239000000454 talc Substances 0.000 description 3
- 235000012222 talc Nutrition 0.000 description 3
- 229910052623 talc Inorganic materials 0.000 description 3
- 108010011485 Aspartame Proteins 0.000 description 2
- 229920002785 Croscarmellose sodium Polymers 0.000 description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- 235000021355 Stearic acid Nutrition 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000000202 analgesic effect Effects 0.000 description 2
- 230000000767 anti-ulcer Effects 0.000 description 2
- 239000000605 aspartame Substances 0.000 description 2
- 235000010357 aspartame Nutrition 0.000 description 2
- 229960003438 aspartame Drugs 0.000 description 2
- 230000003115 biocidal effect Effects 0.000 description 2
- 125000004432 carbon atom Chemical group C* 0.000 description 2
- 230000001055 chewing effect Effects 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 239000013078 crystal Substances 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- YMTINGFKWWXKFG-UHFFFAOYSA-N fenofibrate Chemical compound C1=CC(OC(C)(C)C(=O)OC(C)C)=CC=C1C(=O)C1=CC=C(Cl)C=C1 YMTINGFKWWXKFG-UHFFFAOYSA-N 0.000 description 2
- 229960002297 fenofibrate Drugs 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000594 mannitol Substances 0.000 description 2
- 235000010355 mannitol Nutrition 0.000 description 2
- 239000004531 microgranule Substances 0.000 description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000004014 plasticizer Substances 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000007858 starting material Substances 0.000 description 2
- 239000008117 stearic acid Substances 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- YEYSQTFJKAWMNG-XMZRARIVSA-N (1r,2r)-2-[(dimethylamino)methyl]-1-(3-methoxyphenyl)cyclohexan-1-ol;n-(4-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(O)C=C1.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 YEYSQTFJKAWMNG-XMZRARIVSA-N 0.000 description 1
- FTLYMKDSHNWQKD-UHFFFAOYSA-N (2,4,5-trichlorophenyl)boronic acid Chemical compound OB(O)C1=CC(Cl)=C(Cl)C=C1Cl FTLYMKDSHNWQKD-UHFFFAOYSA-N 0.000 description 1
- RJEIGSKSSKIIHG-RKXJKUSZSA-N (4r,4as,7ar,12bs)-4a-hydroxy-9-methoxy-3-methyl-2,4,5,6,7a,13-hexahydro-1h-4,12-methanobenzofuro[3,2-e]isoquinoline-7-one;n-(4-hydroxyphenyl)acetamide Chemical compound CC(=O)NC1=CC=C(O)C=C1.O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(OC)C2=C5[C@@]13CCN4C RJEIGSKSSKIIHG-RKXJKUSZSA-N 0.000 description 1
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 description 1
- SUBDBMMJDZJVOS-UHFFFAOYSA-N 5-methoxy-2-{[(4-methoxy-3,5-dimethylpyridin-2-yl)methyl]sulfinyl}-1H-benzimidazole Chemical compound N=1C2=CC(OC)=CC=C2NC=1S(=O)CC1=NC=C(C)C(OC)=C1C SUBDBMMJDZJVOS-UHFFFAOYSA-N 0.000 description 1
- 208000030507 AIDS Diseases 0.000 description 1
- WBZFUFAFFUEMEI-UHFFFAOYSA-M Acesulfame k Chemical compound [K+].CC1=CC(=O)[N-]S(=O)(=O)O1 WBZFUFAFFUEMEI-UHFFFAOYSA-M 0.000 description 1
- 206010011224 Cough Diseases 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 208000019505 Deglutition disease Diseases 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 244000024675 Eruca sativa Species 0.000 description 1
- 235000014755 Eruca sativa Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 1
- 241000167880 Hirundinidae Species 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- 229920002774 Maltodextrin Polymers 0.000 description 1
- 239000005913 Maltodextrin Substances 0.000 description 1
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- ILRKKHJEINIICQ-OOFFSTKBSA-N Monoammonium glycyrrhizinate Chemical compound N.O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@H]1CC[C@]2(C)[C@H]3C(=O)C=C4[C@@H]5C[C@](C)(CC[C@@]5(CC[C@@]4(C)[C@]3(C)CC[C@H]2C1(C)C)C)C(O)=O)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O ILRKKHJEINIICQ-OOFFSTKBSA-N 0.000 description 1
- 241001597008 Nomeidae Species 0.000 description 1
- 229940123257 Opioid receptor antagonist Drugs 0.000 description 1
- 239000008896 Opium Substances 0.000 description 1
- RYMZZMVNJRMUDD-UHFFFAOYSA-N SJ000286063 Natural products C12C(OC(=O)C(C)(C)CC)CC(C)C=C2C=CC(C)C1CCC1CC(O)CC(=O)O1 RYMZZMVNJRMUDD-UHFFFAOYSA-N 0.000 description 1
- 239000004376 Sucralose Substances 0.000 description 1
- 206010047700 Vomiting Diseases 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 235000010358 acesulfame potassium Nutrition 0.000 description 1
- 229960004998 acesulfame potassium Drugs 0.000 description 1
- 239000000619 acesulfame-K Substances 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- RZAPELUKMZWLLG-UHFFFAOYSA-N acetic acid;2-hydroxypropane-1,2,3-tricarboxylic acid Chemical compound CC(O)=O.CC(O)=O.CC(O)=O.OC(=O)CC(O)(C(O)=O)CC(O)=O RZAPELUKMZWLLG-UHFFFAOYSA-N 0.000 description 1
- 230000001464 adherent effect Effects 0.000 description 1
- 239000002280 amphoteric surfactant Substances 0.000 description 1
- 239000002269 analeptic agent Substances 0.000 description 1
- 229940035676 analgesics Drugs 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 239000003945 anionic surfactant Substances 0.000 description 1
- 239000000730 antalgic agent Substances 0.000 description 1
- 239000004004 anti-anginal agent Substances 0.000 description 1
- 229940127003 anti-diabetic drug Drugs 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000002924 anti-infective effect Effects 0.000 description 1
- 230000002460 anti-migrenic effect Effects 0.000 description 1
- 230000002141 anti-parasite Effects 0.000 description 1
- 229940125713 antianxiety drug Drugs 0.000 description 1
- 239000003005 anticarcinogenic agent Substances 0.000 description 1
- 239000000935 antidepressant agent Substances 0.000 description 1
- 229940005513 antidepressants Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 239000003096 antiparasitic agent Substances 0.000 description 1
- 239000003443 antiviral agent Substances 0.000 description 1
- 239000002249 anxiolytic agent Substances 0.000 description 1
- 239000002830 appetite depressant Substances 0.000 description 1
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 235000019658 bitter taste Nutrition 0.000 description 1
- 230000023555 blood coagulation Effects 0.000 description 1
- 125000002091 cationic group Chemical group 0.000 description 1
- 239000003093 cationic surfactant Substances 0.000 description 1
- 235000010980 cellulose Nutrition 0.000 description 1
- 229920002678 cellulose Polymers 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 230000002490 cerebral effect Effects 0.000 description 1
- 239000003153 chemical reaction reagent Substances 0.000 description 1
- 239000000812 cholinergic antagonist Substances 0.000 description 1
- 238000001246 colloidal dispersion Methods 0.000 description 1
- 239000000306 component Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 239000002872 contrast media Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 230000002079 cooperative effect Effects 0.000 description 1
- 239000003218 coronary vasodilator agent Substances 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000000850 decongestant Substances 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- 238000002050 diffraction method Methods 0.000 description 1
- QGGZBXOADPVUPN-UHFFFAOYSA-N dihydrochalcone Chemical compound C=1C=CC=CC=1C(=O)CCC1=CC=CC=C1 QGGZBXOADPVUPN-UHFFFAOYSA-N 0.000 description 1
- PXLWOFBAEVGBOA-UHFFFAOYSA-N dihydrochalcone Natural products OC1C(O)C(O)C(CO)OC1C1=C(O)C=CC(C(=O)CC(O)C=2C=CC(O)=CC=2)=C1O PXLWOFBAEVGBOA-UHFFFAOYSA-N 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 206010013663 drug dependence Diseases 0.000 description 1
- 210000001198 duodenum Anatomy 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- XUFQPHANEAPEMJ-UHFFFAOYSA-N famotidine Chemical compound NC(N)=NC1=NC(CSCCC(N)=NS(N)(=O)=O)=CS1 XUFQPHANEAPEMJ-UHFFFAOYSA-N 0.000 description 1
- 229960001596 famotidine Drugs 0.000 description 1
- 239000010408 film Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 230000035784 germination Effects 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 230000003394 haemopoietic effect Effects 0.000 description 1
- 239000005556 hormone Substances 0.000 description 1
- 229940088597 hormone Drugs 0.000 description 1
- 230000000147 hypnotic effect Effects 0.000 description 1
- 229960003444 immunosuppressant agent Drugs 0.000 description 1
- 230000001861 immunosuppressant effect Effects 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960003174 lansoprazole Drugs 0.000 description 1
- 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 description 1
- 229940035034 maltodextrin Drugs 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 210000003097 mucus Anatomy 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- UZHSEJADLWPNLE-GRGSLBFTSA-N naloxone Chemical compound O=C([C@@H]1O2)CC[C@@]3(O)[C@H]4CC5=CC=C(O)C2=C5[C@@]13CCN4CC=C UZHSEJADLWPNLE-GRGSLBFTSA-N 0.000 description 1
- 229960004127 naloxone Drugs 0.000 description 1
- DQCKKXVULJGBQN-XFWGSAIBSA-N naltrexone Chemical compound N1([C@@H]2CC3=CC=C(C=4O[C@@H]5[C@](C3=4)([C@]2(CCC5=O)O)CC1)O)CC1CC1 DQCKKXVULJGBQN-XFWGSAIBSA-N 0.000 description 1
- 229960003086 naltrexone Drugs 0.000 description 1
- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 description 1
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 1
- 239000003176 neuroleptic agent Substances 0.000 description 1
- 230000000701 neuroleptic effect Effects 0.000 description 1
- 239000002736 nonionic surfactant Substances 0.000 description 1
- 229960000381 omeprazole Drugs 0.000 description 1
- 238000011275 oncology therapy Methods 0.000 description 1
- 229960001027 opium Drugs 0.000 description 1
- 229940042126 oral powder Drugs 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001575 pathological effect Effects 0.000 description 1
- 229940127557 pharmaceutical product Drugs 0.000 description 1
- 239000000419 plant extract Substances 0.000 description 1
- 229920000058 polyacrylate Polymers 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229950008882 polysorbate Drugs 0.000 description 1
- 238000003825 pressing Methods 0.000 description 1
- 238000004080 punching Methods 0.000 description 1
- VMXUWOKSQNHOCA-LCYFTJDESA-N ranitidine Chemical compound [O-][N+](=O)/C=C(/NC)NCCSCC1=CC=C(CN(C)C)O1 VMXUWOKSQNHOCA-LCYFTJDESA-N 0.000 description 1
- 229960000620 ranitidine Drugs 0.000 description 1
- 230000000717 retained effect Effects 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 229940085605 saccharin sodium Drugs 0.000 description 1
- 230000001953 sensory effect Effects 0.000 description 1
- RYMZZMVNJRMUDD-HGQWONQESA-N simvastatin Chemical compound C([C@H]1[C@@H](C)C=CC2=C[C@H](C)C[C@@H]([C@H]12)OC(=O)C(C)(C)CC)C[C@@H]1C[C@@H](O)CC(=O)O1 RYMZZMVNJRMUDD-HGQWONQESA-N 0.000 description 1
- 229960002855 simvastatin Drugs 0.000 description 1
- 239000002356 single layer Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 230000002048 spasmolytic effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 235000019408 sucralose Nutrition 0.000 description 1
- BAQAVOSOZGMPRM-QBMZZYIRSA-N sucralose Chemical compound O[C@@H]1[C@@H](O)[C@@H](Cl)[C@@H](CO)O[C@@H]1O[C@@]1(CCl)[C@@H](O)[C@H](O)[C@@H](CCl)O1 BAQAVOSOZGMPRM-QBMZZYIRSA-N 0.000 description 1
- 238000009495 sugar coating Methods 0.000 description 1
- 239000010409 thin film Substances 0.000 description 1
- 229940125725 tranquilizer Drugs 0.000 description 1
- 239000003204 tranquilizing agent Substances 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000003424 uricosuric effect Effects 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 230000008673 vomiting Effects 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
-
- 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
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2/00—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic
- B01J2/003—Processes or devices for granulating materials, e.g. fertilisers in general; Rendering particulate materials free flowing in general, e.g. making them hydrophobic followed by coating of the granules
-
- 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
- A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
- Y10T428/00—Stock material or miscellaneous articles
- Y10T428/29—Coated or structually defined flake, particle, cell, strand, strand portion, rod, filament, macroscopic fiber or mass thereof
- Y10T428/2982—Particulate matter [e.g., sphere, flake, etc.]
- Y10T428/2991—Coated
- Y10T428/2998—Coated including synthetic resin or polymer
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Physiology (AREA)
- Nutrition Science (AREA)
- Zoology (AREA)
- General Chemical & Material Sciences (AREA)
- Rheumatology (AREA)
- Pain & Pain Management (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicines Containing Plant Substances (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Cosmetics (AREA)
- General Preparation And Processing Of Foods (AREA)
Abstract
基于活性成分的包衣颗粒,其中核心和包衣均含活性成分,核心中含有第一活性成分,而包衣中含有本性不同的第二活性成分。
Description
本发明涉及含两种活性成分的包衣颗粒,其制备方法,及含该颗粒的多颗粒片剂。
在单位剂型中含两种活性成分的药剂形式早已存在,例如明胶胶囊或片剂。
在这些药剂形式中,第一种选择方案是分别配制各个活性组分。
然后这两个群体或是不经事先混合就压制成双层药片的形式,这在技术上复杂并且需要特殊的材料以进行压制;或是在压制前先进行混合,然后置于明胶胶囊或小药囊中。
第二种选择方案是同时配制两种活性成分,例如将其混合,随后是成粒步骤,形成的产物可以进行压制、放入明胶胶囊或放入小药囊。
这些混合物常常难以控制,因为它们将大小、质量和形式各自不同的几个活性成分和赋形剂的群体合在一起。由此造成了分离的危险增加,导致两种活性颗粒群体在其混合期间或混合后的药学操作期间,例如在压制或放入明胶胶囊期间,逐渐发生分层。最终的单位剂型中两种活性成分的含量都极其变化不定。
选择活性成分和赋形剂的群体需要极其小心,但仍不足以完全消除这一危险。
在活性成分的混合物的情形,由于另一群体的存在,分离的危险已经很高,如果最高剂量的活性成分与最低剂量的活性成分之间的剂量比高,特别是该比值等于或大于5,优选等于或大于10时,则分离的危险变得更为严重。
为了抵消这种不利的剂量比并保持各级分的各自质量比接近于1,经常向最低剂量的级分中加入活性成分用以成粒的稀释剂。
向颗粒配方中加入稀释剂导致患者要服用的药物剂型的单元尺寸和重量增加,这造成了在配制药物产品时另一个需要克服的障碍,并且使吞咽困难的患者更难服用。
在活性成分组合物中至少一种活性成分,甚至两种活性分,需要包衣来遮盖其令人不快的味道的情形,出现了第二个困难。
在这种情形,颗粒的尺寸由于遮盖味道的聚合物包衣而增大。
因此,最好是有这样一种组合物,它不存在上述的在质量和尺寸方面,以及适当时在含量方面不均匀性的危险,而且适合任何后继的配制操作,例如压制、放入明胶胶囊中或包衣。
为解决这一问题,本申请人发展了一种将两种本性不同的活性成分结合在一起的包衣颗粒,它们分别是作为全部或部分核心的组分的第一种活性成分,和作为全部或部分包衣的组分的第二活性组分。
在本说明书的其余部分,“包衣”代表含至少一个涂层的包膜。如果该包衣由几层构成,则每层应有相同的成分,利用喷涂法施加在核心上。但是应该指出,因为目的之一是得到尺寸尽可能小的包衣颗粒,所以颗粒最好是用单层包覆。围绕着核心施加的包衣要与附加的功能层相区分,所述附加层随后将会得到,它代表施加在基本包衣上的附加层。
换言之,根据本发明,同一颗粒结合两种不同的活性成分使得有可能解决上述与所用颗粒在尺寸和形状方面的群体不均匀性有关的问题。
因此本发明涉及一种以活性成分为基础的包衣颗粒,该颗粒中核心和包衣都含有活性成分,其中核心含有第一活性成分,而包衣含有本质上不同的第二活性成分。
申请人在专利申请02/39981中曾经展示了一种基本上球形的微粒,它由包覆着至少一个涂层的核心构成,核心和涂层各含80-95%重量的活性成分,余下的直至100%由至少一种粘合剂构成。根据该文献,构成核心的活性成分与涂层中包含的相同。此外,实施例中只叙述了基于单一活性成分的实施方案。
因此,为了解决活性成分含量不均匀的问题,如果两种活性成分在包衣颗粒中的浓度不同,则核中包含以最高剂量存在的活性成分,而包衣中包含以最低剂量存在的活性成分。
在一项有利的实施方案中,以最高剂量存在的活性成分(第一活性成分)和以最低剂量存在的活性成分(第二活性成分)之间的剂量比等于或大于5,优选等于或大于10。
该包衣颗粒含有两种活性成分,它们可以选自任何化合的族系,例如胃肠镇静药、抗酸药、镇痛药、消炎药、冠状血管扩张药、外围和脑血管扩张药、抗感染药、抗生素、抗病毒药、抗寄生虫药、抗癌药、抗焦虑药、精神安定药、中枢神经系统兴奋剂、抗抑郁药、抗组胺药、止泻药、缓泻药、营养补充剂、免疫抑制剂、降血胆固醇药、激素、酶、解痉药、抗心绞痛药、影响心律的药品、用于治疗动脉高血压的药物、抗偏头痛药、影响血液凝结性的药物、抗癫痫药、肌肉松弛药、用于治疗糖尿病的药物、用于治疗甲状腺机能障碍的药物、利尿剂、食欲抑制药、抗哮喘药、祛痰药、镇咳药、粘液调节剂、减充血药、催眠药、止呕药、造血药、促尿酸尿药、植物提取物和造影剂,或任何其它族系的化合物,结合在片剂内的活性成分可以选自相同或不同族系化合物。
制药工业特别研究了包括相同或不同族系药物的组合物,以用于治疗需要几种特性产物的联合处方的严重病理状况,因为它们通过减少患者要服用的单元数目有利于坚持治疗,并且有时可以得到协同效应。
活性成分的组合物在止痛领域特别有用,此时希望通过将两种效力适当的止痛药相组合,例如羟考酮与对乙酰氨基酚、氢可酮与对乙酰氨基酚、对乙酰氨基酚与曲马多相组合,或者利用一种阿片类止痛药(例如羟考酮)与一种阿片类受体拮抗剂(例如纳洛酮或纳曲酮)结合形成的组合物,对治疗疼痛产生协同作用,从而避免由于药物成瘾而不正确地使用药物。
在抗溃疡药方面,优选的组合物中将一种抗酸药与一种抗溃疡药组合,例如抗酸药和奥美拉唑或兰索拉唑组合,抗酸药和法莫替丁或雷尼替丁组合。
在降血胆固醇药和抗糖尿病药方面,优选的组合中将非诺贝特与二甲双胍或者非诺贝特与辛伐他汀组合。
还特别研究了其它领域,例如能有效对抗艾滋病的药物产品或抗癌药物。
根据本发明,包衣颗粒的成分将随所用的活性成分的颗粒尺寸和各活性成分在最终包衣颗粒中的含量而变。
在第一种实施方案中,核心中含100%重量的第一活性成分,而包衣中含60-99%重量、最好是80-99%重量的第二活性成分,其余的直至100%由至少一种粘合剂和任选存在的一种抗静电剂组成。
在此第一实施方案中,包衣中直至100%的剩余物也可以只由粘合剂组成。
在第二实施方案中,核心中含60-99%重量、优选80-99%重量的第一活性成分,而包衣中含60-99%重量、优选80-95%重量的第二活性成分,核心和包衣中其余的直至100%由至少一种粘合剂和任选存在的抗静电剂组成.
在此第二实施方案中,核心和包衣中其余部分直至100%重量可以只由粘合剂组成,该粘合剂可以相同或不同。
如上所述,在所有情形里均可考虑向用于包衣的悬浮液或溶液中添加抗静电剂。
粘合剂的选择将不仅决定于它将活性成分的颗粒彼此粘结在包衣核心中的能力,也取决于所希望的包衣核心的功能特性,是否存在后继的功能性包衣。“功能特性”一词特别是、但是非限制性地表示遮盖味道和改变或不改变活性成分释放的性质。
实际上,粘合剂特别是选自纤维素聚合物、丙烯酸聚合物、聚乙烯吡咯烷酮、乙烯基吡咯烷酮共聚物、聚乙烯醇、藻酸、藻酸钠、淀粉、预胶化淀粉、蔗糖及其衍生物、瓜耳胶、聚乙二醇以及它们的混合物。
在制备核心或包衣时,喷涂在溶剂中的粘合剂,该溶剂选自水和有机溶剂,例如乙醇、异丙醇或丙酮,单独使用或以混合物形式使用。
如上所述,核心和包衣中含有抗静电剂,其含量原则上可以为核心重量的最多10%,优选最多达3%,以及包衣重量的最多10%,优选最多达3%,它们可以选自微粒化或非微粒化的滑石、胶体二氧化硅(200)、处理过的二氧化硅(R972)或沉淀法二氧化硅(FR244),以及它们的混合物。
藉助于这种由核心和包覆核心使其基本上成球形的一个涂层所组成的结构,本发明的颗粒随后可以有利地用一附加的功能层包覆,该层的成分要根据所要求的遮盖味道和/或释放活性成分的特性来选择。
附加功能层的成分要依据各活性成分的物理化学特性来选择,并包含至少一种包衣聚合物。
该包衣聚合物最好是选自纤维素聚合物、丙烯酸聚合物及其混合物。
在纤维素聚合物中,优选选择乙基纤维素、羟丙基纤维素(HPC)和羟丙基甲基纤维素(HPMC),单独使用或作为混合物使用。
该附加功能层利用将包衣聚合物在溶剂或溶剂混合物中的溶液、悬浮液或者胶态分散体喷雾进行涂覆,以便形成包覆各颗粒全部表面的连续薄膜,不管颗粒表面光洁度如何,其数量足以实现例如在服用该药物产品时和该包衣颗粒保留在口腔内的整个期间能有效地遮盖住味道。
薄膜的厚度一般为5-75μm,这通常主要取决于包含在包衣内的活性成分(第二活性成分)在唾液pH下的溶解度和其或多或少的显著的苦味特性。
施加在本发明的包衣颗粒的表面上的附加功能层的聚合物,按照被包覆的团块的重量增加计算,可以最高达40%,优选最高达20%。
选择用来将包含在附加功能层中的包衣聚合物喷雾的溶剂可以是水,有机溶剂(例如乙醇、异丙醇或丙酮),或是溶剂混合物。
附加功能层还可任选地含有增塑剂、表面活性剂、抗静电剂、润滑剂。
增塑剂以相对于聚合物干重量的至多40%、优选15-30%的用量使用,选自柠檬酸三乙酸、乙酰三丁基柠檬酸酯、甘油三醋酸酯、柠檬酸三丁酯、邻苯二甲酸二乙酯、聚乙二醇、聚山梨酸酯、一和二乙酰基化的甘油酯及它们的混合物.
表面活性剂选自阴离子型、阳离子型、非离子型和两性型表面活性剂。
抗静电剂以相对于聚合物干重量的至多10%、优选0-3%、最好是少于1%的用量使用,选自微粒化或非微粒化的滑石、胶体二氧化硅(200)、处理过的二氧化硅(R972)或沉淀法二氧化硅(FP244),及它们的混合物。
润滑剂以相对于聚合物干重量的至多10%、优选0-3%、最好是少于1%的用量使用,选自硬脂酸镁、硬脂酸、硬脂酰富马酸钠、聚乙二醇、苯甲酸钠及它们的混合物。
包衣颗粒的尺寸宜为50μm-2mm,优选为100-800μm,更优选为200-500μm,用常规方法测定,例如利用一系列校正过的筛孔尺寸,或者用激光衍射法。
包含这种包衣颗粒的药物或化妆组合物也是本发明的目的之一。
可以包覆着附加功能层的这种包衣颗粒,可以用在打算口服给药的任何剂型中,但在所选择的剂型涉及使包衣颗粒与唾液接触的情形特别合适。
特别优选的药剂形式是打算用于口服的粉剂,包装成小的药囊形式,或是液体形式的可饮用的悬浮液,或者通过临时加入一定体积水重新构成的可饮用的悬浮液,或者是片剂,特别是口中可分散的或在小体积水中可分散的多颗粒片剂。
口中可分散的片剂定义为在口中与唾液接触时,不经咀嚼,在60秒之内,优选在40秒之内,即可崩解或溶解,形成颗粒的悬浮液,它可以有或者无包衣,容易吞咽。
崩解时间相当于从药片放在口中与唾液接触,到由于与唾液接触的药片不经咀嚼而崩解或溶解形成的悬浮液被吞咽的这段时间。
这类片剂描述于例如文献EP 548356、EP 636364、EP 1003484、EP 1058538、WO 98/46215、WO 00/06126、WO 00/27357和WO 00/51568中,但本发明的颗粒也可以用于与上述文献中所述的等价的其它制剂中。
最初,这种包衣颗粒在药片因唾液作用而崩解或溶解之后被释放到口腔中,然后在胃肠道中、胃中或十二指肠中迅速释放出活性成分。
口中可分散片剂由本发明的颗粒和赋形剂混合物形成,该混合物包括至少一种崩解剂、一种可溶性稀释剂、一种润滑剂和任选存在的一种溶胀剂、一种渗透剂、甜味剂和风味剂。
赋形剂混合物与包衣颗粒的相对比例通常为0.4-10、优选1-5重量份。
崩解剂特别是选自商业上用croscarmellose表示的交联的羧甲基纤维素钠,交联的聚乙烯吡咯烷酮及它们的混合物。
崩解剂的用量为片剂重量的1-20%,优选5-15%。在混合物的情形,每种崩解剂为药片重量的0.5-15%,优选5-10%。
稀释剂特别可以选自具有粘合性质的可溶性试剂,优选少于13个碳原子的多元醇、乳糖、纤维素衍生物,优选微晶纤维素。
优选的少于13个碳原子的多元醇是选自甘露醇、木糖醇、山梨醇和麦芽糖醇。
稀释剂以相对于片剂重量的20-90%、优选30-50%的用量使用。
可溶性稀释剂是一种可直接压制的产物形式,其颗粒的平均直径为100-500μm,或者是粉末形式,其颗粒的平均直径小于100μm,这种粉末可单独使用或者与可直接压制的产物混合使用.
在一项优选的实施方案中,多元醇是以可直接压制的产物形式使用。
在第二项优选的实施方案中,将可直接压制的多元醇和粉末形式的多元醇混合,此情形中的多元醇可以相同或不同,可直接压制的多元醇与粉状多元醇的比例为99/1至20/80,优选从80/20至20/80。
润滑剂选自硬脂酸镁、硬脂酸、硬脂酰富马酸钠、聚乙二醇、苯甲酸钠及它们的混合物。
润滑剂以相对于片剂重量的0.02-2%,优选0.5-1%的用量使用。
润滑剂被分散在压片赋形剂混合物中,在压制时完全或部分地喷涂在片剂表面上。
溶胀剂选自微晶纤维素、淀粉和改性淀粉。
溶胀剂以相对于片剂重量1.0-15%的用量使用。
渗透剂以相对于片剂重量的0.5-5.0%的用量使用。
抗静电剂以相对于片剂重量的0.5-5.0%的用量使用。
甜味剂特别可以选自天冬甜素、双氧噁噻嗪钾、糖精钠、新橙皮苷、双氢查耳酮、三氯蔗糖、甘草酸单铵盐及其混合物。
风味剂和染料是药学中通常用于制备片剂的那些风味剂和染料。
本发明还涉及制备上述包衣颗粒的方法。
本发明的方法包括以下步骤:
-制备含第一活性成分的核心,
-通过喷涂含第二活性成分和至少一种粘合剂的溶液,将这样得到的核心包衣,
-干燥。
在第一项优选实施方案中,按照以下步骤制备该颗粒:
-利用水溶液或有机溶液或溶剂混合物形式的粘合剂,使粉末形式的第一活性成分成粒,然后干燥,
-利用喷涂含有第二活性成分和至少一种粘合剂的溶液或悬浮液,将这样得到的核心包衣,
-干燥。
在第二项优选的实施方案中,按照以下步骤制备该颗粒:
-选择粒度为50μm-400μm的微晶构成第一活性成分,
-利用喷涂含第二活性成分和至少一种粘合剂的溶液或悬浮液,将该微粒包衣,
-干燥。
根据这一实施方案,喷涂可以在不同的或相同的装置中进行。
为进行成粒,可以方便地使用高能造粒机、行星式混合器或流化空气床。
在流化空气床中成粒的情形,将含活性成分以及任选加入的稀释剂和抗静电剂的粉末混合物,引入到该装置中,然后通过向该粉末混合物喷涂含至少一种粘合剂的赋形剂溶液或悬浮液,进行成粒。
当两种活性成分彼此不相容,以至于观察到其中之一加速退化时,可以在含第一活性成分的核心和含第二活性成分的包衣之间施加一个任选的聚合物层将两种活性成分隔开。该层于是由聚合物构成,它可以用来作为粘合剂,最好是与制备颗粒的某个步骤中作为粘合剂使用的相同的聚合物,所施加的聚合物数量按照要包覆的物质的重量增加计算,不超过15%,优选不超过5%。
如果颗粒的器官感觉特性确有必要,则进行一个附加的包覆这样得到的包衣颗粒的步骤,其作法是喷涂一个遮盖该味道的附加的功能层,随后干燥。
本发明方法的所有步骤均可在包糖衣盘中或多孔盘中进行,或在流化空气床中进行。
在本发明方法的一项优选实施方案中,用来制备包衣核心和包覆附加层的所有步骤均在流化空气床中进行。
流化空气床装有喷雾嘴,其喷雾方向和位置可以选择。
这种选择使得有可能控制颗粒生长的动力学和避免粘着现象,这与活性成分的本性、被喷雾的粘合或包衣组合物的成分、以及该方法的各种参数(温度,空气压力,溶液流量)有关。
根据一项有利的实施方案,用来制备颗粒的粘合剂和用来遮盖该颗粒的味道的聚合物是相同的。
本发明还涉及制备含有包衣颗粒的多颗粒片剂的方法。
本发明的方法包括以下步骤:
-将按照上述方法得到的颗粒与压制赋形剂干混,
-将该混合物压制得到单元形式。
混合物的压制可以在交替式或旋转式压片机上进行。
在压制步骤中施加的压力可以是5-50kN,优选5-15kN。
这些片剂的硬度,按照欧洲药典(2.9.8)的方法测定,优选为1-10kP,更优选为1-5kP,1kP等于9.8N。
最好是,多颗粒片剂的硬度适合达到按照欧洲药典的方法测得的脆碎度小于2%,同时保持其溶解状况与单独的包衣颗粒的相同,并且该片剂在口中的崩解时间可以小于或等于60秒,优选小于或等于40秒。
该片剂的直径可以为6-17mm。它们可以是圆形、椭圆形或长方形,表面平坦或凹陷,并任选地有沟槽。
在口中可分散的片剂的情形,也可以使用“Polo”(马球)形的冲孔。
片剂的质量为0.1-2.0克。
通过本发明的包衣颗粒和多颗粒片剂的制备实施例,将会更清楚地了解本发明。这些实施例仅仅是作为本发明的示例说明和有利的实施方案而给出,绝不构成对本发明的限制。
材料和分析方法
使用的赋形剂
微晶纤维素:FMC销售的pH 102。
胶体二氧化硅:BASF销售的244FP。
HPMC:SHIN-ETSU销售的603。
天冬甜素:Nutrasweet的产品。
在pH 1.2溶解的方法
→装置:USP II型
→叶片速度:50rpm
→体积:900ml
→温度:37.0℃±0.5℃
→检测:UV分光光度计,氢可酮酒石酸氢盐210nm,盐酸羟考酮280nm,对乙酰氨基酚298nm。
→溶解介质:0.1N HCl。
实施例1:结合盐酸羟考酮和对乙酰氨基酚的包衣颗粒
在装有Würster喷嘴(“底喷”)的GPCG-3型流化空气床内,将含有30.8g盐酸羟考酮(“oxycodone”)和8.0g(相当于oxycodone的25%重量)作为粘合剂的羟丙基甲基纤维素(“HPMC”)的水溶液喷涂到1000g平均尺寸为350μm的对乙酰氨基酚的晶体上。
该包衣颗粒的最终配方见表1:
表1
实施例2:含325mg对乙酰氨基酚和10mg盐酸羟考酮的口中可分散
片剂
将实施例1中得到的包衣颗粒按照表2与赋形剂混合,然后将得到的混合物将装有6圈直径15mm的平面冲孔的SVIAC PR6压片机上压片,从而得到平均含325mg对乙酰氨基酚和10mg羟考酮的单位剂量。
这样得到的片剂的最终配方见表2:表2
该片剂具有以下特性(表)3:
表3
重量(mg) | 1050 |
硬度(kP) | 3.5 |
脆碎度(%) | 0.6 |
在口中崩解(s) | 25 |
在pH为1.2的介质中按前述方法进行溶解试验,以便确定两种活性成分各自的体外试验释放动力学(表4):
表4
时间(分) | %(w/w)释放出的对乙酰氨基酚 | %(w/w)释放出的盐酸羟考酮 |
2.5 | 45 | 80 |
时间(分) | %(w/w)释放出的对乙酰氨基酚 | %(w/w)释放出的盐酸羟考酮 |
15 | 100 | 100 |
30 | 100 | 100 |
60 | 100 | 100 |
实施例3:结合氢可酮酒石酸氢盐和对乙酰氨基酚的包衣颗粒
将含有30.8g氢可酮酒石酸氢盐(“hydrocodone”)和9.2g作为粘合剂(相当于氢可酮的30%重量)的羟丙基甲基纤维素(“HPMC”)的水溶液,在装有Würster喷嘴(“底喷”)的GPCG-3型流化空气床中喷涂到1000g平均尺寸为350μm的对乙酰氨基酚晶体上。
按起始物颗粒的增重计算,总计在颗粒上施加了20%重量的E100。
包衣颗粒的最终配方见表5:
表5
实施例4:含325mg对乙酰氨基酚和10mg氢可酮酒石酸氢盐的口中
可分散片剂
将实施例3中得到的包衣颗粒按照表5与赋形剂混合,然后将这样得到的混合物在装有6圈直径15mm的平面冲孔的SVIAC PR6压片机上压片,得到平均含325mg对乙酰氨基酚和10mg氢可酮的单位剂量。
这样得到的片剂的最终配方见表6:
表6
这些片剂具有以下特性(表7):
表7
重量(mg) | 1400 |
硬度(kP) | 4.0 |
脆碎度(%) | 0.4 |
在口中崩解(s) | 30 |
按前述方法,在pH 1.2的介质中进行溶解试验,以便确定两种活性成分各自的体外试验释放动力学(表8):
表8
时间(分) | %(w/w)释放出的对乙酰氨基酚 | %(w/w)释放出的氢可酮酒石酸氢盐 |
2.5 | 35 | 80 |
15 | 75 | 100 |
30 | 90 | 100 |
60 | 100 | 100 |
Claims (13)
1.一种以活性成分为基础的药用包衣颗粒,其中核心和包衣都含有活性成分,核心中含60-99%重量的第一活性成分,而包衣中含有60-99%重量的不同的第二活性成分,核心和包衣中的其余直至100%重量由至少一种粘合剂和任选加入的抗静电剂组成,其中第一活性成分与第二活性成分的量比等于或大于5;所述包衣层直接包覆在核心上;所述包衣颗粒的尺寸为50μm-2mm。
2.权利要求1的药用包衣颗粒,其中包衣以及核心中其余的直至100%全由粘合剂组成,而且包衣和核心中的粘合剂相同或不同。
3.权利要求1或2的药用包衣颗粒,其中粘合剂选自纤维素聚合物、丙烯酸聚合物、聚乙烯吡咯烷酮、乙烯基吡咯烷酮共聚物、聚乙烯醇、藻酸、藻酸钠、淀粉、预胶化淀粉、蔗糖、瓜耳胶和聚乙二醇,单独使用或以混合物形式使用。
4.权利要求1或2的药用包衣颗粒,其中核心和/或包衣还含有至少一种抗静电剂,其含量为核心重量的最高达10%,包衣重量的最高达10%。
5.权利要求1或2的药用包衣颗粒,其中除包衣外还包含一个附加功能层,其成分根据所要求的遮盖味道和/或释放活性成分来选择。
6.权利要求5的药用包衣颗粒,其中附加功能层由选自纤维素聚合物和丙烯酸聚合物的至少一种包衣聚合物单独地或以混合物形式构成。
7.一种药用组合物,其含有权利要求1至6之一的药用包衣颗粒。
8.权利要求7的药用组合物,其形式为片剂。
9.一种制备用活性成分包衣的颗粒的方法,该颗粒的核心含有第一活性成分,而包衣中含第二活性成分,其中第一活性成分与第二活性成分的量比等于或大于5;所述包衣层直接包覆在核心上;所述包衣颗粒的尺寸为50μm-2mm,所述方法包括以下步骤:
-制备含60-99%重量的第一活性成分的核心,
-利用喷涂由60-99%重量的第二活性成分和至少一种粘合剂及任选加入的抗静电剂组成的溶液或悬浮液,将这样得到的核心包衣,
-干燥。
10.权利要求9的方法,其中制备核心的步骤包括将水溶液或有机溶液或溶剂混合物形式的粘合剂将粉末形式的第一活性成分粒化,然后干燥。
11.权利要求9的方法,其中核心的制备包括选择尺寸为50-400μm的微晶构成第一活性成分。
12.权利要求9的方法,其中包括用附加功能层包覆的附加步骤,该层的成分根据所要求的遮盖味道和/或释放活性成分的特性来选择,其中附加的层由选自纤维素聚合物、丙烯酸聚合物及其混合物的至少一种包衣聚合物组成。
13.权利要求9的方法,其中粘合剂选自纤维素聚合物、丙烯酸聚合物、聚乙烯吡咯烷酮、乙烯基吡咯烷酮共聚物、聚乙烯醇、藻酸、藻酸钠、淀粉、预胶化淀粉、蔗糖、瓜耳胶和聚乙二醇,单独使用或以混合物形式使用。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
FR0301308 | 2003-02-05 | ||
FR0301308A FR2850576B1 (fr) | 2003-02-05 | 2003-02-05 | Composition comprenant un melange de principes actifs, et procede de preparation |
US44719803P | 2003-02-13 | 2003-02-13 | |
US60/447,198 | 2003-02-13 | ||
PCT/EP2004/050035 WO2004069135A2 (en) | 2003-02-05 | 2004-01-21 | Composition comprising a mixture of active principles, and method of preparation |
Publications (2)
Publication Number | Publication Date |
---|---|
CN1747723A CN1747723A (zh) | 2006-03-15 |
CN1747723B true CN1747723B (zh) | 2010-05-12 |
Family
ID=32852330
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN200480003558XA Expired - Fee Related CN1747723B (zh) | 2003-02-05 | 2004-01-21 | 含活性成分混合物的组合物及其制备方法 |
Country Status (19)
Country | Link |
---|---|
US (2) | US7846460B2 (zh) |
EP (1) | EP1589954B1 (zh) |
JP (1) | JP4791348B2 (zh) |
KR (1) | KR20050096963A (zh) |
CN (1) | CN1747723B (zh) |
AU (1) | AU2004210438B2 (zh) |
BR (1) | BRPI0407116B1 (zh) |
CA (1) | CA2514446C (zh) |
EA (1) | EA010972B1 (zh) |
ES (1) | ES2590807T3 (zh) |
FR (1) | FR2850576B1 (zh) |
HK (1) | HK1087015A1 (zh) |
IL (1) | IL169880A (zh) |
IS (1) | IS7998A (zh) |
MX (1) | MXPA05008161A (zh) |
NO (1) | NO341294B1 (zh) |
NZ (1) | NZ541886A (zh) |
PL (1) | PL223347B1 (zh) |
WO (1) | WO2004069135A2 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8465776B2 (en) | 2006-08-04 | 2013-06-18 | Ethypharm | Granule and orally disintegrating tablet comprising oxycodone |
Families Citing this family (22)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TWI483944B (zh) | 2004-03-30 | 2015-05-11 | Euro Celtique Sa | 含有小於25ppm14-羥可待因酮之羥可酮鹽酸鹽組成物、醫藥劑型、延遲釋出口服劑型及醫藥上可以接受的包裝 |
US8163114B2 (en) * | 2004-04-07 | 2012-04-24 | New Jersey Institute Of Technology | Netshape manufacturing processes and compositions |
CN101277757B (zh) | 2005-08-02 | 2011-11-30 | 索尔-格尔科技有限公司 | 非水溶性成分的金属氧化物涂布 |
FR2897267A1 (fr) * | 2006-02-16 | 2007-08-17 | Flamel Technologies Sa | Formes pharmaceutiques multimicroparticulaires pour administration per os |
DK3103448T3 (da) * | 2006-09-26 | 2019-10-07 | Novartis Ag | Farmaceutiske sammensætninger, der omfatter en S1P-modulator |
WO2008089774A1 (fr) * | 2007-01-22 | 2008-07-31 | Crd Saidal | Formulation d'un comprime orodispersible a base de paracetamol enrobe |
MX2009008250A (es) | 2007-02-01 | 2009-08-27 | Sol Gel Technologies Ltd | Composiciones para aplicacion topica que comprenden un peroxido y retinoide. |
EP2223683B1 (en) * | 2007-12-27 | 2014-06-18 | Taiho Pharmaceutical Co., Ltd. | Oral particulate antitumor preparation |
TW201041608A (en) * | 2009-05-01 | 2010-12-01 | Eurand Inc | Orally disintegrating tablet compositions comprising combinations of high and low-dose drugs |
CN102526124B (zh) * | 2011-01-31 | 2013-11-20 | 成都科尔医药技术有限公司 | 一种中药粉体及其制备方法 |
AU2013203493B2 (en) * | 2012-03-02 | 2016-02-04 | Rhodes Pharmaceuticals L.P. | Tamper resistant immediate release formulations |
JP6320297B2 (ja) * | 2012-09-13 | 2018-05-09 | ライオン株式会社 | 発泡性口腔用組成物、発泡性口腔用固形製剤及び発泡性口腔用製品 |
EP2906202A4 (en) * | 2012-10-15 | 2016-04-27 | Isa Odidi | DRUG FORMULATIONS FOR ORAL ADMINISTRATION |
KR101484608B1 (ko) * | 2012-11-26 | 2015-01-22 | 한국과학기술연구원 | Pva와 알지네이트 기반 코어-쉘 구조의 복합담체 및 그 제조방법 |
US9687465B2 (en) | 2012-11-27 | 2017-06-27 | Sol-Gel Technologies Ltd. | Compositions for the treatment of rosacea |
CN105102117A (zh) | 2013-02-01 | 2015-11-25 | 格雷斯公司 | 作为用于液体技术的载体的多孔硅胶 |
CA3042642A1 (en) | 2013-08-12 | 2015-02-19 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded immediate release abuse deterrent pill |
WO2015095391A1 (en) | 2013-12-17 | 2015-06-25 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
US9492444B2 (en) | 2013-12-17 | 2016-11-15 | Pharmaceutical Manufacturing Research Services, Inc. | Extruded extended release abuse deterrent pill |
CA2955229C (en) | 2014-07-17 | 2020-03-10 | Pharmaceutical Manufacturing Research Services, Inc. | Immediate release abuse deterrent liquid fill dosage form |
EP3209282A4 (en) | 2014-10-20 | 2018-05-23 | Pharmaceutical Manufacturing Research Services, Inc. | Extended release abuse deterrent liquid fill dosage form |
CN111990641A (zh) * | 2020-05-06 | 2020-11-27 | 焦作百仑斯生物科技有限公司 | 一种解酒护肝片及施工方法 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000044404A (ja) * | 1998-07-27 | 2000-02-15 | Otsuka Chem Co Ltd | 農業用混合粒剤 |
US6296874B1 (en) * | 2000-05-01 | 2001-10-02 | Aeropharm Technology Incorporated | Core formulation comprising troglitazone and abiguanide |
Family Cites Families (5)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2259727A1 (en) * | 1999-01-18 | 2000-07-18 | Bernard Charles Sherman | A two-layer pharmaceutical tablet comprising an nsaid and misoprostol |
US6451342B2 (en) * | 2000-05-01 | 2002-09-17 | Aeropharm Technology Incorporated | Core formulation comprised of troglitazone and a biguanide |
US20030086972A1 (en) * | 2000-08-09 | 2003-05-08 | Appel Leah E. | Hydrogel-driven drug dosage form |
FR2816507B1 (fr) * | 2000-11-16 | 2003-02-28 | Ethypharm Lab Prod Ethiques | Microgranules a base de principe actif, procede de fabrication et compositons pharmaceutiques integrant lesdits microgranules |
JP4616009B2 (ja) * | 2002-12-26 | 2011-01-19 | ポーゼン インコーポレイテッド | NSAIDsおよびトリプタンを含有する多層剤型 |
-
2003
- 2003-02-05 FR FR0301308A patent/FR2850576B1/fr not_active Expired - Lifetime
-
2004
- 2004-01-21 WO PCT/EP2004/050035 patent/WO2004069135A2/en active Search and Examination
- 2004-01-21 JP JP2006501987A patent/JP4791348B2/ja not_active Expired - Fee Related
- 2004-01-21 ES ES04703798.1T patent/ES2590807T3/es not_active Expired - Lifetime
- 2004-01-21 EP EP04703798.1A patent/EP1589954B1/en not_active Expired - Lifetime
- 2004-01-21 PL PL376465A patent/PL223347B1/pl unknown
- 2004-01-21 KR KR1020057014021A patent/KR20050096963A/ko not_active Application Discontinuation
- 2004-01-21 CN CN200480003558XA patent/CN1747723B/zh not_active Expired - Fee Related
- 2004-01-21 US US10/544,311 patent/US7846460B2/en active Active
- 2004-01-21 EA EA200501250A patent/EA010972B1/ru not_active IP Right Cessation
- 2004-01-21 NZ NZ541886A patent/NZ541886A/en not_active IP Right Cessation
- 2004-01-21 MX MXPA05008161A patent/MXPA05008161A/es active IP Right Grant
- 2004-01-21 BR BRPI0407116-6A patent/BRPI0407116B1/pt not_active IP Right Cessation
- 2004-01-21 CA CA2514446A patent/CA2514446C/en not_active Expired - Lifetime
- 2004-01-21 AU AU2004210438A patent/AU2004210438B2/en not_active Ceased
-
2005
- 2005-07-26 IL IL169880A patent/IL169880A/en active IP Right Grant
- 2005-08-11 NO NO20053799A patent/NO341294B1/no not_active IP Right Cessation
- 2005-08-25 IS IS7998A patent/IS7998A/is unknown
-
2006
- 2006-06-22 HK HK06107140.8A patent/HK1087015A1/xx not_active IP Right Cessation
-
2010
- 2010-11-16 US US12/947,551 patent/US20110081389A1/en not_active Abandoned
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JP2000044404A (ja) * | 1998-07-27 | 2000-02-15 | Otsuka Chem Co Ltd | 農業用混合粒剤 |
US6296874B1 (en) * | 2000-05-01 | 2001-10-02 | Aeropharm Technology Incorporated | Core formulation comprising troglitazone and abiguanide |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US8465776B2 (en) | 2006-08-04 | 2013-06-18 | Ethypharm | Granule and orally disintegrating tablet comprising oxycodone |
Also Published As
Publication number | Publication date |
---|---|
WO2004069135A2 (en) | 2004-08-19 |
BRPI0407116B1 (pt) | 2018-04-03 |
EP1589954B1 (en) | 2016-08-31 |
JP4791348B2 (ja) | 2011-10-12 |
CA2514446A1 (en) | 2004-08-19 |
MXPA05008161A (es) | 2005-10-05 |
EP1589954A2 (en) | 2005-11-02 |
EA010972B1 (ru) | 2008-12-30 |
BRPI0407116A (pt) | 2006-01-10 |
AU2004210438A1 (en) | 2004-08-19 |
CN1747723A (zh) | 2006-03-15 |
WO2004069135A3 (en) | 2004-10-28 |
NZ541886A (en) | 2008-12-24 |
ES2590807T3 (es) | 2016-11-23 |
IL169880A0 (en) | 2007-07-04 |
PL223347B1 (pl) | 2016-10-31 |
IL169880A (en) | 2013-10-31 |
FR2850576B1 (fr) | 2007-03-23 |
HK1087015A1 (en) | 2006-10-06 |
US20060134422A1 (en) | 2006-06-22 |
US7846460B2 (en) | 2010-12-07 |
KR20050096963A (ko) | 2005-10-06 |
EA200501250A1 (ru) | 2006-02-24 |
FR2850576A1 (fr) | 2004-08-06 |
AU2004210438B2 (en) | 2007-08-16 |
NO341294B1 (no) | 2017-10-02 |
US20110081389A1 (en) | 2011-04-07 |
PL376465A1 (en) | 2005-12-27 |
IS7998A (is) | 2005-08-25 |
NO20053799L (no) | 2005-08-11 |
CA2514446C (en) | 2012-04-10 |
JP2006516597A (ja) | 2006-07-06 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN1747723B (zh) | 含活性成分混合物的组合物及其制备方法 | |
JP6014044B2 (ja) | 迅速分散顆粒、口腔内崩壊錠、および方法 | |
US10406105B2 (en) | Pharmaceutical formulation for the production of rapidly disintegrating tablets | |
CA2563440C (en) | Orally disintegrating tablets and methods of manufacture | |
JP5572616B2 (ja) | 口腔内分散性多層錠剤 | |
AU623560B2 (en) | Pharmaceutical granules and drug dosage units made therefrom | |
TW201041608A (en) | Orally disintegrating tablet compositions comprising combinations of high and low-dose drugs | |
EP2654735A2 (en) | Rapidly disintegrating, solid coated dosage form | |
JP4699350B2 (ja) | 味マスキング被覆粒子、その調製方法および前記被覆粒子を含有する口腔内崩壊錠剤 | |
US20150050336A1 (en) | Taste Masking System For Non-Plasticizing Drugs | |
EP1621187A1 (en) | Pharmaceutical multiparticulate tablet formulations and process for their preparation | |
WO2011040195A1 (ja) | 不快味マスキング粒子及びこれを含有する経口製剤 | |
CA3178341A1 (en) | Swellable oral pharmaceutical compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
C06 | Publication | ||
PB01 | Publication | ||
C10 | Entry into substantive examination | ||
SE01 | Entry into force of request for substantive examination | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: DE Ref document number: 1087015 Country of ref document: HK |
|
C14 | Grant of patent or utility model | ||
GR01 | Patent grant | ||
REG | Reference to a national code |
Ref country code: HK Ref legal event code: GR Ref document number: 1087015 Country of ref document: HK |
|
CF01 | Termination of patent right due to non-payment of annual fee | ||
CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20100512 |