JPH021405A - Preparation of release control type and production thereof - Google Patents
Preparation of release control type and production thereofInfo
- Publication number
- JPH021405A JPH021405A JP1030882A JP3088289A JPH021405A JP H021405 A JPH021405 A JP H021405A JP 1030882 A JP1030882 A JP 1030882A JP 3088289 A JP3088289 A JP 3088289A JP H021405 A JPH021405 A JP H021405A
- Authority
- JP
- Japan
- Prior art keywords
- substance
- porous membrane
- group
- hydrophobic
- cellulose
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 24
- 238000004519 manufacturing process Methods 0.000 title claims description 4
- 239000000126 substance Substances 0.000 claims abstract description 94
- 229920001600 hydrophobic polymer Polymers 0.000 claims abstract description 18
- 229920002678 cellulose Polymers 0.000 claims abstract description 14
- 229920001477 hydrophilic polymer Polymers 0.000 claims abstract description 7
- 229920001282 polysaccharide Polymers 0.000 claims abstract description 7
- 239000005017 polysaccharide Substances 0.000 claims abstract description 7
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims abstract description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims abstract description 7
- 150000004676 glycans Chemical class 0.000 claims abstract description 6
- 229920000642 polymer Polymers 0.000 claims abstract description 6
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims abstract description 6
- 229920003086 cellulose ether Polymers 0.000 claims abstract description 5
- 229920000609 methyl cellulose Polymers 0.000 claims abstract description 5
- 239000001923 methylcellulose Substances 0.000 claims abstract description 5
- 235000010981 methylcellulose Nutrition 0.000 claims abstract description 5
- 229920001290 polyvinyl ester Polymers 0.000 claims abstract description 4
- QAOWNCQODCNURD-UHFFFAOYSA-L sulfate group Chemical group S(=O)(=O)([O-])[O-] QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims description 50
- 239000012528 membrane Substances 0.000 claims description 46
- 230000002209 hydrophobic effect Effects 0.000 claims description 33
- 238000009472 formulation Methods 0.000 claims description 30
- 239000001856 Ethyl cellulose Substances 0.000 claims description 26
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 26
- 229920001249 ethyl cellulose Polymers 0.000 claims description 26
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 26
- -1 di-substituted amino groups Chemical group 0.000 claims description 19
- 239000011162 core material Substances 0.000 claims description 18
- 238000005507 spraying Methods 0.000 claims description 13
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 11
- 239000004480 active ingredient Substances 0.000 claims description 11
- 239000001913 cellulose Substances 0.000 claims description 11
- 235000010980 cellulose Nutrition 0.000 claims description 11
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 11
- 239000000463 material Substances 0.000 claims description 11
- 229920002554 vinyl polymer Polymers 0.000 claims description 11
- 229920002125 Sokalan® Polymers 0.000 claims description 8
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 8
- 239000002253 acid Substances 0.000 claims description 7
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 5
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims description 4
- 125000004181 carboxyalkyl group Chemical group 0.000 claims description 4
- 239000003791 organic solvent mixture Substances 0.000 claims description 4
- 229920003169 water-soluble polymer Polymers 0.000 claims description 4
- OBXSIXYVJSEUIV-UHFFFAOYSA-N 3-(3-ethenylpyridin-2-yl)prop-2-enoic acid Chemical compound OC(=O)C=CC1=NC=CC=C1C=C OBXSIXYVJSEUIV-UHFFFAOYSA-N 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- 150000003862 amino acid derivatives Chemical class 0.000 claims description 3
- 239000003405 delayed action preparation Substances 0.000 claims description 3
- 150000007524 organic acids Chemical class 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 229920003121 gastrosoluble polymer Polymers 0.000 claims description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 claims description 2
- 239000001384 succinic acid Substances 0.000 claims description 2
- 229920006163 vinyl copolymer Polymers 0.000 claims description 2
- 125000000217 alkyl group Chemical group 0.000 claims 1
- 125000004103 aminoalkyl group Chemical group 0.000 claims 1
- 125000001453 quaternary ammonium group Chemical group 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 20
- 238000000576 coating method Methods 0.000 abstract description 19
- 239000011248 coating agent Substances 0.000 abstract description 17
- 229940079593 drug Drugs 0.000 abstract description 16
- 239000003814 drug Substances 0.000 abstract description 16
- 238000010828 elution Methods 0.000 abstract description 5
- 239000008187 granular material Substances 0.000 description 24
- 238000013270 controlled release Methods 0.000 description 15
- 229920001577 copolymer Polymers 0.000 description 15
- IDGUHHHQCWSQLU-UHFFFAOYSA-N ethanol;hydrate Chemical compound O.CCO IDGUHHHQCWSQLU-UHFFFAOYSA-N 0.000 description 11
- 239000002245 particle Substances 0.000 description 10
- 239000000243 solution Substances 0.000 description 10
- ZFXYFBGIUFBOJW-UHFFFAOYSA-N theophylline Chemical compound O=C1N(C)C(=O)N(C)C2=C1NC=N2 ZFXYFBGIUFBOJW-UHFFFAOYSA-N 0.000 description 10
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- BAPJBEWLBFYGME-UHFFFAOYSA-N Methyl acrylate Chemical compound COC(=O)C=C BAPJBEWLBFYGME-UHFFFAOYSA-N 0.000 description 8
- 238000007664 blowing Methods 0.000 description 8
- 229920002301 cellulose acetate Polymers 0.000 description 8
- 239000003795 chemical substances by application Substances 0.000 description 8
- 238000000034 method Methods 0.000 description 8
- 239000002861 polymer material Substances 0.000 description 8
- FEDJGPQLLNQAIY-UHFFFAOYSA-N 2-[(6-oxo-1h-pyridazin-3-yl)oxy]acetic acid Chemical compound OC(=O)COC=1C=CC(=O)NN=1 FEDJGPQLLNQAIY-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 229960005316 diltiazem hydrochloride Drugs 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 6
- ABBQHOQBGMUPJH-UHFFFAOYSA-M Sodium salicylate Chemical compound [Na+].OC1=CC=CC=C1C([O-])=O ABBQHOQBGMUPJH-UHFFFAOYSA-M 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 235000019441 ethanol Nutrition 0.000 description 6
- 239000012530 fluid Substances 0.000 description 6
- 239000003960 organic solvent Substances 0.000 description 6
- 229960004025 sodium salicylate Drugs 0.000 description 6
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 5
- 230000000694 effects Effects 0.000 description 5
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 5
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 5
- 239000000454 talc Substances 0.000 description 5
- 229910052623 talc Inorganic materials 0.000 description 5
- 235000012222 talc Nutrition 0.000 description 5
- 229960000278 theophylline Drugs 0.000 description 5
- 229920002472 Starch Polymers 0.000 description 4
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 4
- 239000011230 binding agent Substances 0.000 description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 4
- 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 description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 4
- 239000000546 pharmaceutical excipient Substances 0.000 description 4
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 4
- 239000000843 powder Substances 0.000 description 4
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
- 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 3
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 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 description 3
- 229930006000 Sucrose Natural products 0.000 description 3
- 230000002744 anti-aggregatory effect Effects 0.000 description 3
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 230000007423 decrease Effects 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 239000008101 lactose Substances 0.000 description 3
- 239000000314 lubricant Substances 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 3
- 239000011148 porous material Substances 0.000 description 3
- KGIGUEBEKRSTEW-UHFFFAOYSA-N 2-vinylpyridine Chemical compound C=CC1=CC=CC=N1 KGIGUEBEKRSTEW-UHFFFAOYSA-N 0.000 description 2
- VJOWMORERYNYON-UHFFFAOYSA-N 5-ethenyl-2-methylpyridine Chemical compound CC1=CC=C(C=C)C=N1 VJOWMORERYNYON-UHFFFAOYSA-N 0.000 description 2
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 2
- SOGAXMICEFXMKE-UHFFFAOYSA-N Butylmethacrylate Chemical compound CCCCOC(=O)C(C)=C SOGAXMICEFXMKE-UHFFFAOYSA-N 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-M Butyrate Chemical compound CCCC([O-])=O FERIUCNNQQJTOY-UHFFFAOYSA-M 0.000 description 2
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Natural products CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 description 2
- DQEFEBPAPFSJLV-UHFFFAOYSA-N Cellulose propionate Chemical compound CCC(=O)OCC1OC(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C1OC1C(OC(=O)CC)C(OC(=O)CC)C(OC(=O)CC)C(COC(=O)CC)O1 DQEFEBPAPFSJLV-UHFFFAOYSA-N 0.000 description 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 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
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 2
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 229930195725 Mannitol Natural products 0.000 description 2
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000005299 abrasion Methods 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 125000003277 amino group Chemical class 0.000 description 2
- 239000002246 antineoplastic agent Substances 0.000 description 2
- 125000000484 butyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229920006217 cellulose acetate butyrate Polymers 0.000 description 2
- 229920006184 cellulose methylcellulose Polymers 0.000 description 2
- 229920006218 cellulose propionate Polymers 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- CRVGKGJPQYZRPT-UHFFFAOYSA-N diethylamino acetate Chemical compound CCN(CC)OC(C)=O CRVGKGJPQYZRPT-UHFFFAOYSA-N 0.000 description 2
- 238000007922 dissolution test Methods 0.000 description 2
- 125000001301 ethoxy group Chemical group [H]C([H])([H])C([H])([H])O* 0.000 description 2
- 239000010419 fine particle Substances 0.000 description 2
- 210000001035 gastrointestinal tract Anatomy 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 239000003721 gunpowder Substances 0.000 description 2
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 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
- 230000003204 osmotic effect Effects 0.000 description 2
- 150000003839 salts Chemical class 0.000 description 2
- 238000003860 storage Methods 0.000 description 2
- 239000003826 tablet Substances 0.000 description 2
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 2
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 description 1
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 description 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N 1-ethenoxybutane Chemical compound CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 description 1
- HGXMBYDYKWXJNH-UHFFFAOYSA-N 2-amino-2-(2-ethenylphenyl)acetic acid Chemical compound OC(=O)C(N)C1=CC=CC=C1C=C HGXMBYDYKWXJNH-UHFFFAOYSA-N 0.000 description 1
- YQUDMNIUBTXLSX-UHFFFAOYSA-N 2-ethenyl-5-ethylpyridine Chemical compound CCC1=CC=C(C=C)N=C1 YQUDMNIUBTXLSX-UHFFFAOYSA-N 0.000 description 1
- DEXFNLNNUZKHNO-UHFFFAOYSA-N 6-[3-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperidin-1-yl]-3-oxopropyl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1CCN(CC1)C(CCC1=CC2=C(NC(O2)=O)C=C1)=O DEXFNLNNUZKHNO-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- 229920001817 Agar Polymers 0.000 description 1
- UIERETOOQGIECD-UHFFFAOYSA-N Angelic acid Natural products CC=C(C)C(O)=O UIERETOOQGIECD-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 229920002261 Corn starch Polymers 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
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 229920000896 Ethulose Polymers 0.000 description 1
- 239000001859 Ethyl hydroxyethyl cellulose Substances 0.000 description 1
- 229920003134 Eudragit® polymer Polymers 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 240000005979 Hordeum vulgare Species 0.000 description 1
- 235000007340 Hordeum vulgare Nutrition 0.000 description 1
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- CERQOIWHTDAKMF-UHFFFAOYSA-M Methacrylate Chemical compound CC(=C)C([O-])=O CERQOIWHTDAKMF-UHFFFAOYSA-M 0.000 description 1
- 239000004373 Pullulan Substances 0.000 description 1
- 229920001218 Pullulan Polymers 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- GUGOEEXESWIERI-UHFFFAOYSA-N Terfenadine Chemical compound C1=CC(C(C)(C)C)=CC=C1C(O)CCCN1CCC(C(O)(C=2C=CC=CC=2)C=2C=CC=CC=2)CC1 GUGOEEXESWIERI-UHFFFAOYSA-N 0.000 description 1
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- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 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 1
- 239000008186 active pharmaceutical agent Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 239000008272 agar Substances 0.000 description 1
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- 229940072056 alginate Drugs 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 229910052783 alkali metal Inorganic materials 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 150000001413 amino acids Chemical class 0.000 description 1
- 230000000202 analgesic effect Effects 0.000 description 1
- 230000000954 anitussive effect Effects 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 239000003006 anti-agglomeration agent Substances 0.000 description 1
- 230000001387 anti-histamine Effects 0.000 description 1
- 230000003276 anti-hypertensive effect Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001754 anti-pyretic effect Effects 0.000 description 1
- 239000003416 antiarrhythmic agent Substances 0.000 description 1
- 229940088710 antibiotic agent Drugs 0.000 description 1
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000001961 anticonvulsive agent Substances 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 239000000739 antihistaminic agent Substances 0.000 description 1
- 229940030600 antihypertensive agent Drugs 0.000 description 1
- 239000002220 antihypertensive agent Substances 0.000 description 1
- 239000003524 antilipemic agent Substances 0.000 description 1
- 229940034982 antineoplastic agent Drugs 0.000 description 1
- 239000002221 antipyretic Substances 0.000 description 1
- 229940124584 antitussives Drugs 0.000 description 1
- 210000000467 autonomic pathway Anatomy 0.000 description 1
- 239000002585 base Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 210000001124 body fluid Anatomy 0.000 description 1
- 239000010839 body fluid Substances 0.000 description 1
- 235000008429 bread Nutrition 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 description 1
- MKJXYGKVIBWPFZ-UHFFFAOYSA-L calcium lactate Chemical compound [Ca+2].CC(O)C([O-])=O.CC(O)C([O-])=O MKJXYGKVIBWPFZ-UHFFFAOYSA-L 0.000 description 1
- 239000001527 calcium lactate Substances 0.000 description 1
- 229960002401 calcium lactate Drugs 0.000 description 1
- 235000011086 calcium lactate Nutrition 0.000 description 1
- 239000001506 calcium phosphate Substances 0.000 description 1
- 229910000389 calcium phosphate Inorganic materials 0.000 description 1
- 235000011010 calcium phosphates Nutrition 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
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 239000000496 cardiotonic agent Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000013329 compounding Methods 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 229940127089 cytotoxic agent Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 230000001079 digestive effect Effects 0.000 description 1
- PCHPORCSPXIHLZ-UHFFFAOYSA-N diphenhydramine hydrochloride Chemical compound [Cl-].C=1C=CC=CC=1C(OCC[NH+](C)C)C1=CC=CC=C1 PCHPORCSPXIHLZ-UHFFFAOYSA-N 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002934 diuretic Substances 0.000 description 1
- 230000001882 diuretic effect Effects 0.000 description 1
- 150000002148 esters Chemical class 0.000 description 1
- NJSUFZNXBBXAAC-UHFFFAOYSA-N ethanol;toluene Chemical compound CCO.CC1=CC=CC=C1 NJSUFZNXBBXAAC-UHFFFAOYSA-N 0.000 description 1
- UYMKPFRHYYNDTL-UHFFFAOYSA-N ethenamine Chemical class NC=C UYMKPFRHYYNDTL-UHFFFAOYSA-N 0.000 description 1
- 235000019326 ethyl hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000003172 expectorant agent Substances 0.000 description 1
- 230000003419 expectorant effect Effects 0.000 description 1
- 229940066493 expectorants Drugs 0.000 description 1
- 238000001125 extrusion Methods 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- 235000011389 fruit/vegetable juice Nutrition 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 229940125695 gastrointestinal agent Drugs 0.000 description 1
- 239000004083 gastrointestinal agent Substances 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 235000001727 glucose Nutrition 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 125000004029 hydroxymethyl group Chemical group [H]OC([H])([H])* 0.000 description 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 239000005554 hypnotics and sedatives Substances 0.000 description 1
- 229940126904 hypoglycaemic agent Drugs 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000001788 irregular Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 239000003589 local anesthetic agent Substances 0.000 description 1
- 229960005015 local anesthetics Drugs 0.000 description 1
- 229940037627 magnesium lauryl sulfate Drugs 0.000 description 1
- HBNDBUATLJAUQM-UHFFFAOYSA-L magnesium;dodecyl sulfate Chemical compound [Mg+2].CCCCCCCCCCCCOS([O-])(=O)=O.CCCCCCCCCCCCOS([O-])(=O)=O HBNDBUATLJAUQM-UHFFFAOYSA-L 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 230000007721 medicinal effect Effects 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 210000004080 milk Anatomy 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000003158 myorelaxant agent Substances 0.000 description 1
- BVWUEIUNONATML-UHFFFAOYSA-N n-benzylethenamine Chemical compound C=CNCC1=CC=CC=C1 BVWUEIUNONATML-UHFFFAOYSA-N 0.000 description 1
- IQFXJRXOTKFGPN-UHFFFAOYSA-N n-ethenyl-n-ethylethanamine Chemical compound CCN(CC)C=C IQFXJRXOTKFGPN-UHFFFAOYSA-N 0.000 description 1
- 210000005036 nerve Anatomy 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
- 229940065472 octyl acrylate Drugs 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000011368 organic material Substances 0.000 description 1
- 239000012466 permeate Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 239000004014 plasticizer Substances 0.000 description 1
- 239000002574 poison Substances 0.000 description 1
- 231100000614 poison Toxicity 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 102000004196 processed proteins & peptides Human genes 0.000 description 1
- 108090000765 processed proteins & peptides Proteins 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- OVARTBFNCCXQKS-UHFFFAOYSA-N propan-2-one;hydrate Chemical compound O.CC(C)=O OVARTBFNCCXQKS-UHFFFAOYSA-N 0.000 description 1
- 235000019423 pullulan Nutrition 0.000 description 1
- 239000003169 respiratory stimulant agent Substances 0.000 description 1
- 229940066293 respiratory stimulants Drugs 0.000 description 1
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 1
- 235000010234 sodium benzoate Nutrition 0.000 description 1
- 239000004299 sodium benzoate 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
- 239000011877 solvent mixture Substances 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 230000001256 tonic effect Effects 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940124549 vasodilator Drugs 0.000 description 1
- 239000003071 vasodilator agent Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
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Landscapes
- Medicinal Preparation (AREA)
Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、新規放出制御型製剤およびその製法に関する
。DETAILED DESCRIPTION OF THE INVENTION [Field of Industrial Application] The present invention relates to a novel controlled-release formulation and a method for producing the same.
従来より、疎水性高分子物質の緻密な皮膜で被覆した医
薬品製剤が知られている。BACKGROUND ART Pharmaceutical preparations coated with a dense film of a hydrophobic polymeric substance have been known.
この製剤は耐水性、耐光性、耐湿性、耐摩耗性、保存安
定性などに優れているという長所を有している。This formulation has the advantage of being excellent in water resistance, light resistance, moisture resistance, abrasion resistance, storage stability, etc.
しかしながら、疎水性高分子物質の緻密な皮膜で被覆し
た製剤は内部薬物の放出速度が遅く、また薬物が完全に
放出されないという点に課題が残されている。However, problems remain in that preparations coated with a dense film of hydrophobic polymeric substances have a slow release rate of the internal drug, and the drug is not completely released.
すなわら、被覆された薬物の放出は、皮膜の間隙を介し
て侵入した消化液などの水分により薬物が飽和濃度まで
溶解することによって生じる外部との濃度差及び浸透圧
差に基づいている。しかし、疎水性高分子物質の緻密な
皮膜は間隙が少ないため、皮膜内部への水分浸透が遅く
、また外部へ薬物を放出し得るだけの浸透圧差が生じて
も、放出に寄与する間隙の全面積が小さいので、溶出速
度が充分でないという問題を生じる。In other words, the release of the coated drug is based on the concentration difference and osmotic pressure difference between the coated drug and the outside, which are generated when the drug is dissolved to a saturation concentration by moisture such as digestive juices that have entered through gaps in the coating. However, because the dense film of a hydrophobic polymer substance has few pores, water permeation into the film is slow, and even if there is a difference in osmotic pressure sufficient to release the drug to the outside, the pores that contribute to drug release are completely absorbed. Since the area is small, the problem arises that the elution rate is not sufficient.
これらの問題点を解決する方法として、疎水性高分子物
質の皮膜中に水溶性物質の粒子を埋め込み、消化管内で
の該水溶性物質の溶解・離脱によって皮膜を多孔化する
方法が知られている。A known method to solve these problems is to embed particles of a water-soluble substance in a film of a hydrophobic polymer substance and make the film porous by dissolving and releasing the water-soluble substance in the gastrointestinal tract. There is.
しかしながら、この方法では、水溶性物質を皮膜中に埋
めこむために、コーティングに特別な工夫が必要であり
、また分散剤、可塑剤、凝集防止剤など種々の添加物が
必要で処方が複雑化する上、消化管中で皮膜が多孔性膜
となるとしても、その多孔度は、水溶性物質の粒度や皮
膜中の該物質の分散度により影響を受け、必ずしも多孔
度を正６１に制御しうるとは言い難い
〔発明の構成及び効果〕
本発明者らは、疎水性高分子物質で被覆した製剤の物理
的強度の大きさ、保存安定性の良さ等の長所を生かしつ
つ、放出制御を可能ならしめるべく鋭意研究を重ねた結
果、疎水性高分子物質の多孔性膜を形成させることに成
功すると共に、皮膜の多孔度を任意に調整することで所
望の溶出速度を持つ放出制御型製剤が得られることを見
出し、前記問題点を解決するに至った。However, with this method, special measures are required for the coating in order to embed water-soluble substances in the film, and various additives such as dispersants, plasticizers, and anti-agglomeration agents are required, making the formulation complex. Even if the membrane becomes a porous membrane in the gastrointestinal tract, the porosity is influenced by the particle size of the water-soluble substance and the degree of dispersion of the substance in the membrane, and it is not always possible to control the porosity to a positive value. [Structure and Effects of the Invention] The present inventors have developed a drug that makes it possible to control release while taking advantage of the strong physical strength and good storage stability of a preparation coated with a hydrophobic polymeric substance. As a result of intensive research, we succeeded in forming a porous film of a hydrophobic polymer substance, and by arbitrarily adjusting the porosity of the film, we were able to create a controlled-release formulation with a desired dissolution rate. The inventors have found that the above-mentioned problems can be solved.
即ち、本発明は、医薬活性成分を含有する芯物質が疎水
性高分子物質の多孔性膜で被覆されてなる放出制御型お
よびその製法である。That is, the present invention is a controlled-release drug in which a core material containing a pharmaceutically active ingredient is coated with a porous membrane of a hydrophobic polymer material, and a method for producing the same.
本発明において、多孔性膜で被覆される芯物質の形態は
特に制限されず、裸錠剤、火剤、顆粒、細粒など種々の
形態のものをいずれも好適に用いることが出来、特に、
平均粒径が約３（１０μｍ〜約２（１００μｍ、とりわ
け約５（１０μｍ〜約８５０μｍに造粒したものを用い
るのが好ましい。また、本発明の芯物質は疎水性、水溶
性、水不溶性芯物質のいずれも好適に用いることができ
る。In the present invention, the form of the core substance coated with the porous membrane is not particularly limited, and various forms such as bare tablets, gunpowder, granules, and fine particles can be suitably used, and in particular,
It is preferable to use granules having an average particle size of about 3 (10 μm to about 2 (100 μm), particularly about 5 (10 μm to about 850 μm).The core material of the present invention may have a hydrophobic, water-soluble, or water-insoluble core. Any of these substances can be suitably used.
多孔性膜を構成する疎水性高分子物質としては、皮膜形
成能力があり、かつ水には不溶であるが水と混和する有
機溶媒には溶解するものであれば特に限定されない。か
かる疎水性高分子物質としては、例エバセルロースエー
テル、セルロースエステル、ポリビニルエステル、第４
級アンモニウムアルキル基を有するアクリル酸系重合体
等があげられる。具体的には、例えばエチルセルロース
、ブチルセルロース；セルロースアセテート、セルロー
スプロピオネート；ポリビニルアセテート、ポリビニル
ブチレート；オイドラギッドＲＳ （ローム・ファーマ
社商品名、化学名；アクリル酸エチル・メタアクリル酸
メチル・メタアクリル酸塩化トリメチルアンモニウムエ
チル共重合体）等があげられ、このうち好ましい疎水性
高分子物質としては、例えばエチルセルロース、ブチル
セルロース、セルロースアセテート、セルロースプロピ
オネートまたはオイドラギッドＲ５等があげられる。こ
のうち、好ましいものはエチルセルロースまたはセルロ
ースアセテートであり、最も好ましいものはエチルセル
ロースである。エチルセルロースは、とりわけ水不溶性
のエチルセルロースが好ましく、例えば、エトキシ含有
率が約４０〜約５５％、とりわけ約４３％〜約５１％で
あり、粘度〔トルエン−エタノール（４： １ ） ’
ｌＲ？＆のエチルセルロース５％濃度溶液の２５℃にお
ける粘度〕が約４〜約３５０ｃＰのものが好ましい。The hydrophobic polymeric substance constituting the porous membrane is not particularly limited as long as it has a film-forming ability and is insoluble in water but soluble in an organic solvent that is miscible with water. Examples of such hydrophobic polymer substances include evacellulose ether, cellulose ester, polyvinyl ester, quaternary
Examples include acrylic acid polymers having a grade ammonium alkyl group. Specifically, for example, ethyl cellulose, butyl cellulose; cellulose acetate, cellulose propionate; polyvinyl acetate, polyvinyl butyrate; Among them, preferred hydrophobic polymer substances include ethyl cellulose, butyl cellulose, cellulose acetate, cellulose propionate, and Eudragid R5. Among these, preferred is ethyl cellulose or cellulose acetate, and most preferred is ethyl cellulose. Ethylcellulose is particularly preferably water-insoluble ethylcellulose, for example, having an ethoxy content of about 40 to about 55%, especially about 43% to about 51%, and a viscosity of [toluene-ethanol (4:1)'
lR? A 5% concentration solution of ethyl cellulose with a viscosity of about 4 to about 350 cP at 25°C is preferred.
また、本発明における多孔性膜は、疎水性高分子物質の
みからなる多孔性膜以外に、疎水性高分子物質と親水性
高分子物質からなる多孔性膜であってもよい。この場合
、親水性高分子物質とじては水溶性高分子物質、腸溶性
高分子物質、胃溶性高分子物質、胃腸両溶性高分子物質
などを好適に用いることができる。Further, the porous membrane in the present invention may be a porous membrane consisting of a hydrophobic polymeric substance and a hydrophilic polymeric substance, in addition to a porous membrane consisting only of a hydrophobic polymeric substance. In this case, as the hydrophilic polymeric substance, water-soluble polymeric substances, enteric-coated polymeric substances, gastric-soluble polymeric substances, gastrointestinal-compatible polymeric substances, etc. can be suitably used.
例えば水溶性高分子物質の好ましい例としては、プルラ
ン、デキストリン、アルギン酸アルカリ金属塩等の硫酸
基を有していてもよい多糖類、ヒドロキシプロピルセル
ロース、ヒドロキシプロピルメチルセルロース、カルボ
キシメチルセルロースナトリウム等のヒドロキシアルキ
ル基又はカルボキシアルキル基を有する多糖類、メチル
セルロース、ポリビニルピロリドン、ポリビニルアルコ
ールもしくはポリエチレングリコール等があげられる。For example, preferred examples of water-soluble polymeric substances include polysaccharides that may have sulfate groups such as pullulan, dextrin, alginate alkali metal salts, hydroxyalkyl groups such as hydroxypropylcellulose, hydroxypropylmethylcellulose, and sodium carboxymethylcellulose. Alternatively, polysaccharides having a carboxyalkyl group, methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, polyethylene glycol, etc. may be mentioned.
これらのうち、より好ましい水溶性高分子物質としては
ヒドロキシプロピルセルロース又はポリエチレングリコ
ールがあげられる。Among these, more preferable water-soluble polymer substances include hydroxypropyl cellulose and polyethylene glycol.
また腸溶性高分子物質としては、ｐＨ５以上の水に溶解
し皮膜形成能のある高分子物質であればよく、例えば（
１）カルボキシアルキルセルロースエーテル、（２）二
塩基性酸のモノエステル結合を有するセルロース誘導体
、（３）二塩基性酸のモノエステル結合を有するポリビ
ニル誘導体、（４）マレイン酸−ビニル系共重合体又は
（５）アクリル酸系重合体等があげられる。（１１の具
体例としてはカルボキシメチルエチルセルロース、（２
）の具体例としてはセルロース・アセテート・フタレー
ト、セルロース・アセテート・サクシネート、メチルセ
ルロース・フタレート、ヒドロキシメチル・エチルセル
ロース・フタレート、ヒドロキシプロピルメチルセルロ
ース・フタレート、ヒドロキシプロピル・メチルセルロ
ース・アセテート・サクシネート等があげられ、（３）
の具体例としてはポリビニルアセテート・フタレート、
ポリビニルブチレート・フタレート、ポリビニルアセト
アセタール・フタレート等があげられる、また（４）の
具体例としてはビニルアセテート・マレイン酸無水物共
重合体、ビニルブチルエーテル・マレイン酸無水物共重
合体、スチレン・マレイン酸モノエステル共重合体があ
げられ、（５）の具体例としてはメチルアクリレート・
メタアクリル酸共重合体、スチレン・アクリル酸共重合
体、メチルアクリレート・メタアクリル酸・オクチルア
クリレート共重合体、オイドラギソドＬ及びＳ（ローム
・ファーマ社商品名、メタアクリル酸・メタアクリル酸
メチル共重合体）等があげられる。これらのうち、より
好ましい腸溶性高分子物質はカルボキシメチルエチルセ
ルロース、ヒドロキシプロピル・メチルセルロース・ア
セテート・サクシネート又はオイドラギッドしである。In addition, the enteric polymer substance may be any polymer substance that dissolves in water with a pH of 5 or more and has the ability to form a film, such as (
1) carboxyalkyl cellulose ether, (2) cellulose derivative having a dibasic acid monoester bond, (3) polyvinyl derivative having a dibasic acid monoester bond, (4) maleic acid-vinyl copolymer or (5) acrylic acid polymers. (Specific examples of 11 include carboxymethylethyl cellulose, (2
) Specific examples include cellulose acetate phthalate, cellulose acetate succinate, methylcellulose phthalate, hydroxymethyl ethylcellulose phthalate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, etc. )
Specific examples include polyvinyl acetate phthalate,
Examples include polyvinyl butyrate/phthalate, polyvinyl acetoacetal/phthalate, etc. Specific examples of (4) include vinyl acetate/maleic anhydride copolymer, vinyl butyl ether/maleic anhydride copolymer, styrene/malein. Examples of acid monoester copolymers include methyl acrylate and (5).
Methacrylic acid copolymer, styrene/acrylic acid copolymer, methyl acrylate/methacrylic acid/octyl acrylate copolymer, Eudragisod L and S (Rohm Pharma Co., Ltd. trade name, methacrylic acid/methyl methacrylate copolymer) combination), etc. Among these, more preferred enteric polymeric substances are carboxymethylethylcellulose, hydroxypropyl methylcellulose acetate succinate, or eudragit.
更に、胃溶性高分子物質としては、ｐ Ｈ６以下の水に
溶解し皮膜形成能のある高分子物質であればよく、例え
ば（ａ）モノ又はジ置換アミノ基を有するセルロース誘
導体、（ｂ）モノ又はジ置換アミノ基を有するポリビニ
ル誘導体、（Ｃｌモノ置換アミノ基を有するアクリル酸
系重合体等があげられる。（ａ）の具体例としてはベン
ジルアミノメチルセルロース、ジエチルアミノメチルセ
ルロース、ピペリジル・エチル・ヒドロキシエチルセル
ロース等のアミノセルロース類、セルロース・アセテー
ト・ジエチルアミノアセテート等のアミノセルロースエ
ステル類があげられる。（ｂ）の具体例としてはビニル
ジエチルアミン・ビニルアセテート共重合体、ビニルベ
ンジルアミン・ビニルアセテート共重合体等のビニルア
ミン類化合物、ポリビニルアセクール・ジエチルアミノ
アセテート、ビニルピペリジルアセトアセクール・ビニ
ルアセテート共重合体等のアミノビニルアセクール類化
合物、ポリジエチルアミノメチルスチレン等があげられ
、（Ｃ）の具体例としてはオイドラギッドＥ（ローム・
ファーマ社商品名、メタアクリル酸メチル・メタアクリ
ル酸ブチル・メタアクリル酸ジメチルアミノエチル共重
合体）、ポリジメチルアミノエチルメタアクリレート等
があげられる。これらのうち、より好ましい胃溶性高分
子物質は、ポリビニルアセクール・ジエチルアミノアセ
テート又はオイドラギッドＥである。Furthermore, the gastric soluble polymeric substance may be any polymeric substance that dissolves in water with a pH of 6 or less and has film-forming ability, such as (a) cellulose derivatives having mono- or di-substituted amino groups, (b) mono- or di-substituted amino groups, Or polyvinyl derivatives having a di-substituted amino group, acrylic acid polymers having a Cl-mono-substituted amino group, etc. Specific examples of (a) include benzylaminomethylcellulose, diethylaminomethylcellulose, piperidyl ethyl hydroxyethylcellulose, etc. Examples of (b) include aminocelluloses and aminocellulose esters such as cellulose acetate and diethylaminoacetate.Specific examples of (b) include vinylamines such as vinyldiethylamine/vinyl acetate copolymers and vinylbenzylamine/vinyl acetate copolymers. Examples of (C) include Eudragid E ( ROHM・
Examples include methyl methacrylate/butyl methacrylate/dimethylaminoethyl methacrylate copolymer), polydimethylaminoethyl methacrylate, and the like (product name of Pharma Co., Ltd.). Among these, more preferable gastrosoluble polymer substances are polyvinyl acecool diethylaminoacetate or Eudragid E.
胃腸両溶性高分子物質としては、ｐＨ４，５以下の水お
よびｐＨ６以上の水に溶解し皮膜形成能のある高分子物
質であればよく、例えばビニルピリジン−アクリル酸系
共重合体、モノ又はジ置換アミノ基を有するカルボキシ
メチル多ＩＪ！類又はポリビニルアミノ酸誘導体があげ
られる。ビニルピリジン−アクリル酸系共重合体の具体
例としては、２−メチル−５−ビニルピリジン・メチル
メタアクリレート・メタアクリル酸共重合体１．２−メ
チル−５−ビニルピリジン・メチルアクリレート・メタ
アクリル酸共重合体、２−ビニル−５−エチルピリジン
・メタアクリル酸・スチレン共重合体、２−ビニル−５
−エチルピリジン・メタアクリル酸・メチルアクリレー
ト共重合体、２−ビニルピリジン・メタアクリル酸・メ
チルアクリレート共重合体、２−ビニルピリジン・メタ
アクリル酸・アクリロニトリル共重合体等があげられる
。またモノ又はジ置換アミノ基を有するカルボキシメチ
ル多Ｉ！類の具体例としてはカルボキシメチル・ピペリ
ジル・デンプン、カルボキシメチル・ベンジルアミノセ
ルロース等があげられ、ポリビニルアミノ酸誘導体の具
体例としてはポリ２−ビニルフェニルグリシン、Ｎ−ビ
ニルグリシン−スチレン共重合体等があげられるわせに
は特に制限はないが、好ましい組み合わせとしては、疎
水性高分子物質と水溶性高分子物質または腸溶性高分子
物質との組み合わせがあげられる。とりわけ好ましい組
み合わせとしては、疎水性高分子物質たるエチルセルロ
ースと水溶性高分子物質たるヒドロキシプロピルセルロ
ース、腸溶性高分子物質たるカルボキシメチルエチルセ
ルロース又はヒドロキシプロピル・メチルセルロース・
アセテート・サクシネートとの組み合わせがあげられる
。疎水性高分子物質と親水性高分子物質の使用比率は疎
水性高分子物質１重量部に対して親水性高分子物質が約
０．０５〜０．５重量部であるのが望ましい。The gastrointestinal-compatible polymeric substance may be any polymeric substance that dissolves in water with a pH of 4.5 or lower and in water with a pH of 6 or higher and has a film-forming ability, such as vinylpyridine-acrylic acid copolymer, mono- or di-copolymer. Carboxymethyl multi-IJ with substituted amino group! and polyvinyl amino acid derivatives. Specific examples of vinylpyridine-acrylic acid copolymers include 2-methyl-5-vinylpyridine/methyl methacrylate/methacrylic acid copolymer 1.2-methyl-5-vinylpyridine/methyl acrylate/methacrylic acid copolymer Acid copolymer, 2-vinyl-5-ethylpyridine/methacrylic acid/styrene copolymer, 2-vinyl-5
Examples include -ethylpyridine/methacrylic acid/methyl acrylate copolymer, 2-vinylpyridine/methacrylic acid/methyl acrylate copolymer, and 2-vinylpyridine/methacrylic acid/acrylonitrile copolymer. Also, carboxymethyl poly(I) having a mono- or di-substituted amino group! Specific examples of these include carboxymethyl piperidyl starch, carboxymethyl benzylaminocellulose, etc. Specific examples of polyvinyl amino acid derivatives include poly 2-vinylphenylglycine, N-vinylglycine-styrene copolymer, etc. Although there are no particular limitations on the combinations that can be mentioned, preferred combinations include combinations of hydrophobic polymeric substances and water-soluble polymeric substances or enteric polymeric substances. Particularly preferred combinations include ethyl cellulose as a hydrophobic polymer and hydroxypropyl cellulose as a water-soluble polymer, carboxymethylethyl cellulose or hydroxypropyl methylcellulose as an enteric polymer.
A combination with acetate succinate is mentioned. The ratio of the hydrophobic polymeric substance to the hydrophilic polymeric substance used is preferably about 0.05 to 0.5 parts by weight of the hydrophilic polymeric substance per 1 part by weight of the hydrophobic polymeric substance.
上記の如き疎水性高分子物質又は疎水性高分子物質と親
水性高分子物質からなる多孔性膜は一般的に海綿状の外
観を有し、顕微鏡的サイズの相互に連通ずる規則的また
は不規則的な空孔を有している。A porous membrane made of a hydrophobic polymeric material or a hydrophobic polymeric material and a hydrophilic polymeric material as described above generally has a spongy appearance, and has microscopically interconnected regular or irregular structures. It has many pores.
また多孔性膜の多孔度は、一般的に式
疎水性高分子物質と親水性高分子物質の組み合で示すこ
とができ、該多孔度は任意に変化させ得るが、通常は約
０．４〜０，９、とりわけ０．５〜０．８５の範囲にあ
るのが好ましい。The porosity of a porous membrane can generally be expressed by a combination of a hydrophobic polymeric material and a hydrophilic polymeric material, and the porosity can be changed arbitrarily, but is usually about 0.4. It is preferably in the range from 0.9 to 0.9, especially from 0.5 to 0.85.
また、皮膜の厚さは、疎水性高分子物質の芯物質に対す
る被覆量で調製すればよく、芯物質に対して疎水性高分
子物質を約３〜１（１０ Ｗ／Ｗ％の範囲、とりわけ約
５〜５四八％となるよう用いるのが望ましい。また、疎
水性高分子物質と親水性高分子物質を併用するときも、
画商分子物質を併せて上記範囲の被覆量であるのが好ま
しい。The thickness of the film may be adjusted by adjusting the coating amount of the hydrophobic polymer material to the core material. It is desirable to use it so that it is about 5 to 548%.Also, when using a hydrophobic polymer substance and a hydrophilic polymer substance together,
It is preferable that the coating amount including the art dealer molecular substance be within the above range.
本発明の製剤においては、皮膜の厚さと多孔度を適宜調
節することにより、所望の溶出速度をもつ製剤とするこ
とができ、例えば芯物質に含有されている医薬活性成分
が投与後短時間で薬効を奏することが望ましい薬物であ
る場合は、皮膜を薄く、多孔度を大きくすればよ（、ま
た長時間持続的に放出することが望まれる薬物の場合に
は、皮膜を厚く、多孔度を小さくすればよい。In the preparation of the present invention, by appropriately adjusting the thickness and porosity of the film, it is possible to obtain a preparation with a desired dissolution rate. If the drug is desired to have a medicinal effect, the coating should be thinner and the porosity should be increased (and if the drug is desired to be released continuously for a long time, the coating should be thicker and the porosity should be increased). Just make it smaller.
また該芯物質に含有され得る医薬活性成分としては、経
口投与可能な薬物であれば特に限定されない。かかる医
薬活性成分としては、例えばビタミン類、アミノ酸、ペ
プチド、化学療法剤、抗生物質、呼吸促進剤、鎮咳去た
ん剤、抗悪性腫瘍剤、自律神経用薬剤、精神神経用薬剤
、局所麻酔剤、筋弛緩剤、消化器官用薬剤、抗ヒスタミ
ン剤、中毒治療剤、催眠鎮静剤、抗てんかん剤、解熱鎮
痛消炎剤、強心剤、不整脈治療剤、降圧利尿剤、血管拡
張剤、抗脂血剤、滋養強壮変質剤、抗凝血剤、肝臓用薬
剤、血糖降下剤、血圧降下剤などがあげられる。また、
芯物質中には通常この分野で常用される種々の配合剤、
例えば結合剤、賦形剤、凝集防止剤、緩衝剤等が配合さ
れていてもよい。Furthermore, the pharmaceutically active ingredient that can be contained in the core substance is not particularly limited as long as it is an orally administrable drug. Such pharmaceutical active ingredients include, for example, vitamins, amino acids, peptides, chemotherapeutic agents, antibiotics, respiratory stimulants, antitussive expectorants, antineoplastic agents, agents for autonomic nerves, agents for psychiatric nerves, local anesthetics, Muscle relaxant, gastrointestinal agent, antihistamine, poison treatment agent, hypnotic sedative, antiepileptic agent, antipyretic, analgesic, antiinflammatory agent, cardiotonic agent, antiarrhythmia agent, antihypertensive diuretic, vasodilator, antilipidemic agent, nourishing tonic and altering agent. drugs, anticoagulants, liver drugs, hypoglycemic agents, antihypertensive agents, etc. Also,
The core material usually contains various compounding agents commonly used in this field,
For example, binders, excipients, anti-aggregation agents, buffers, etc. may be included.
賦形剤としては、白字）１、乳糖、マンニトール、グル
コース等の糖類、でんぷん、結晶セルロース、リン酸カ
ルシウム、硫酸カルシウム、乳酸カルシウムなどがあげ
られ、結合剤としては、ポリビニルアルコール、ポリア
クリル酸、ポリメタクリル酸、ポリビニルピロリドン、
グルコース、白ネ唐、乳ｔＬ 麦ＷｔＬソルビトール、
マンニトール、ヒドロキシエチルセルロース、ヒドロキ
シプロピルメチルセルロース、ヒドロキシプロピルセル
ロース、マクロゴール類、アラビアゴム、ゼラチン、寒
天、でんぷんなどがあげられる。又、滑沢剤、凝集防止
剤としては、タルク、ステアリン酸マグネシウム、ステ
アリン酸カルシウム、コロイダルシリカ、ステアリン酸
、ワックス類、硬化油、ポリエチレングリコール類、安
息香酸ナトリウム、ラウリル硫酸ナトリウム、ラウリル
硫酸マグネシウムなどがあげられる。更に緩衝剤として
は、通常用いられる無機塩類の他、フマル酸、コハク酸
、クエン酸、リンゴ酸などの有機酸もしくはその塩など
があげられる。Examples of excipients include sugars such as lactose, mannitol, and glucose, starch, crystalline cellulose, calcium phosphate, calcium sulfate, and calcium lactate; examples of binders include polyvinyl alcohol, polyacrylic acid, and polymethacrylate. acid, polyvinylpyrrolidone,
Glucose, white tang, milk tL barley WtL sorbitol,
Examples include mannitol, hydroxyethylcellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, macrogols, gum arabic, gelatin, agar, and starch. In addition, as lubricants and anti-aggregation agents, talc, magnesium stearate, calcium stearate, colloidal silica, stearic acid, waxes, hydrogenated oils, polyethylene glycols, sodium benzoate, sodium lauryl sulfate, magnesium lauryl sulfate, etc. can give. Furthermore, examples of buffering agents include organic acids such as fumaric acid, succinic acid, citric acid, and malic acid, or salts thereof, in addition to commonly used inorganic salts.
本発明の製剤は、医薬活性成分を含む裸錠剤、顆粒、火
剤、細粒などの芯物質を、疎水性高分子物質、或いは疎
水性高分子物質と親水性高分子物質を含む水−有機溶媒
混液で噴霧コーティングして、芯物質の表面に当該高分
子物質の多孔性膜を形成させることにより、製造するこ
とができる。In the preparation of the present invention, the core material of a bare tablet, granule, gunpowder, fine granule, etc. containing a pharmaceutically active ingredient is replaced with a hydrophobic polymeric material, or an aqueous-organic material containing a hydrophobic polymeric material and a hydrophilic polymeric material. It can be manufactured by spray coating with a solvent mixture to form a porous film of the polymer material on the surface of the core material.
芯物質の調製は、レミントンズ・ファーマシューティカ
ル・サイエンス、第１７版、１６０３〜１６３２．１６
３３〜１６４３頁（マーク・パブリッシング・カンパニ
ー １９８５年発行）に記載されているような通常の製
剤化手法で実施することができる。例えば、医薬化合物
に適当な賦形剤、結合剤、滑沢剤等を混合し、湿式押し
出し造粒法、流動層造粒法等により調製してもよく、或
いは、結合剤を水、低級アルコール（メチルアルコール
、エチルアルコール、プロピルアルコール、イソプロピ
ルアルコール、ブチルアルコール等）、低級アルカノン
（アセトン、メチルエチルケトン等）、クロロホルム、
ジクロロメタン、ジクロロエタン又はこれらの混合物な
どの適当な溶媒に溶解した溶液を、中心核となる不活性
担体粒子上にスプレーしながら、医薬化合物或いはこれ
と賦形剤、滑沢剤等との混合物を少量づつ添加して行う
転勤造粒法、パンコーティング法、流動層コーティング
法等により調製することもできる。この場合、不活性坦
体粒子としては、例えば、白糖、乳糖、でんぷん、結晶
セルロース等で製造されたものが好適に使用できる。ま
たその平均粒子径は約３（１０μｍ〜約１５（１０μｍ
であるものが好ましい。Preparation of core materials is described in Remington's Pharmaceutical Science, 17th edition, 1603-1632.16
It can be carried out by conventional formulation techniques such as those described on pages 33-1643 (published by Mark Publishing Company, 1985). For example, the pharmaceutical compound may be mixed with suitable excipients, binders, lubricants, etc., and prepared by wet extrusion granulation, fluidized bed granulation, etc., or the binder may be mixed with water, lower alcohol, etc. (methyl alcohol, ethyl alcohol, propyl alcohol, isopropyl alcohol, butyl alcohol, etc.), lower alkanones (acetone, methyl ethyl ketone, etc.), chloroform,
A small amount of the pharmaceutical compound or its mixture with excipients, lubricants, etc. is sprayed onto the core inert carrier particles by dissolving the solution in a suitable solvent such as dichloromethane, dichloroethane or a mixture thereof. It can also be prepared by a transfer granulation method, a pan coating method, a fluidized bed coating method, etc. in which the components are added in batches. In this case, as the inert carrier particles, for example, those manufactured from white sugar, lactose, starch, crystalline cellulose, etc. can be suitably used. The average particle diameter is about 3 (10 μm to about 15 μm)
It is preferable that
かくして得られる芯物質を多孔性膜で被覆するに際し、
水と共に混合溶媒を形成する有機溶媒としては、疎水性
高分子物質を溶解するものであれば特に限定されず用い
ることができ、例えばメチルアルコール、エチルアルコ
ール、イソプロピルアルコール、ｎ−プロピルアルコー
ル、ｎ ７’チルアルコール等の低級アルコール、ア
セトン、メチルエチルケトン等の低級アルカノン、アセ
トニトリルなどがあげられる。これらのうち、より好ま
しい溶媒は低級アルコールであり、とりわけ好ましい溶
媒はエチルアルコール、イソプロピルアルコールである
。水と有機溶媒の混合比率は、水１容量に対して有機溶
媒９〜０．５容量の範囲で、適宜変化させることができ
、その比率に応じて疎水性高分子物質或いは疎水性高分
子物質と親水性高分子物質からなる多孔性膜の多孔度を
任意に調整することができる。多孔性膜の多孔度は、概
して言えば水−有機溶媒混液中の水の割合を増加させる
と大きくなり、有機溶媒の割合を増加させると小さくな
る。When covering the core material thus obtained with a porous membrane,
The organic solvent that forms the mixed solvent with water is not particularly limited and can be used as long as it dissolves the hydrophobic polymeric substance, such as methyl alcohol, ethyl alcohol, isopropyl alcohol, n-propyl alcohol, n7 Examples include lower alcohols such as methyl alcohol, lower alkanones such as acetone and methyl ethyl ketone, and acetonitrile. Among these, more preferred solvents are lower alcohols, and particularly preferred solvents are ethyl alcohol and isopropyl alcohol. The mixing ratio of water and organic solvent can be changed as appropriate within the range of 9 to 0.5 volumes of organic solvent per 1 volume of water, and depending on the ratio, hydrophobic polymeric substances or hydrophobic polymeric substances can be mixed. The porosity of the porous membrane made of the hydrophilic polymer material and the hydrophilic polymer material can be adjusted as desired. Generally speaking, the porosity of a porous membrane increases as the proportion of water in the water-organic solvent mixture increases, and decreases as the proportion of organic solvent increases.
水−有機溶媒混液中の疎水性高分子物質の濃度は約２〜
３０Ｗ／Ｗ／％であるのが好ましい。また、疎水性高分
子物質と親水性高分子物質を併用するときも、画商分子
物質を合わせ上記範囲の濃度であるのが好ましい。The concentration of the hydrophobic polymer substance in the water-organic solvent mixture is about 2~
Preferably, it is 30 W/W/%. Also, when a hydrophobic polymeric substance and a hydrophilic polymeric substance are used together, it is preferable that the concentration of the artist's molecular substance is within the above range.
噴霧コーティングは、通常のコーティング法により実施
することができる。例えば、疎水性高分子物質或いは疎
水性高分子物質と親水性高分子物質を水−有機溶媒の混
合物に溶解させたコーテイング液を、例えば、流動層コ
ーティング法、パンコーティング法等により、芯物質上
にスプレーコーティングすることにより容易に実施する
ことができる。例えばパンコーティング法によるときは
、芯物質をコーティングパンに入れ、該コーティングパ
ンを回転させつつ、スプレーガンのノズルから疎水性高
分子物質或いは疎水性高分子物質と親水性高分子物質を
含む水−有機溶媒混液を適当な速度で噴霧したのち乾燥
することにより実施することができる。Spray coating can be carried out by conventional coating methods. For example, a coating liquid in which a hydrophobic polymer substance or a hydrophobic polymer substance and a hydrophilic polymer substance are dissolved in a mixture of water and an organic solvent is coated on the core material by, for example, a fluidized bed coating method or a pan coating method. This can be easily done by spray coating. For example, when using the pan coating method, the core material is placed in a coating pan, and while the coating pan is rotated, a hydrophobic polymer material or water containing a hydrophobic polymer material and a hydrophilic polymer material is sprayed from a spray gun nozzle. This can be carried out by spraying an organic solvent mixture at an appropriate rate and then drying.
このとき、所望により、タルク、二酸化チタン等を凝集
防止剤として添加することもできる。At this time, if desired, talc, titanium dioxide, etc. can be added as an anti-aggregation agent.
かくして得られる本発明の放出制御型製剤は、そのまま
投与してもよく、また該製剤が顆粒ないし細粒である場
合はカプセル等に充填して投与することもできる。The thus obtained controlled-release preparation of the present invention may be administered as is, or if the preparation is in the form of granules or fine particles, it may be filled into a capsule or the like and administered.
本発明の製剤は、皮膜が多孔性であるため、投与直後か
ら体液が製剤内部に浸透し医薬活性成分の溶解がはじま
り、放出の立ち上がりが早いという特徴がある。しかも
、同時に該多孔性膜の多孔度を調整し得るので、多孔度
を調整すれば、立ら上がりが早いというだけでなく、放
出速度をコントロールすることが可能となるという従来
の製剤には見られなかった優れた利点を有する。具体的
には例えば、医薬活性成分の主作用と副作用の発現濃度
が接近し濃度幅を狭い範囲に保つ必要のあるもの、ある
いは長時間一定の血中濃度を維持する必要のあるもので
ある場合には、多孔度を小さくすれば、所望の濃度と放
出時間を得ることができる。また、医薬活性成分に速効
性をもたせる必要がある場合は、多孔度の大きい皮膜で
被覆すれば、投与直後から医薬活性成分を溶出させるこ
とが出来る。更に、疎水性高分子物質と親水性高分子物
質とからなる多孔性膜で被覆した製剤は、投与後医薬成
分の溶出が早くなると共に、多孔性膜の一部を構成する
親水性高分子物質の層も溶解し、膜自体の多孔度が更に
大きくなるので短時間に医薬活性成分を放出させること
ができる。Since the formulation of the present invention has a porous film, body fluids permeate into the formulation immediately after administration, and dissolution of the pharmaceutically active ingredient begins, resulting in a rapid onset of release. Moreover, since the porosity of the porous membrane can be adjusted at the same time, adjusting the porosity not only improves the rise time but also makes it possible to control the release rate, unlike conventional formulations. It has excellent advantages not found in other countries. Specifically, for example, when the main effect of the active pharmaceutical ingredient and the concentration at which side effects occur are close to each other and the concentration range needs to be kept within a narrow range, or when it is necessary to maintain a constant blood concentration for a long period of time. The desired concentration and release time can be obtained by reducing the porosity. In addition, if it is necessary to give the pharmaceutically active ingredient immediate effect, by covering it with a highly porous film, the pharmaceutically active ingredient can be eluted immediately after administration. Furthermore, in preparations coated with a porous membrane consisting of a hydrophobic polymeric substance and a hydrophilic polymeric substance, the medicinal ingredient elutes quickly after administration, and the hydrophilic polymeric substance that forms part of the porous membrane layer also dissolves, and the porosity of the membrane itself becomes even greater, allowing the release of pharmaceutically active ingredients in a short period of time.
しかも、本発明の製剤は、従来の緻密な疎水性皮膜を有
する製剤に較べて耐湿性、遮光性、耐水性、対摩耗性な
どの点で何ら遜色がない。In addition, the formulation of the present invention is comparable to conventional formulations having a dense hydrophobic film in terms of moisture resistance, light shielding properties, water resistance, abrasion resistance, etc.
以上の通り、本発明の製剤は、従来の疎水性高分子物質
による被覆の課題を解決した放出制御に優れたものであ
ると共に、従来の製剤がもつ長所をそのまま維持した優
れた作用効果を奏する。As described above, the formulation of the present invention has excellent release control that solves the problems of conventional coatings with hydrophobic polymer substances, and also exhibits excellent effects while maintaining the advantages of conventional formulations. .
実験例
＋１１製剤の調製
粒径７１０〜８４０μｍのノンバレル（結晶白糖の商品
名、フロイント社製）１ｋｇを遠心流動造粒機（ＣＦ−
３６０ＥＸ型、フロイント社製）に入れ転勤させ、これ
に白ｔＪ！ ４（１０ｇを含・む水−エタノール溶液（
重量比＝３ ： １）を噴霧しながら塩酸ジルチアゼム
粉末１ ｋｇを徐々に添加して、ノンバレルの周囲に被
覆する。ついで、得られた塩酸ジルチアゼム素顆粒に、
エチルセルロース（エトキシ含有率、 ４９．６χ）
３（１０ｇを、水−エタノール混液（重量比＝３＝７．
２；８又は１．５ ： ８．５ ） ２．７ ｋｇに溶
解した溶液を、温風を吹き込みつつ噴霧する。噴霧後乾
燥するごとにより、多孔度のそれぞれ異なる多孔性エチ
ルセルロース膜で被覆された塩酸ジルチアゼム含有製剤
を得る。Experimental Example +11 Preparation of Preparation 1 kg of non-barrel (trade name of crystalline white sugar, manufactured by Freund) with a particle size of 710 to 840 μm was placed in a centrifugal fluid granulator (CF-
360EX (manufactured by Freund) and was transferred to a new location, and a white tJ! 4 (water-ethanol solution containing 10g (
1 kg of diltiazem hydrochloride powder is gradually added while spraying at a weight ratio of 3:1) to coat the area around the non-barrel. Then, to the obtained diltiazem hydrochloride elementary granules,
Ethyl cellulose (ethoxy content, 49.6χ)
3 (10g was mixed with water-ethanol mixture (weight ratio = 3 = 7.
2;8 or 1.5:8.5) Spray the solution dissolved in 2.7 kg while blowing hot air. By each spraying and drying process, preparations containing diltiazem hydrochloride coated with porous ethylcellulose membranes having different porosities are obtained.
（２）放出速度の比較
上記で得られた各製剤を、第１１改正日本薬局方の、パ
ドル法による溶出試験規格に基づき溶出試験を実施した
。(2) Comparison of release rate Each of the preparations obtained above was subjected to a dissolution test based on the paddle method dissolution test specifications of the 11th edition of the Japanese Pharmacopoeia.
（３）結果 結果は下記第１表に示す通りである。(3) Results The results are shown in Table 1 below.
第 １ 表 （注） 傘２ ；多孔度は上記式（１）に従って計算した。Table 1 (note) Umbrella 2: Porosity was calculated according to the above formula (1).
上記第１表から明らかなように、被覆時の溶媒として水
−エタノール（３： ７）混液を用いた製剤（Ａ）は、
皮膜の多孔度が太きく２４時間で塩酸ジルチアゼムが１
（１０％溶出し、製剤（Ｂ）〜（Ｃ）では水−エタノー
ル混液中の水の比率が小さくなるに従って多孔度が小さ
くなり１（１０％溶出までの所要時間が大きくなること
が認められる。As is clear from Table 1 above, the formulation (A) using a water-ethanol (3:7) mixture as a solvent during coating had the following properties:
The porosity of the film is so thick that diltiazem hydrochloride can be absorbed by 1 in 24 hours.
(10% elution) For formulations (B) to (C), it is observed that as the ratio of water in the water-ethanol mixture decreases, the porosity decreases and the time required to reach 10% elution increases.
実施例１
粒径７１０〜８４０μｍのノンバレル５（１０ｇを遠心
流動造粒機に入れ転動させ、これに白ｔｌ！ ２７０ｇ
を水１４５ｄに溶解した溶液を噴霧しながらテオフィリ
ン（化学名；３，７−シヒドロー１．３−ジメチル−１
１１−プリン−２，６−ジオン）微粉末１ ｋｇを徐々
に添加しノンバレルの周囲に被覆する。ついで、得られ
たテオフィリン素顆粒１ ｋｇを遠心流動造粒機に入れ
転勤させ、これにエチルセルロース９０ｇ及びヒドロキ
シプロピルセルロース１０ｇを水−エタノール（３：
７）の混液１．９ｋｇに溶解した溶液を温風を吹き込み
つつ噴霧する。ついで乾燥することにより多孔性エチル
セルロース−ヒドロキシプロピルセルロース膜で被覆さ
れた放出制御型テオフィリン顆粒１ 、１ ｋｇを得る
。Example 1 Non-barrel 5 (10 g with a particle size of 710 to 840 μm was placed in a centrifugal flow granulator and rolled, and 270 g of white tl.
Theophylline (chemical name: 3,7-sihydro-1,3-dimethyl-1) was sprayed while spraying a solution of
Gradually add 1 kg of fine powder (11-purine-2,6-dione) and coat around the non-barrel. Next, 1 kg of the obtained theophylline granules was placed in a centrifugal flow granulator, and 90 g of ethyl cellulose and 10 g of hydroxypropyl cellulose were mixed with water-ethanol (3:
A solution dissolved in 1.9 kg of the mixture of 7) is sprayed while blowing hot air. Then, by drying, 1.1 kg of controlled-release theophylline granules coated with a porous ethylcellulose-hydroxypropylcellulose membrane are obtained.
得られた製剤は皮膜の多孔度が０．８１であった。The resulting formulation had a film porosity of 0.81.
実施例２
粒径７１０〜８４０μｍのノンバレル１ ｋｇを遠心流
動造粒機に入れ転勤させ、これに白Ｗ ４（１０ｇ含有
水−エタノール混液８（１０ｇを噴霧しつつ、サリチル
酸ナトリウムの粉末１ ｋｇを徐々に添加しノンバレル
の周囲に付着させる。ついで得られたサリチル酸ナトリ
ウム素顆粒５（１０ｇを遠心流動造粒機に入れ、空気を
吹き込んで吹上転勤させながら、エチルセルロース１（
１０ｇを水−エタノール（２：８）の混液９（１０ｇに
溶解し、タルク５０ ｇを加えた混合物を温風を吹き込
みつつ噴霧する。噴霧後乾燥することにより多孔性エチ
ルセルロース膜で被覆された放出制御型サリチル酸ナト
リウム顆粒６（１０ｇを得る。Example 2 1 kg of a non-barrel with a particle size of 710 to 840 μm was placed in a centrifugal fluid granulator, and 1 kg of sodium salicylate powder was added to it while spraying 8 (10 g) of a water-ethanol mixture containing 10 g of White W4 (1 kg). Gradually add the sodium salicylate raw granules 5 (10 g) to a centrifugal fluid granulator, and while blowing air and transferring the ethyl cellulose 1 (
A mixture of 10 g of water-ethanol (2:8) mixed solution 9 (10 g) and 50 g of talc added thereto is sprayed while blowing hot air. After spraying, the mixture is dried and coated with a porous ethyl cellulose membrane. Obtain Controlled Sodium Salicylate Granules 6 (10 g).
得られた製剤は皮膜の多孔度が０．６８であった。The resulting formulation had a film porosity of 0.68.
実施例３
粒径５（１０〜７１０１７ｍのノンバレル１．３３ ｋ
ｇを遠心流動造粒機に入れ転勤させ、これに白糖６５２
ｇを水−エタノール（３： １）の混液１９５７ｇに溶
解した溶液を噴霧しながら（＋）−（２Ｓ、３Ｓ ）−
３−アセトキシ−８−クロロ−５−（２−（ジメチルア
ミノ）エチル） −２，３−ジヒドロ−２−（４−メ
トキシフェニル）−１，５−ベンゾチアゼピン−４（５
１１）−オン・マレイン酸塩の微粉末１ ｋｇ及びコハ
ク酸１．６７ ｋｇの混合物を徐々に添加しノンバレル
の周囲に被覆する。Example 3 Particle size 5 (10-71017 m non-barrel 1.33 k
g into a centrifugal fluid granulator, and add 652 g of white sugar to it.
(+)-(2S,3S)- while spraying a solution prepared by dissolving g in 1957 g of water-ethanol (3:1) mixture.
3-acetoxy-8-chloro-5-(2-(dimethylamino)ethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine-4(5
11) A mixture of 1 kg of fine powder of -one maleate and 1.67 kg of succinic acid is gradually added and coated around the non-barrel.
ついで得られた素顆粒２ ｋｇを遠心流動造粒機に入れ
転勤させ、これにエチルセルロース１９０ ｇ 及びヒ
ドロキシプロピルセルロース１０ ｇを水−エタノール
（３： ７）の混液１．８ｋｇに溶解した溶液を温風を
吹き込みつつ噴霧する。ついで乾燥することにより多孔
性エチルセルロース−ヒドロキシプロピルセルロース膜
で被覆された放出制御型顆粒２．２ｋｇを得る。Next, 2 kg of the obtained elementary granules were transferred to a centrifugal fluid granulator, and a solution of 190 g of ethyl cellulose and 10 g of hydroxypropyl cellulose dissolved in 1.8 kg of a water-ethanol (3:7) mixture was heated therein. Spray while blowing in the wind. Then, by drying, 2.2 kg of controlled release granules coated with a porous ethylcellulose-hydroxypropylcellulose membrane are obtained.
得られた製剤は皮膜の多孔度が０．８５であった。The resulting formulation had a film porosity of 0.85.
実施例４
塩酸ジルチアゼム３（１０ｇ 、乳糖６１１ｇ 及ヒコ
ーンスターチ１５０ｇを混合し、ポリビニルピロリドン
３０ｇと水１（１０−の混合液を加えて練合して整粒し
打錠用顆粒を調製する。ついでこれにステアリン酸マグ
ネシウム８ｇを加えロータリー弐打錠機（ＲＴ Ｆ−９
−２型、菊水製作所製）で打錠し、直径８１１の錠剤を
製する。得られた塩酸ジルチアゼム含有素錠５（１０ｇ
をコーチイブパン中に入れ、これにエチルセルロースを
５ Ｗ／Ｗχ含有する水−エタノール混液（３： ７）
１．０ ｋｇを常温で噴霧する。ついで乾燥すること
により多孔性エチルセルロース膜で被覆された放出制御
型塩酸ジルチアゼム錠を得る。Example 4 Diltiazem hydrochloride 3 (10 g), lactose 611 g, and corn starch 150 g are mixed, and a mixture of 30 g polyvinylpyrrolidone and water 1 (10) is added, kneaded, and sized to prepare granules for tabletting. Add 8g of magnesium stearate to this and use a rotary tablet press (RT F-9).
-2 type, manufactured by Kikusui Seisakusho) to produce tablets with a diameter of 811 mm. Obtained uncoated tablets containing diltiazem hydrochloride 5 (10g
into a coach bread, and add a water-ethanol mixture (3:7) containing 5 W/Wx of ethyl cellulose.
Spray 1.0 kg at room temperature. Then, by drying, controlled-release diltiazem hydrochloride tablets coated with a porous ethylcellulose membrane are obtained.
得られた製剤は皮膜の多孔度が０．６７であった。The resulting formulation had a film porosity of 0.67.
実施例５
実施例１と同様にして得たテオフィリン素顆粒５（１０
ｇを遠心流動造粒機に入れ、これにエチルセルロース５
０ｇを水−イツブロバノール混’１（１（４：６）９５
０ｇに溶解した溶液を温風を吹き込みつつ噴霧する。つ
いで乾燥することにより多孔性エチルセルロース膜で被
覆された放出制御型テオフィリン顆粒約５５０ｇを得る
。Example 5 Theophylline granules 5 (10
g into a centrifugal fluid granulator, and add 5 ml of ethyl cellulose to it.
0 g to water-ituburobanol mixture '1 (1 (4:6) 95
A solution dissolved in 0 g is sprayed while blowing hot air. Then, by drying, about 550 g of controlled release theophylline granules coated with a porous ethylcellulose membrane are obtained.
得られた製剤は皮膜の多孔度が０．７８であった。The resulting formulation had a film porosity of 0.78.
実施例６
実施例２と同様にして得たサリチル酸ナトリウム素顆粒
５（１０ｇを流動層コーティング装置に入れ、セルロー
スアセテ−） １（１０ｇを水−アセトン（２：８）の
混液９（１０ｇに溶解し、これにタルク５０ｇを加えた
混合物を、温風を吹き込みつつ噴霧する。噴霧後、乾燥
することにより多孔性セルロースアセテート膜で被覆さ
れた放出制御型サリチル酸ナトリウム顆粒６（１０ｇを
得る。Example 6 Sodium salicylate base granules obtained in the same manner as in Example 2 5 (10 g was placed in a fluidized bed coating device, cellulose acetate) 1 (10 g was dissolved in a water-acetone (2:8) mixture 9 (10 g) Then, a mixture of 50 g of talc and 50 g of talc is sprayed while blowing hot air. After spraying, the mixture is dried to obtain 10 g of controlled-release sodium salicylate granules 6 coated with a porous cellulose acetate membrane.
得られた製剤は皮膜の多孔度が０．７４であった。The resulting formulation had a film porosity of 0.74.
実施例７
実施例６において、セルロースアセテートに代えてセル
ロースアセテートブチレート１（１０ｇを用いるほかは
、実施例６と同様に実施することにより、多孔性セルロ
ースアセテートブチレート膜で被覆された放出制御型サ
リチル酸ナトリウム顆粒６（１０ｇを得る。Example 7 A controlled release type coated with a porous cellulose acetate butyrate membrane was prepared by carrying out the same procedure as in Example 6 except that cellulose acetate butyrate 1 (10 g was used instead of cellulose acetate). Sodium salicylate granules 6 (obtain 10 g).
得られた製剤は皮膜の多孔度が０．７８であった。The resulting formulation had a film porosity of 0.78.
実施例８
実施例３で得られた素顆粒１．０ｋｇを遠心流動造粒機
に入れ転勤させ、これにエチルセルロース９５ｇ及びポ
リビニルピロリドン５ｇを水−エタノール＜３７７）の
混液９（１０ｇに溶解した溶液を温風を吹き込みつつ噴
霧する。噴霧後、乾燥することにより多孔性エチルセル
ロース−ポリビニルピロリドン膜で被覆された放出制御
型顆粒１ 、１ ｋｇを得る。Example 8 1.0 kg of elementary granules obtained in Example 3 was transferred to a centrifugal flow granulator, and a solution of 95 g of ethyl cellulose and 5 g of polyvinylpyrrolidone dissolved in 10 g of water-ethanol <377) was added. is sprayed while blowing hot air. After spraying, the mixture is dried to obtain 1.1 kg of controlled-release granules coated with a porous ethyl cellulose-polyvinylpyrrolidone membrane.
得られた製剤は皮膜の多孔度が０．８１であった。The resulting formulation had a film porosity of 0.81.
実施例９
皮膜剤としてエチルセルロース９５ｇ及びポリエチレン
グリコール（Ｐ Ｅ ０４（１００） ５ ｇを用い、
実施例８と同様に処理することにより多孔性エチルセル
ロース−ポリエチレングリコール膜でＭＪＩれた放出制
御型顆粒１ 、１ ｋｇを得る。Example 9 Using 95 g of ethyl cellulose and 5 g of polyethylene glycol (P E 04 (100)) as a coating agent,
By treating in the same manner as in Example 8, 1.1 kg of controlled release granules subjected to MJI with a porous ethyl cellulose-polyethylene glycol membrane are obtained.
得られた製剤は皮膜の多孔度が０．７９であった。The resulting formulation had a film porosity of 0.79.
実施例１０
皮膜剤としてエチルセルロース９５ｇ及びメチルセルロ
ース５ｇを用い、実施例８と同様に処理することにより
多孔性エチルセルロースーメチルセルロース膜で被覆さ
れた放出制御型顆粒１ 、１ ｋｇを得る。Example 10 Using 95 g of ethyl cellulose and 5 g of methyl cellulose as coating agents, the same procedure as in Example 8 was carried out to obtain 1.1 kg of controlled release granules coated with a porous ethyl cellulose-methyl cellulose membrane.
得られた製剤は皮膜の多孔度が０．８２であった。The resulting formulation had a film porosity of 0.82.
実施例１１
皮膜剤としてエチルセルロース９５ｇ及びヒドロキシプ
ロピルメチルセルロース５ｇを用い、実施例８と同様に
処理することにより多孔性エチルセルロースーヒドロキ
シプロピルメチルセルロース膜で被覆された放出制御型
顆粒１．１ｋｇを得る。Example 11 Using 95 g of ethyl cellulose and 5 g of hydroxypropyl methyl cellulose as coating agents, 1.1 kg of controlled release granules coated with a porous ethyl cellulose-hydroxypropyl methyl cellulose membrane are obtained by the same treatment as in Example 8.
得られた製剤は皮膜の多孔度が０．７６であった。The resulting formulation had a film porosity of 0.76.
実施例１２
皮膜剤としてエチルセルロース９５ｇ及びヒドロキシプ
ロピルセルロースアセテートサクシネート５ｇを用い、
実施例８と同様に処理することによす多孔性エチルセル
ロース−ヒドロキシプロピルセルロースアセテートサク
シネート膜で被覆された放出制御型顆粒１．１ｋｇを得
る。Example 12 Using 95 g of ethyl cellulose and 5 g of hydroxypropyl cellulose acetate succinate as a coating agent,
1.1 kg of controlled release granules coated with a porous ethylcellulose-hydroxypropylcellulose acetate succinate membrane are obtained by the same treatment as in Example 8.
得られた製剤は皮膜の多孔度が０．８４であった。The resulting formulation had a film porosity of 0.84.
実施例１３
皮膜剤としてエチルセルロース９５ｇ及びオイドラギフ
ドＬ５ｇを用い、実施例８と同様に処理することにより
多孔性エチルセルロースーオイドラギッドＬ膜で被覆さ
れた放出制御型顆粒１．１ｋｇを得る。Example 13 Using 95 g of ethyl cellulose and 5 g of Eudragid L as a coating agent, the same procedure as in Example 8 was carried out to obtain 1.1 kg of controlled release granules coated with a porous ethyl cellulose-Eudragid L membrane.
得られた製剤は皮膜の多孔度が０．７９であった。The resulting formulation had a film porosity of 0.79.
Claims (1)
質又は疎水性高分子物質と親水性高分子物質からなる多
孔性膜で被覆されてなる放出制御型製剤。 （２）多孔性膜が約０．４〜０．９の多孔度を有する請
求項１記載の製剤。 （３）多孔性膜が約０．５〜０．８５の多孔度を有する
請求項１記載の製剤。 （４）多孔性膜が疎水性高分子物質からなる多孔性膜で
ある請求項１又は２記載の製剤。（５）多孔性膜が疎水
性高分子物質と親水性高分子物質からなる多孔性膜であ
る請求項１又は２記載の製剤。 （６）多孔性膜が、疎水性高分子物質１重量部に対して
親水性高分子物質約０．０５〜０．５重量部からなる多
孔性膜である請求項５記載の製剤。 （７）疎水性高分子物質がセルロースエーテル、セルロ
ースエステル、ポリビニルエステル及びアミノアルキル
基を有するアクリル酸系重合体からなる群より選ばれる
一種である請求項４記載の製剤。 （８）疎水性高分子物質がセルロースエーテル、セルロ
ースエステル、ポリビニルエステル及び第４級アンモニ
ウムアルキル基を有するアクリル酸系重合体からなる群
より選ばれる一種であり、親水性高分子物質が水溶性高
分子物質、腸溶性高分子物質、胃溶性高分子物質及び胃
腸両溶性高分子物質からなる群より選ばれる一種である
請求項６記載の製剤。（９）水溶性高分子物質が、硫酸
基を有していてもよい多糖類、ヒドロキシアルキル基を
有する多糖類、カルボキシアルキル基を有する多糖類、
メチルセルロース、ポリビニルピロリドン、ポリビニル
アルコール及びポリエチレングリコールからなる群より
選ばれる一種であり、腸溶性高分子物質が、カルボキシ
アルキルセルロースエーテル、二塩基性酸のモノエステ
ル結合を有するセルロース誘導体、二塩基性酸のモノエ
ステル結合を有するポリビニル誘導体、マレイン酸−ビ
ニル系共重合体及びアクリル酸系重合体からなる群より
選ばれる一種であり、胃溶性高分子物質が、モノ又はジ
置換アミノ基を有するセルロース誘導体、モノ又はジ置
換アミノ基を有するポリビニル誘導体及びモノ置換アミ
ノ基を有するアクリル酸系重合体からなる群より選ばれ
る一種であり、胃腸両溶性高分子物質が、ビニルピリジ
ン−アクリル酸系共重合体、モノ又はジ置換アミノ基を
有するカルボキシメチル多糖類及びポリビニルアミノ酸
誘導体からなる群より選ばれる一種である請求項８記載
の製剤。 （１０）多孔性膜が疎水性高分子物質と水溶性高分子物
質又は疎水性高分子物質と腸溶性高分子物質からなる多
孔性膜である請求項９記載の製剤。 （１１）多孔性膜がエチルセルロースとヒドロキシプロ
ピルセルロースからなる多孔性膜である請求項１０記載
の製剤。 （１２）芯物質に医薬活性成分と共に有機酸を含有する
請求項１１記載の製剤。 （１３）有機酸が、コハク酸である請求項１２記載の製
剤。 （１４）医薬活性成分を含有する芯物質を、疎水性高分
子物質又は疎水性高分子物質と親水性高分子物質を含む
水−有機溶媒混液で噴霧コーティングして、芯物質の表
面に疎水性高分子物質又は疎水性高分子物質と親水性高
分子物質からなる多孔性膜を形成させることを特徴とす
る放出制御型製剤の製法。[Scope of Claims] (1) A controlled-release preparation in which a core material containing a pharmaceutically active ingredient is coated with a porous membrane consisting of a hydrophobic polymeric material or a hydrophobic polymeric material and a hydrophilic polymeric material. 2. The formulation of claim 1, wherein the porous membrane has a porosity of about 0.4 to 0.9. 3. The formulation of claim 1, wherein the porous membrane has a porosity of about 0.5 to 0.85. (4) The preparation according to claim 1 or 2, wherein the porous membrane is a porous membrane made of a hydrophobic polymeric substance. (5) The preparation according to claim 1 or 2, wherein the porous membrane is a porous membrane composed of a hydrophobic polymeric substance and a hydrophilic polymeric substance. (6) The preparation according to claim 5, wherein the porous membrane is a porous membrane consisting of about 0.05 to 0.5 parts by weight of a hydrophilic polymeric substance per 1 part by weight of a hydrophobic polymeric substance. (7) The preparation according to claim 4, wherein the hydrophobic polymeric substance is one selected from the group consisting of cellulose ether, cellulose ester, polyvinyl ester, and acrylic acid polymer having an aminoalkyl group. (8) The hydrophobic polymer substance is a type selected from the group consisting of cellulose ether, cellulose ester, polyvinyl ester, and acrylic acid polymer having a quaternary ammonium alkyl group, and the hydrophilic polymer substance is a water-soluble polymer. 7. The preparation according to claim 6, which is one selected from the group consisting of molecular substances, enteric-coated polymeric substances, gastric-soluble polymeric substances, and gastrointestinal-compatible polymeric substances. (9) The water-soluble polymer substance is a polysaccharide that may have a sulfate group, a polysaccharide that has a hydroxyalkyl group, a polysaccharide that has a carboxyalkyl group,
It is a type selected from the group consisting of methylcellulose, polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol, and the enteric polymer substance is a carboxyalkyl cellulose ether, a cellulose derivative having a monoester bond of a dibasic acid, or a cellulose derivative having a monoester bond of a dibasic acid. It is a type selected from the group consisting of polyvinyl derivatives having monoester bonds, maleic acid-vinyl copolymers, and acrylic acid polymers, and the gastrosoluble polymer substance is a cellulose derivative having mono- or di-substituted amino groups, It is a type selected from the group consisting of polyvinyl derivatives having a mono- or di-substituted amino group and acrylic acid polymers having a mono-substituted amino group, and the gastrointestinal-compatible polymer substance is a vinylpyridine-acrylic acid copolymer, 9. The preparation according to claim 8, which is one selected from the group consisting of carboxymethyl polysaccharides and polyvinyl amino acid derivatives having mono- or di-substituted amino groups. (10) The preparation according to claim 9, wherein the porous membrane is a porous membrane consisting of a hydrophobic polymeric substance and a water-soluble polymeric substance, or a hydrophobic polymeric substance and an enteric polymeric substance. (11) The preparation according to claim 10, wherein the porous membrane is a porous membrane consisting of ethyl cellulose and hydroxypropyl cellulose. (12) The preparation according to claim 11, wherein the core substance contains an organic acid together with a pharmaceutically active ingredient. (13) The formulation according to claim 12, wherein the organic acid is succinic acid. (14) Spray coating a core material containing a pharmaceutically active ingredient with a hydrophobic polymeric substance or a water-organic solvent mixture containing a hydrophobic polymeric substance and a hydrophilic polymeric substance to make the surface of the core substance hydrophobic. A method for producing a controlled-release preparation, which comprises forming a porous membrane consisting of a polymeric substance or a hydrophobic polymeric substance and a hydrophilic polymeric substance.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP1030882A JPH0791184B2 (en) | 1988-03-31 | 1989-02-09 | Controlled release formulation and process for producing the same |
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP63-80604 | 1988-03-31 | ||
| JP8060488 | 1988-03-31 | ||
| JP1030882A JPH0791184B2 (en) | 1988-03-31 | 1989-02-09 | Controlled release formulation and process for producing the same |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| JPH021405A true JPH021405A (en) | 1990-01-05 |
| JPH0791184B2 JPH0791184B2 (en) | 1995-10-04 |
Family
ID=26369315
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP1030882A Expired - Fee Related JPH0791184B2 (en) | 1988-03-31 | 1989-02-09 | Controlled release formulation and process for producing the same |
Country Status (1)
| Country | Link |
|---|---|
| JP (1) | JPH0791184B2 (en) |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2002003366A (en) * | 2000-06-23 | 2002-01-09 | Freunt Ind Co Ltd | Aqueous coating composition for solid medicine |
| JP2005506336A (en) * | 2001-10-09 | 2005-03-03 | フラメル・テクノロジー | Microparticulate oral galenical dosage form for delayed and controlled release of pharmaceutically active ingredients |
| JP2006001941A (en) * | 1992-05-28 | 2006-01-05 | Elan Corp Plc | Tablet formulation |
| JP2006507298A (en) * | 2002-10-30 | 2006-03-02 | ファルマシア コーポレーション | Oral sustained-release tablets and methods for making and using the same |
| JP2006508891A (en) * | 2001-01-30 | 2006-03-16 | カウンシル・オブ・サイエンティフィック・アンド・インダストリアル・リサーチ | Pharmaceutical composition for long-term / sustained release of therapeutically active ingredients |
| JP2008501014A (en) * | 2004-05-28 | 2008-01-17 | ハンミ ファーム． シーオー．， エルティーディー． | Sustained release composition for oral administration of niacin |
| WO2009048073A1 (en) * | 2007-10-09 | 2009-04-16 | Takeda Pharmaceutical Company Limited | Method of coating granules |
| JP2011117361A (en) * | 2009-12-03 | 2011-06-16 | Honda Motor Co Ltd | Engine rocker arm switching device |
| WO2021171972A1 (en) * | 2020-02-28 | 2021-09-02 | 株式会社Ｓｃｒｅｅｎホールディングス | Solid preparation |
Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5711912A (en) * | 1980-05-20 | 1982-01-21 | Alza Corp | Diffusive activator dispenser |
| JPS60139616A (en) * | 1983-12-23 | 1985-07-24 | ソシエテ・デチユ−ドウ・シヤンテイフイツク・エ・アンデユストリエル・ドウ・リ−ルドウフランス | Orally administrable novel galenunu medicine of sulpiride |
| JPS60156617A (en) * | 1983-12-22 | 1985-08-16 | エラン コーポレーシヨン ピー エル シー | Phamaceutical blend |
| JPS635021A (en) * | 1986-06-20 | 1988-01-11 | エラン コ−ポレ−シヨン ピ− エル シ− | Absorption controlled drug composition |
-
1989
- 1989-02-09 JP JP1030882A patent/JPH0791184B2/en not_active Expired - Fee Related
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS5711912A (en) * | 1980-05-20 | 1982-01-21 | Alza Corp | Diffusive activator dispenser |
| JPS60156617A (en) * | 1983-12-22 | 1985-08-16 | エラン コーポレーシヨン ピー エル シー | Phamaceutical blend |
| JPS60139616A (en) * | 1983-12-23 | 1985-07-24 | ソシエテ・デチユ−ドウ・シヤンテイフイツク・エ・アンデユストリエル・ドウ・リ−ルドウフランス | Orally administrable novel galenunu medicine of sulpiride |
| JPS635021A (en) * | 1986-06-20 | 1988-01-11 | エラン コ−ポレ−シヨン ピ− エル シ− | Absorption controlled drug composition |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2006001941A (en) * | 1992-05-28 | 2006-01-05 | Elan Corp Plc | Tablet formulation |
| JP2010209108A (en) * | 1992-05-28 | 2010-09-24 | Elan Pharma Internatl Ltd | Tablet formulation |
| JP2002003366A (en) * | 2000-06-23 | 2002-01-09 | Freunt Ind Co Ltd | Aqueous coating composition for solid medicine |
| JP2006508891A (en) * | 2001-01-30 | 2006-03-16 | カウンシル・オブ・サイエンティフィック・アンド・インダストリアル・リサーチ | Pharmaceutical composition for long-term / sustained release of therapeutically active ingredients |
| JP2005506336A (en) * | 2001-10-09 | 2005-03-03 | フラメル・テクノロジー | Microparticulate oral galenical dosage form for delayed and controlled release of pharmaceutically active ingredients |
| JP2006507298A (en) * | 2002-10-30 | 2006-03-02 | ファルマシア コーポレーション | Oral sustained-release tablets and methods for making and using the same |
| JP2008501014A (en) * | 2004-05-28 | 2008-01-17 | ハンミ ファーム． シーオー．， エルティーディー． | Sustained release composition for oral administration of niacin |
| WO2009048073A1 (en) * | 2007-10-09 | 2009-04-16 | Takeda Pharmaceutical Company Limited | Method of coating granules |
| JP2011117361A (en) * | 2009-12-03 | 2011-06-16 | Honda Motor Co Ltd | Engine rocker arm switching device |
| WO2021171972A1 (en) * | 2020-02-28 | 2021-09-02 | 株式会社Ｓｃｒｅｅｎホールディングス | Solid preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0791184B2 (en) | 1995-10-04 |
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