EP0559645A1 - Composition for solid pharmaceutical preparations containing active vitamins d 3? and process for preparation thereof - Google Patents
Composition for solid pharmaceutical preparations containing active vitamins d 3? and process for preparation thereofInfo
- Publication number
- EP0559645A1 EP0559645A1 EP91910918A EP91910918A EP0559645A1 EP 0559645 A1 EP0559645 A1 EP 0559645A1 EP 91910918 A EP91910918 A EP 91910918A EP 91910918 A EP91910918 A EP 91910918A EP 0559645 A1 EP0559645 A1 EP 0559645A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- composition
- vitamins
- pharmaceutical preparations
- solid pharmaceutical
- active vitamins
- 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.)
- Withdrawn
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 45
- 239000000825 pharmaceutical preparation Substances 0.000 title claims abstract description 14
- 239000007787 solid Substances 0.000 title claims abstract description 13
- 238000000034 method Methods 0.000 title claims description 13
- 239000011782 vitamin Substances 0.000 title abstract description 8
- 235000013343 vitamin Nutrition 0.000 title abstract description 8
- 229940088594 vitamin Drugs 0.000 title abstract description 8
- 229930003231 vitamin Natural products 0.000 title abstract description 8
- 238000002360 preparation method Methods 0.000 title description 9
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 21
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 21
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 229920000642 polymer Polymers 0.000 claims abstract description 9
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 8
- 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 abstract description 8
- 239000011710 vitamin D Substances 0.000 claims description 23
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000002904 solvent Substances 0.000 claims description 12
- 230000001476 alcoholic effect Effects 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 5
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 5
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 4
- 238000004519 manufacturing process Methods 0.000 claims description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 3
- 239000011647 vitamin D3 Substances 0.000 claims description 2
- QYSXJUFSXHHAJI-YRZJJWOYSA-N vitamin D3 Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)CCC1=C QYSXJUFSXHHAJI-YRZJJWOYSA-N 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 abstract description 3
- 239000001913 cellulose Substances 0.000 abstract description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 235000010354 butylated hydroxytoluene Nutrition 0.000 description 5
- 238000005469 granulation Methods 0.000 description 5
- 230000003179 granulation Effects 0.000 description 5
- 229920002472 Starch Polymers 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
- 239000008107 starch Substances 0.000 description 4
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 3
- 239000011612 calcitriol Substances 0.000 description 3
- 239000001768 carboxy methyl cellulose Substances 0.000 description 3
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 3
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- PYGGFMISRIMKTA-IBSHMIGKSA-N (1s)-5-[(z)-2-[(1r,3ar,7as)-2-ethyl-1-[(5s)-5-hydroxyheptyl]-4,7a-dimethyl-2,3,3a,5,6,7-hexahydro-1h-inden-4-yl]ethenyl]-4-methylcyclohexa-2,4-dien-1-ol Chemical compound C([C@]1(C)[C@@H]2CC(CC)[C@H]1CCCC[C@@H](O)CC)CCC2(C)\C=C/C1=C(C)C=C[C@@H](O)C1 PYGGFMISRIMKTA-IBSHMIGKSA-N 0.000 description 2
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 description 2
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 2
- 239000001856 Ethyl cellulose Substances 0.000 description 2
- 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 2
- 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 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 2
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 230000003078 antioxidant effect Effects 0.000 description 2
- 235000006708 antioxidants Nutrition 0.000 description 2
- 239000003613 bile acid Substances 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- CZBZUDVBLSSABA-UHFFFAOYSA-N butylated hydroxyanisole Chemical compound COC1=CC=C(O)C(C(C)(C)C)=C1.COC1=CC=C(O)C=C1C(C)(C)C CZBZUDVBLSSABA-UHFFFAOYSA-N 0.000 description 2
- GMRQFYUYWCNGIN-NKMMMXOESA-N calcitriol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C GMRQFYUYWCNGIN-NKMMMXOESA-N 0.000 description 2
- 235000020964 calcitriol Nutrition 0.000 description 2
- 150000001720 carbohydrates Chemical class 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 235000012000 cholesterol Nutrition 0.000 description 2
- 150000001841 cholesterols Chemical class 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000003086 colorant Substances 0.000 description 2
- 230000003413 degradative effect Effects 0.000 description 2
- 235000019325 ethyl cellulose Nutrition 0.000 description 2
- 229920001249 ethyl cellulose Polymers 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 235000019359 magnesium stearate Nutrition 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000010298 pulverizing process Methods 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000004094 surface-active agent Substances 0.000 description 2
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 description 2
- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical compound CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 description 1
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- SPSPIUSUWPLVKD-UHFFFAOYSA-N 2,3-dibutyl-6-methylphenol Chemical compound CCCCC1=CC=C(C)C(O)=C1CCCC SPSPIUSUWPLVKD-UHFFFAOYSA-N 0.000 description 1
- FCKJYANJHNLEEP-SRLFHJKTSA-N 24,25-dihydroxycholecalciferol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCC(O)C(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C FCKJYANJHNLEEP-SRLFHJKTSA-N 0.000 description 1
- JWUBBDSIWDLEOM-UHFFFAOYSA-N 25-Hydroxycholecalciferol Natural products C1CCC2(C)C(C(CCCC(C)(C)O)C)CCC2C1=CC=C1CC(O)CCC1=C JWUBBDSIWDLEOM-UHFFFAOYSA-N 0.000 description 1
- 239000003872 25-hydroxy-cholecalciferol Substances 0.000 description 1
- 235000021318 Calcifediol Nutrition 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 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 1
- NOOLISFMXDJSKH-UHFFFAOYSA-N DL-menthol Natural products CC(C)C1CCC(C)CC1O NOOLISFMXDJSKH-UHFFFAOYSA-N 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920002884 Laureth 4 Polymers 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 235000011037 adipic acid Nutrition 0.000 description 1
- 239000001361 adipic acid Substances 0.000 description 1
- 229960000250 adipic acid Drugs 0.000 description 1
- OFHCOWSQAMBJIW-AVJTYSNKSA-N alfacalcidol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@H](C)CCCC(C)C)=C\C=C1\C[C@@H](O)C[C@H](O)C1=C OFHCOWSQAMBJIW-AVJTYSNKSA-N 0.000 description 1
- 229960002535 alfacalcidol Drugs 0.000 description 1
- 229940087168 alpha tocopherol Drugs 0.000 description 1
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 1
- 235000010323 ascorbic acid Nutrition 0.000 description 1
- 239000011668 ascorbic acid Substances 0.000 description 1
- 229960005070 ascorbic acid Drugs 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- JWUBBDSIWDLEOM-DTOXIADCSA-N calcidiol Chemical compound C1(/[C@@H]2CC[C@@H]([C@]2(CCC1)C)[C@@H](CCCC(C)(C)O)C)=C\C=C1\C[C@@H](O)CCC1=C JWUBBDSIWDLEOM-DTOXIADCSA-N 0.000 description 1
- WMYIVSWWSRCZFA-DKRDSXHXSA-N calcitriol 26,23-lactone Chemical compound C([C@@H](C)[C@@H]1[C@]2(CCCC(/[C@@H]2CC1)=C\C=C\1C([C@@H](O)C[C@H](O)C/1)=C)C)C1CC(C)(O)C(=O)O1 WMYIVSWWSRCZFA-DKRDSXHXSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 229920002301 cellulose acetate Polymers 0.000 description 1
- WZNRVWBKYDHTKI-UHFFFAOYSA-N cellulose, acetate 1,2,4-benzenetricarboxylate Chemical compound OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.OC1C(O)C(O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.CC(=O)OCC1OC(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C1OC1C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(COC(C)=O)O1.OC(=O)C1=CC(C(=O)O)=CC=C1C(=O)OCC1C(OC2C(C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(OC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)C(COC(=O)C=3C(=CC(=CC=3)C(O)=O)C(O)=O)O2)OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)C(OC(=O)C=2C(=CC(=CC=2)C(O)=O)C(O)=O)O1 WZNRVWBKYDHTKI-UHFFFAOYSA-N 0.000 description 1
- 229960004106 citric acid Drugs 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 239000011162 core material Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 239000001341 hydroxy propyl starch Substances 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 235000013828 hydroxypropyl starch Nutrition 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- -1 magnesium metasilicate aluminate Chemical class 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229940041616 menthol Drugs 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000004570 mortar (masonry) Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 239000002245 particle Substances 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920000136 polysorbate Polymers 0.000 description 1
- 229940068965 polysorbates Drugs 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 1
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000005096 rolling process Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 1
- 238000005507 spraying Methods 0.000 description 1
- 230000000087 stabilizing effect Effects 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 238000006467 substitution reaction Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229960000984 tocofersolan Drugs 0.000 description 1
- 125000005591 trimellitate group Chemical group 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 235000001892 vitamin D2 Nutrition 0.000 description 1
- 150000003703 vitamin D2 derivatives Chemical class 0.000 description 1
- 239000002076 α-tocopherol Substances 0.000 description 1
- 235000004835 α-tocopherol Nutrition 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- 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
- A61K31/59—Compounds containing 9, 10- seco- cyclopenta[a]hydrophenanthrene ring systems
-
- 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
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
Landscapes
- Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Composition pour des préparations pharmaceutiques solides renfermant des vitamines D3 actives permettant de stabiliser de manière significative les vitamines D3 actives et d'améliorer leur manipulation. Ladite composition comprend de la cellulose d'hydroxypropylméthyle. Sur la cellulose sont fixées des vitamines D3 actives et un polymère qui se dissout rapidement dans un solvant organique.Composition for solid pharmaceutical preparations containing active vitamins D3 making it possible to significantly stabilize active vitamins D3 and to improve their handling. Said composition comprises hydroxypropylmethyl cellulose. On the cellulose are fixed active vitamins D3 and a polymer which dissolves quickly in an organic solvent.
Description
TITLE OF THE INVENTION
COMPOSITION FOR SOLID PHARMACEUTICAL
PREPARATIONS CONTAINING ACTIVE VITAMINS D3
AND PROCESS FOR PREPARATION THEREOF
BACKGROUND OF THE INVENTION
This invention relates to a composition for solid pharmaceutical preparations containing active vitamins D3 and a process for the preparation thereof, and more particularly to a composition for solid pharmaceutical preparations containing active vitamins D3 in which hydroxypropyl methyl cellulose is used as an excipient.
In general, active vitamins D3 are labile and sensitive to heat and light and apt to be readily oxidized, so that the formation of pharmaceutical preparations containing active vitamins D3 requires to stabilize them.
In order to stabilize active vitamins D3, some techniques were proposed such as a method for forming an
inclusion compound between the vitamins and bile acids as disclosed in Japanese Patent Application Laid-Open Publication No. 69562/1980, a method for forming a complex between the vitamins and cholesterols as disclosed in Japanese Patent
Application Laid-Open Publication No. 40461/1982, a method for dispersing the vitamins in polyvinyl pyrrolidone as disclosed in Japanese Patent Application Laid-Open Publication No.
206533/1983 and the like.
In the proposed methods, the preparations are obtained by dissolving active vitamins D3 together with bile acids,
cholesterols or polyvinyl pyrrolidone in an alcoholic solvent such as ethanol, methanol, propanol or the like which permits both to be dissolved therein, followed by removal of the solvent under reduced pressure. Unfortunately, each of the proposed methods exhibits a disadvantage of causing the composition to be partially resinified during the removal of the solvent under reduced pressure. Also, each of the conventional methods proposed causes the composition to be rendered non-uniform in grain size when it is pulverized.
In view of the above, a method was proposed wherein an excipient which is slightly soluble in an organic solvent is suspended in a solution in which active vitamins D3 are
dissolved and then a solvent of the solution is removed
according to a suitable procedure, to thereby obtain a
composition for solid pharmaceutical preparations of active vitamins D3, as disclosed in Japanese Patent Application Laid-Open Publication No. 155309/1984.
However, restrictions in preparation of the composition cause a core material for the composition to be limited to an excipient which is slightly soluble in an organic solvent.
Also, a large volume of organic solvent must be used to form an outer layer for the composition of an excipient which is readily soluble in an organic solvent, so that much energy is required to remove the organic solvent by drying.
SUMMARY OF THE INVENTION
The present invention has been made in view of the foregoing disadvantage of the prior art.
The inventors have made a careful study for the purpose of preparing a composition for solid pharmaceutical preparations which is capable of stabilizing active vitamins D3, having a uniform content and facilitating the handling. As a result, it has been found that a composition for solid pharmaceutical preparations containing active vitamins D3 which comprises hydroxypropylmethyl cellulose (hereinafter referred to as
"HPMC"), and an active vitamins D3 and a polymer which is readily soluble in an organic solvent each attached to HPMC meets such requirements.
Accordingly, it is an object of the present invention to provide a composition for solid pharmaceutical preparations containing active vitamins D3 which is capable of permitting the active vitamins D3 to be significantly thermally stabilized and being improved in handling.
It is another object of the present invention to provide a process for preparing a composition for solid
pharmaceutical preparations containing active vitamins D3 which is capable of highly facilitating the preparation while ensuring thermal stability of the vitamins D3.
In accordance with one aspect of the present invention, a composition for solid pharmaceutical preparations containing active vitamins D3 is provided. The composition comprises hydroxypropyl methyl cellulose, and an active vitamin D3 and a polymer which is readily soluble in an organic solvent each attached to the hydroxypropyl methyl cellulose.
In accordance with another aspect of the present
invention, a process for preparing such a composition as described above is provided. The method uses an alcoholic solvent.
DETAILED DESCRIPTION OF THE INVENTION
The polymer which is readily soluble in an organic solvent includes polyvinyl pyrrolidone (hereinafter referred to as "PVP"), HMPC and the like.
The active vitamins D3 of the present invention include vitamins D3 of which positions 1α and/or 25 are subject to hydroxidation, such as, for example, 1α - hydroxycholecalciferol; 25-hydroxycholecalciferol; 1α, 25- dihydroxycholecalciferol; 26, 26, 26, 27, 27, 27-hexafluoro-1α, 25-dihydroxycholecalciferol (hereinafter referred to as "ST- 630); 1α, 25-dihydroxycholecalciferol; 24, 25- dihydroxycholecalciferol, 1α-dihydroxycholecalciferol; 1α , 25- dihydroxy-26, 27-dimethylcholecalciferol; 1α-hydroxy-26, 27- dimethylcholecalciferol; 25-hydroxy-26, 27- dimethylcholecalciferol; 1α, 25-dihydroxy-24, 24-difluoro-26, 27-dimethylcholecalciferol; 1α, 25-dihydroxy-26, 27-diethylcholecalciferol; 25-hydroxy-26, 27-dimethylcholecalciferol;; 25-hydroxy-26, 26, 26, 27, 27, 27-hexafluorocalciferol; 25-hydroxy-26, 26, 26, 27, 27, 27-hexafluoroepicalciferol; 1α, 25-dihydroxy-24, 24-difluorohomocholecalciferol; 1α, 25-dihydroxycholecalciferol-26, 23-lactone; 1α, 25-dihydroxy-22-oxacholecalciferol; 1α-hydroxy-22-oxacholecalciferol; and ergocalciferols corresponding to the above.
HPMC used as an excipient in the composition of the present invention is loaded in an amount of from 50% to 99.9% by weight and preferably from 65% to 99.9% by weight in the
composition. The polymer which is readily soluble in an organic solvent is loaded in an amount of from 0.1% to 50% by weight and preferably from 0.1% to 35% by weight in the composition.
The composition of the present invention is obtained by preparing HPMC using an alcoholic solution in which the active vitamins D3 and the polymer which is readily soluble in an organic solvent are dissolved. The alcoholic solvent suitable for use for this purpose includes, for example, ethanol
containing 20% or less water.
In the preparation of the composition, HPMC acts as an excipient. Any prior art is silent concerning the use of HPMC as a sole excipient in wet granulation as in the present
invention. The reason would be that HPMC highly exhibits a film forming property, therefore, the granulation of a composition using a solvent in which HPMC is dissolved causes removal and subsequent pulverization of the composition to be rendered difficult or troublesome.
As described above, the composition of the present invention is prepared using the alcoholic solvent in which HPMC is dissolved. The use of the alcoholic solvent permits the surface of HPMC particles acting as a nucleus of the composition to be dissolved in the solvent, so that the active vitamins D3 are taken in HPMC, resulting in being substantially stabilized.
The composition thus obtained may be formed into
pharmaceutical preparations as it is or, if necessary, while being mixed with at least one of any suitable additives known in the art such as an excipient, a degradative agent, a binder, a lubricant, an anti-oxidant, a coating agent, a coloring agent, a corrigent, a surface active agent and the like.
The excipient includes, for example, lactose, starch, crystalline cellulose, calcium hydrogenphosphate, light silica, titanium oxide, magnesium metasilicate aluminate, polyethylene glycol and the like.
The degradative agent includes, for example,
carboxymethyl cellulose, calcium carboxymethylcellulose, sodium carboxymethylcellulose, croscarmellose sodium. Type A (Ac-Di-Sol®) starch, crystalline cellulose, hydroxypropyl starch, starch of which a part is modified into α-starch and the like.
The binder includes, for example, hydroxypropyl cellulose, gelatin, gum arabic, ethyl cellulose, polyvinyl
alcohol, pullulan and the like.
The lubricant includes, for example, stearic acid, magnesium stearate, calcium stearate, talc, hardened oil, fatty saccharide and the like.
The anti-oxidant includes, for example, dibutyl hydroxytoluene (BHT), gallic propyl, butylhydroxy anisole (BHA), α-tocopherol, citric acid and the like.
The coating agent includes, for example, HPMC,
hydroxypropyl cellulose, methyl cellulose, ethyl cellulose, hydroxypropylmethyl cellulose phthalate, polyvinylacetal
diethylaminoacetate, aminoalkyl methacrylate copolymer,
hydroxypropylmethyl cellulose acetate succinate, methacrylic acid coplymer, cellulose acetate trimellitate (CAT), polyvinyl acetate phthalate, and the like.
The coloring agent includes, for example, a tar pigment, titanium oxide and the like.
The corrigent includes, for example, citric acid, adipic acid, ascorbic acid, menthol and the like.
The surface active agent includes, for example, glycerin monostearate, polysorbates, sodium lauryl sulfate,
lauromacrogol, fatty saccharide, and the like.
The composition for solid pharmaceutical preparations according to the present invention may be prepared according to a conventional wet granulation process. However, the
composition is preferably prepared using an apparatus
constructed so as to concurrently dry the alcoholic solution in which the active vitamins D3 and polymer are dissolved while spraying it. The apparatus includes, for example, a fluidized bed type apparatus, a rolling and flowing type apparatus, a centrifugal flowing type apparatus, a vacuum type apparatus.
The present invention will be described in detail with reference to the following examples.
Example 1
500g of HPMC 2910 (hereinafter referred to as "TC-5R") was subject to stirring granulation using a solution prepared by dissolving 5mg of ST-630, 12.5g of BHT and 125g of PVP-K30 in 187.5g of 90% ethanol and then pulverized after drying, to thereby provide a composition of the present invention.
The composition was sealedly put in a glass bottle and stored at 40°C to examine the stability. A variation in residual rate of ST-630 with time was as indicated in Table 1.
A composition for reference was prepared by adding 5ml of an ethanol solution containing ST-63 of 100μg/ml in
concentration to 50g of lactose in a mortar and mixing them, followed by drying.
Table 1
Samples Residual Rate of ST-630 (%)
Storage Temperature: 40°C
One Month Two Months Three Months Present Invention 97 95 98
Reference 64 46 38
Table 1 clearly reveals that in the reference, decomposition of ST-630 occurred rapidly, whereas ST-630 in the composition of the present invention was stabilized for a long period of time.
Example 2
500g of TC-5R was subject to stirring granulation using a solution prepared by dissolving 5mg of ST-630, 12.5g of BHT and 125g of TC-5R in 187.5g of 90% ethanol and then pulverized after drying, to thereby provide a composition of the present invention.
Example 3
500g of TC-5R was subject to agitating granulation using a solution prepared by dissolving 5mg of ST- 630, 12.5g of BHT and 125g of PVP-K30 in 500g of ethanol and then pulverized
after drying, to thereby provide a composition of the present invention.
127.5g of the so-obtained composition, 867.5g of mannitol and 200g of hydroxypropyl cellulose having a low degree of substitution were fully mixed together to prepare a mixture and then 450g of purified water was added to the mixture, followed by stirring granulation and pulverization after drying , resulting in a powder for preparation of tablets. Then, 5g of magnesium stearate was added to the powder, which was then formed into tablets of 7mm in diameter and 120mg in weight and containing ST-630 in an amount of about 0.1ug.
Subsequently, the tablets each were sealedly put in a glass bottle and stored at 40°C to examine the stability. A variation in residual rate of ST-630 with time was as indicated in Table 2.
Table 2
Sample Residual Rate of ST-630 (%)
Storage Temperature: 40°C
One Month Two Months Three Months Present Invention 100 98 95
Table 2 clearly indicates that in each of the tablets prepared using the composition of the present invention, ST-630 was kept stabilized for a long period of time.
Claims
1. A composition for solid pharmaceutical preparations containing active-type vitamins D3, comprising
hydroxypropylmethyl cellulose, and an active vitamins D3 and a polymer which is readily soluble in an organic solvent each attached to said hydroxypropyl methyl cellulose.
2. A composition as defined in Claim 1, wherein said polymer is selected from the group consisting of polyvinyl pyrrolidone and hydroxypropylmethyl cellulose.
3. A composition as defined in Claim 1 or 2, wherein said active vitamin D3 is 26, 26, 26, 27, 27, 27-hexafluoro-1 , 25-dihydroxycholecalciferol.
4. A process for preparing a composition defined in any one of Claims 1 to 3, wherein an alcoholic solvent is used.
5. A process as defined in Claim 4, wherein said alcoholic solvent comprises ethanol containing 20% or less water.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP2332013A JPH04198129A (en) | 1990-11-28 | 1990-11-28 | Active type vitamin d>=3*s-containing composition |
| JP332013/90 | 1990-11-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| EP0559645A1 true EP0559645A1 (en) | 1993-09-15 |
Family
ID=18250168
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| EP91910918A Withdrawn EP0559645A1 (en) | 1990-11-28 | 1991-04-25 | Composition for solid pharmaceutical preparations containing active vitamins d 3? and process for preparation thereof |
Country Status (4)
| Country | Link |
|---|---|
| EP (1) | EP0559645A1 (en) |
| JP (1) | JPH04198129A (en) |
| AU (1) | AU8096591A (en) |
| WO (1) | WO1992009271A1 (en) |
Families Citing this family (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| NZ242271A (en) * | 1991-04-09 | 1993-10-26 | Takeda Chemical Industries Ltd | Medicaments containing a vitamin d compound stabilised by a basic substance |
| US5795882A (en) * | 1992-06-22 | 1998-08-18 | Bone Care International, Inc. | Method of treating prostatic diseases using delayed and/or sustained release vitamin D formulations |
| CA2116238C (en) * | 1992-06-22 | 2007-09-04 | Joyce C. Knutson | Oral 1 .alpha.-hydroxyprevitamin d |
| IL103224A (en) * | 1992-09-18 | 1998-08-16 | Teva Pharma | Stabilized pharmaceutical compositions containing derivatives of vitamins d2 and d3 |
| US6004996A (en) * | 1997-02-05 | 1999-12-21 | Hoffman-La Roche Inc. | Tetrahydrolipstatin containing compositions |
| KR100688618B1 (en) * | 2001-09-12 | 2007-03-09 | 주식회사 유유 | A pharmaceutical composition of vitamin D compound using controlled delivery |
| WO2007068287A1 (en) * | 2005-12-15 | 2007-06-21 | Laboratoria Qualiphar | Sustained release vitamin preparation |
| DK1993559T3 (en) | 2006-02-03 | 2016-10-03 | Opko Renal Llc | Treatment of vitamin D deficiency and MALFUNCTION with 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3 |
| SI2037936T1 (en) | 2006-06-21 | 2014-11-28 | Opko Renal, Llc | Method of treating and preventing secondary hyperparathyroidism |
| KR20190141269A (en) | 2007-04-25 | 2019-12-23 | 사이토크로마 인코포레이티드 | Oral controlled release compositions comprising vitamin d compound and waxy carrier |
| CA2587805C (en) | 2007-04-25 | 2014-02-18 | The Procter & Gamble Company | Improved vitamin d content uniformity in pharmaceutical dosage forms |
| US11752158B2 (en) | 2007-04-25 | 2023-09-12 | Eirgen Pharma Ltd. | Method of treating vitamin D insufficiency and deficiency |
| RS60087B1 (en) | 2010-03-29 | 2020-05-29 | Opko Ireland Global Holdings Ltd | Methods and compositions for reducing parathyroid levels |
| EP2468265A3 (en) * | 2010-12-04 | 2013-01-02 | DEEF Pharmaceutical Industries Co. | Homogeneous preparations containing vitamin D |
| KR101847947B1 (en) | 2013-03-15 | 2018-05-28 | 옵코 아이피 홀딩스 Ⅱ 인코포레이티드 | Stabilized modified release vitamin d formulation |
| CN114681468A (en) | 2014-08-07 | 2022-07-01 | 欧普科爱尔兰环球控股有限公司 | Adjunctive therapy with 25-hydroxyvitamin D |
| JP7034595B2 (en) * | 2016-03-23 | 2022-03-14 | 株式会社ファンケル | Vitamin D3 stabilizing composition |
| CN108883120A (en) | 2016-03-28 | 2018-11-23 | 欧普科爱尔兰环球控股有限公司 | Vitamin D treatment method |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS59155309A (en) * | 1983-02-22 | 1984-09-04 | Teijin Ltd | Active type vitamin d3 composition and its preparation |
| JPS62149619A (en) * | 1985-09-05 | 1987-07-03 | Teijin Ltd | Injection composition of active type vitamin d3 |
| SE8801537D0 (en) * | 1988-04-26 | 1988-04-26 | Ellco Food Ab | CELL CULTURE MEDIUM AND PROCEDURES FOR ITS PREPARATION |
| JPH02240024A (en) * | 1989-03-13 | 1990-09-25 | Ss Pharmaceut Co Ltd | Composition for active type vitamin d3s preparation |
-
1990
- 1990-11-28 JP JP2332013A patent/JPH04198129A/en active Pending
-
1991
- 1991-04-25 WO PCT/US1991/002846 patent/WO1992009271A1/en not_active Application Discontinuation
- 1991-04-25 AU AU80965/91A patent/AU8096591A/en not_active Abandoned
- 1991-04-25 EP EP91910918A patent/EP0559645A1/en not_active Withdrawn
Non-Patent Citations (1)
| Title |
|---|
| See references of WO9209271A1 * |
Also Published As
| Publication number | Publication date |
|---|---|
| WO1992009271A1 (en) | 1992-06-11 |
| AU8096591A (en) | 1992-06-25 |
| JPH04198129A (en) | 1992-07-17 |
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