EP1596849A1 - Pharmazeutische zusammensetzungen zur kontrollierten freisetzung von tamsulosin - Google Patents
Pharmazeutische zusammensetzungen zur kontrollierten freisetzung von tamsulosinInfo
- Publication number
- EP1596849A1 EP1596849A1 EP03780445A EP03780445A EP1596849A1 EP 1596849 A1 EP1596849 A1 EP 1596849A1 EP 03780445 A EP03780445 A EP 03780445A EP 03780445 A EP03780445 A EP 03780445A EP 1596849 A1 EP1596849 A1 EP 1596849A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- tamsulosin
- composition
- cellulose
- mixtures
- enteric
- 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- Withdrawn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
- DRHKJLXJIQTDTD-OAHLLOKOSA-N Tamsulosine Chemical compound CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 DRHKJLXJIQTDTD-OAHLLOKOSA-N 0.000 title claims abstract description 67
- 229960002613 tamsulosin Drugs 0.000 title claims abstract description 66
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 27
- 238000013270 controlled release Methods 0.000 title claims abstract description 23
- 239000000203 mixture Substances 0.000 claims abstract description 96
- 150000003839 salts Chemical class 0.000 claims abstract description 42
- 238000000034 method Methods 0.000 claims description 74
- 230000008569 process Effects 0.000 claims description 62
- 229920000642 polymer Polymers 0.000 claims description 55
- 239000003795 chemical substances by application Substances 0.000 claims description 36
- 239000002702 enteric coating Substances 0.000 claims description 28
- 238000009505 enteric coating Methods 0.000 claims description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 28
- 229920001577 copolymer Polymers 0.000 claims description 24
- 239000001993 wax Substances 0.000 claims description 23
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 20
- 239000000194 fatty acid Substances 0.000 claims description 20
- 229930195729 fatty acid Natural products 0.000 claims description 20
- 150000004665 fatty acids Chemical class 0.000 claims description 20
- 229910052751 metal Inorganic materials 0.000 claims description 20
- 239000002184 metal Substances 0.000 claims description 20
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 claims description 19
- 239000002775 capsule Substances 0.000 claims description 15
- 238000000576 coating method Methods 0.000 claims description 15
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 15
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical group CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 14
- 150000004668 long chain fatty acids Chemical class 0.000 claims description 14
- 235000019359 magnesium stearate Nutrition 0.000 claims description 14
- 239000004014 plasticizer Substances 0.000 claims description 14
- 229920003176 water-insoluble polymer Polymers 0.000 claims description 14
- 229920003169 water-soluble polymer Polymers 0.000 claims description 14
- 229920000623 Cellulose acetate phthalate Polymers 0.000 claims description 13
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 13
- 229940081734 cellulose acetate phthalate Drugs 0.000 claims description 13
- 239000011248 coating agent Substances 0.000 claims description 12
- PNJWIWWMYCMZRO-UHFFFAOYSA-N pent‐4‐en‐2‐one Natural products CC(=O)CC=C PNJWIWWMYCMZRO-UHFFFAOYSA-N 0.000 claims description 12
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 claims description 12
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 11
- 235000021355 Stearic acid Nutrition 0.000 claims description 9
- 239000008187 granular material Substances 0.000 claims description 9
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical group CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 9
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 9
- 239000008117 stearic acid Substances 0.000 claims description 9
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 8
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 8
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 8
- 229920002301 cellulose acetate Polymers 0.000 claims description 8
- 239000003085 diluting agent Substances 0.000 claims description 8
- 239000006185 dispersion Substances 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 8
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 claims description 8
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 claims description 8
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 8
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 8
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 8
- 239000003607 modifier Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- -1 sachets Substances 0.000 claims description 8
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 claims description 7
- 239000001856 Ethyl cellulose Substances 0.000 claims description 7
- 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 7
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 claims description 7
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 7
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 7
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 claims description 7
- 230000003113 alkalizing effect Effects 0.000 claims description 7
- 239000008116 calcium stearate Substances 0.000 claims description 7
- 235000013539 calcium stearate Nutrition 0.000 claims description 7
- 229920003123 carboxymethyl cellulose sodium Polymers 0.000 claims description 7
- 229940063834 carboxymethylcellulose sodium Drugs 0.000 claims description 7
- 235000010980 cellulose Nutrition 0.000 claims description 7
- 229920002678 cellulose Polymers 0.000 claims description 7
- 239000001913 cellulose Substances 0.000 claims description 7
- 239000003086 colorant Substances 0.000 claims description 7
- 229920001249 ethyl cellulose Polymers 0.000 claims description 7
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 7
- 239000000796 flavoring agent Substances 0.000 claims description 7
- 235000013355 food flavoring agent Nutrition 0.000 claims description 7
- 239000012458 free base Substances 0.000 claims description 7
- VZCYOOQTPOCHFL-OWOJBTEDSA-M fumarate(1-) Chemical compound OC(=O)\C=C\C([O-])=O VZCYOOQTPOCHFL-OWOJBTEDSA-M 0.000 claims description 7
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 7
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 claims description 7
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 7
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 7
- 239000001923 methylcellulose Substances 0.000 claims description 7
- 235000010981 methylcellulose Nutrition 0.000 claims description 7
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 7
- 239000003605 opacifier Substances 0.000 claims description 7
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 7
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 7
- MUZDXNQOSGWMJJ-UHFFFAOYSA-N 2-methylprop-2-enoic acid;prop-2-enoic acid Chemical compound OC(=O)C=C.CC(=C)C(O)=O MUZDXNQOSGWMJJ-UHFFFAOYSA-N 0.000 claims description 6
- 229920002126 Acrylic acid copolymer Polymers 0.000 claims description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 6
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 6
- 229920002554 vinyl polymer Polymers 0.000 claims description 6
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 5
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 5
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 5
- 125000001453 quaternary ammonium group Chemical group 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 4
- 206010004446 Benign prostatic hyperplasia Diseases 0.000 claims description 3
- 208000004403 Prostatic Hyperplasia Diseases 0.000 claims description 3
- 239000010410 layer Substances 0.000 claims description 3
- 238000001035 drying Methods 0.000 claims description 2
- 208000024891 symptom Diseases 0.000 claims description 2
- 238000009472 formulation Methods 0.000 abstract description 12
- 239000002245 particle Substances 0.000 description 8
- 238000005563 spheronization Methods 0.000 description 8
- 229940079593 drug Drugs 0.000 description 7
- 239000003814 drug Substances 0.000 description 7
- 239000002552 dosage form Substances 0.000 description 6
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 229940081735 acetylcellulose Drugs 0.000 description 5
- 238000004090 dissolution Methods 0.000 description 5
- 238000001125 extrusion Methods 0.000 description 5
- 210000000936 intestine Anatomy 0.000 description 5
- 239000013543 active substance Substances 0.000 description 4
- GDCRSXZBSIRSFR-UHFFFAOYSA-N ethyl prop-2-enoate;2-methylprop-2-enoic acid Chemical compound CC(=C)C(O)=O.CCOC(=O)C=C GDCRSXZBSIRSFR-UHFFFAOYSA-N 0.000 description 4
- 239000000463 material Substances 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- 229920003138 Eudragit® L 30 D-55 Polymers 0.000 description 3
- 229920003134 Eudragit® polymer Polymers 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 3
- 238000010521 absorption reaction Methods 0.000 description 3
- 239000004480 active ingredient Substances 0.000 description 3
- 230000001419 dependent effect Effects 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 239000000126 substance Substances 0.000 description 3
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 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
- 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
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 229920001800 Shellac Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- 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 2
- 229930006000 Sucrose Natural products 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- ZFOZVQLOBQUTQQ-UHFFFAOYSA-N Tributyl citrate Chemical compound CCCCOC(=O)CC(O)(C(=O)OCCCC)CC(=O)OCCCC ZFOZVQLOBQUTQQ-UHFFFAOYSA-N 0.000 description 2
- 230000002378 acidificating effect Effects 0.000 description 2
- 229920006318 anionic polymer Polymers 0.000 description 2
- 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 2
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 description 2
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 229940093334 flomax Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000030136 gastric emptying Effects 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000010348 incorporation Methods 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 230000007935 neutral effect Effects 0.000 description 2
- 239000008363 phosphate buffer Substances 0.000 description 2
- 229940100467 polyvinyl acetate phthalate Drugs 0.000 description 2
- 235000013874 shellac Nutrition 0.000 description 2
- ZLGIYFNHBLSMPS-ATJNOEHPSA-N shellac Chemical compound OCCCCCC(O)C(O)CCCCCCCC(O)=O.C1C23[C@H](C(O)=O)CCC2[C@](C)(CO)[C@@H]1C(C(O)=O)=C[C@@H]3O ZLGIYFNHBLSMPS-ATJNOEHPSA-N 0.000 description 2
- 239000004208 shellac Substances 0.000 description 2
- 229940113147 shellac Drugs 0.000 description 2
- 239000000377 silicon dioxide Substances 0.000 description 2
- 230000003381 solubilizing effect Effects 0.000 description 2
- 239000012798 spherical particle Substances 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- ZZIZZTHXZRDOFM-XFULWGLBSA-N tamsulosin hydrochloride Chemical compound [H+].[Cl-].CCOC1=CC=CC=C1OCCN[C@H](C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-XFULWGLBSA-N 0.000 description 2
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 2
- WRIDQFICGBMAFQ-UHFFFAOYSA-N (E)-8-Octadecenoic acid Natural products CCCCCCCCCC=CCCCCCCC(O)=O WRIDQFICGBMAFQ-UHFFFAOYSA-N 0.000 description 1
- ZZIZZTHXZRDOFM-UHFFFAOYSA-N 2-(2-ethoxyphenoxy)ethyl-[1-(4-methoxy-3-sulfamoylphenyl)propan-2-yl]azanium;chloride Chemical compound Cl.CCOC1=CC=CC=C1OCCNC(C)CC1=CC=C(OC)C(S(N)(=O)=O)=C1 ZZIZZTHXZRDOFM-UHFFFAOYSA-N 0.000 description 1
- LQJBNNIYVWPHFW-UHFFFAOYSA-N 20:1omega9c fatty acid Natural products CCCCCCCCCCC=CCCCCCCCC(O)=O LQJBNNIYVWPHFW-UHFFFAOYSA-N 0.000 description 1
- QSBYPNXLFMSGKH-UHFFFAOYSA-N 9-Heptadecensaeure Natural products CCCCCCCC=CCCCCCCCC(O)=O QSBYPNXLFMSGKH-UHFFFAOYSA-N 0.000 description 1
- 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 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229920003084 Avicel® PH-102 Polymers 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 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
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 206010053155 Epigastric discomfort Diseases 0.000 description 1
- 229920003139 Eudragit® L 100 Polymers 0.000 description 1
- 229920003135 Eudragit® L 100-55 Polymers 0.000 description 1
- 229920003153 Eudragit® NE polymer Polymers 0.000 description 1
- 229920003151 Eudragit® RL polymer Polymers 0.000 description 1
- 229920003152 Eudragit® RS polymer Polymers 0.000 description 1
- 229920003141 Eudragit® S 100 Polymers 0.000 description 1
- 206010019280 Heart failures Diseases 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 239000005642 Oleic acid Substances 0.000 description 1
- ZQPPMHVWECSIRJ-UHFFFAOYSA-N Oleic acid Natural products CCCCCCCCC=CCCCCCCCC(O)=O ZQPPMHVWECSIRJ-UHFFFAOYSA-N 0.000 description 1
- 229920002845 Poly(methacrylic acid) Polymers 0.000 description 1
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 1
- 239000004698 Polyethylene Substances 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 239000004793 Polystyrene Substances 0.000 description 1
- XTXRWKRVRITETP-UHFFFAOYSA-N Vinyl acetate Chemical compound CC(=O)OC=C XTXRWKRVRITETP-UHFFFAOYSA-N 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- IYKJEILNJZQJPU-UHFFFAOYSA-N acetic acid;butanedioic acid Chemical compound CC(O)=O.OC(=O)CCC(O)=O IYKJEILNJZQJPU-UHFFFAOYSA-N 0.000 description 1
- GAMPNQJDUFQVQO-UHFFFAOYSA-N acetic acid;phthalic acid Chemical compound CC(O)=O.OC(=O)C1=CC=CC=C1C(O)=O GAMPNQJDUFQVQO-UHFFFAOYSA-N 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 125000000129 anionic group Chemical group 0.000 description 1
- 230000000181 anti-adherent effect Effects 0.000 description 1
- 239000003911 antiadherent Substances 0.000 description 1
- 235000013871 bee wax Nutrition 0.000 description 1
- 229940092738 beeswax Drugs 0.000 description 1
- 239000012166 beeswax Substances 0.000 description 1
- 239000011230 binding agent Substances 0.000 description 1
- 239000002981 blocking agent Substances 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 230000015556 catabolic process Effects 0.000 description 1
- 229920001688 coating polymer Polymers 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- 238000009792 diffusion process Methods 0.000 description 1
- 239000004815 dispersion polymer Substances 0.000 description 1
- 238000012377 drug delivery Methods 0.000 description 1
- 239000000428 dust Substances 0.000 description 1
- 230000003628 erosive effect Effects 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 238000013265 extended release Methods 0.000 description 1
- 238000011049 filling Methods 0.000 description 1
- 230000002496 gastric effect Effects 0.000 description 1
- 210000003736 gastrointestinal content Anatomy 0.000 description 1
- 210000005095 gastrointestinal system Anatomy 0.000 description 1
- 230000008570 general process Effects 0.000 description 1
- 239000011521 glass Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000001087 glyceryl triacetate Substances 0.000 description 1
- 235000013773 glyceryl triacetate Nutrition 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 201000006747 infectious mononucleosis Diseases 0.000 description 1
- 239000002198 insoluble material Substances 0.000 description 1
- 230000007794 irritation Effects 0.000 description 1
- QXJSBBXBKPUZAA-UHFFFAOYSA-N isooleic acid Natural products CCCCCCCC=CCCCCCCCCC(O)=O QXJSBBXBKPUZAA-UHFFFAOYSA-N 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- VTHJTEIRLNZDEV-UHFFFAOYSA-L magnesium dihydroxide Chemical compound [OH-].[OH-].[Mg+2] VTHJTEIRLNZDEV-UHFFFAOYSA-L 0.000 description 1
- 239000000347 magnesium hydroxide Substances 0.000 description 1
- 229910001862 magnesium hydroxide Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000004519 manufacturing process Methods 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- ZQPPMHVWECSIRJ-KTKRTIGZSA-N oleic acid Chemical compound CCCCCCCC\C=C/CCCCCCCC(O)=O ZQPPMHVWECSIRJ-KTKRTIGZSA-N 0.000 description 1
- 230000003204 osmotic effect Effects 0.000 description 1
- 230000036470 plasma concentration Effects 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 229940069328 povidone Drugs 0.000 description 1
- 210000002307 prostate Anatomy 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 239000004576 sand Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 238000009491 slugging Methods 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000002195 soluble material Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000013268 sustained release Methods 0.000 description 1
- 239000012730 sustained-release form Substances 0.000 description 1
- 230000009885 systemic effect Effects 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 229960003198 tamsulosin hydrochloride Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
- 238000005550 wet granulation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/16—Amides, e.g. hydroxamic acids
- A61K31/18—Sulfonamides
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P13/00—Drugs for disorders of the urinary system
- A61P13/08—Drugs for disorders of the urinary system of the prostate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
-
- 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
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- 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
-
- 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
- A61K9/1682—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
Definitions
- the technical field of the invention relates to controlled release pharmaceutical compositions of tamsulosin or pharmaceutically acceptable salts thereof. More particularly, the invention relates to a controlled release individual unit or multiple unit formulation comprising a spherical core obtained by adding a release controlling agent to a mixture of tamsulosin and a spheronizing agent. The invention also relates to methods of preparing such formulations. Background of the Invention
- modified release formulations The need to improve the clinical results of modified release formulations is well documented in the prior art. This is particularly important for drugs that have short half- lives, region specific absorption, produce gastric irritation, or have other side effects at high plasma concentrations.
- One of the most common methods of achieving modified drug release involves the use of monolithic systems designed to have modified release characteristics. These monolithic systems vary from osmotic drug delivery systems to bioerodible or non-erodible matrix based systems.
- the final dosage form consists of a collection of the multiple units, compressed into a tablet, or filled into a capsule or sachet.
- the individual units When administered, the individual units are dispersed freely into the gastrointestinal contents, avoiding the high local concentration of drug which may lead to irritation of gastrointestinal mucosa.
- the performance of the dosage form is independent of inter- and intra-patient variability in gastric emptying time because of the small size of the individual units that make up the system.
- Multiple unit dosage forms possess large surface area, which promotes complete and uniform absorption, minimize peak plasma fluctuations and thus reduce the potential for systemic side effects. Further advantages of these dosage forms are that high local concentrations of the active substance in the gastrointestinal system is avoided, due to the units being distributed freely throughout the tract, less variation in absorption is observed and there is reproducibility in the dissolution characteristics.
- Drug release from such extended release multiple units is controlled either by diffusion of a coating or by erosion of the coating by a process dependent on enzymes or pH.
- the erodible coatings involve the use of enteric polymers, which rapidly erode in the intestines.
- roller compaction Extrusion/spheronization is a multistep process used to make uniformly sized particles. It is used primarily to produce multiparticulates for controlled or sustained release applications. This process is also used to increase the bulk density, improve flow properties and reduces the problem of dust usually encountered with low-density, finely divided active and excipient powders.
- the general process involves separate processes of wet massing, followed by extrusion of this wet mass into cylindrical segments and subsequent spheronization of these segments to round off these cylindrical segments into spherical particles. Extrusion involves forcing the wet mass through dies and shaped into cylindrical particles with uniform diameter. The extrudate particles break at similar lengths.
- Tamsulosin 5-[(2R)-2-[[2-(2-ethoxy-phenoxy) ethyl] amino] propyl]-2-methoxy benzene sulfonamide, is an ⁇ i-adrenoceptor blocking agent, exhibiting selectivity for ⁇ i- receptors in the human prostate. It is disclosed in EP 34432 and U.S. Patent No. 4,731,478 as a pharmaceutically active substance having alpha-adrenergic blocking activity that is useful for treatment of cardiac insufficiencies and benign prostatic hyperplasia. The pharmacokinetic studies of tamsulosin show that it is absorbed from the intestine and is almost completely bioavailable.
- U.S. Patent No. 4,772,475 discloses an oral pharmaceutical controlled release multiple unit formulation in which the individual units comprise a granulation product of a release controlling agent, physiologically active substance and units-forming substance (s).
- the patent emphasizes that the unit-forming substance (crystalline cellulose) should at least be 50% by weight.
- the drug containing units of this invention have high mechanical strength and can control dissolution rate without enteric coating.
- the object should be to develop a composition, which releases the drug gradually in the intestine where it is completely absorbed.
- enteric-coated, controlled release formulation of tamsulosin provides release at the desired site.
- the controlled release formulation can be prepared with less than 50% w/w of a spheronizing agent.
- a controlled release pharmaceutical composition of tamsulosin that includes a spheroid core.
- the core includes tamsulosin, about 10% to about 45% w/w of a spheronizing agent and one or more rate controlling polymers; and an outer enteric coating layer.
- the enteric coating is placed over the core.
- the core may include one or more of sugar, a non-pareil seed, microcrystalline cellulose, celphere, sand silicon dioxide, glass, plastic, polystyrene, hydroxypropyl methylcellulose.
- the sugar may include one or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose.
- the core may include one or more of an insoluble material, a soluble material, and a swellable material.
- Embodiments of the pharmaceutical composition are prepared by a spheronization process.
- the spheronizing agent may be microcrystalline cellulose.
- the tamsulosin may include one or more of free base, pharmaceutically acceptable salts and isomers of tamsulosin.
- the pharmaceutically acceptable salts of tamsulosin may be one or more of hydrochloride, hydroiodide, hydrobromide, hydrogen fumarate, and the like.
- the pharmaceutically acceptable salt of tamsulosin may be hydrochloride.
- the pharmaceutical composition may contain a concentration of from about 0.03% to about 0.33% by weight of tamsulosin.
- the rate controlling polymer may include one or more of enteric polymers, water insoluble polymers, water-soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof.
- the rate controlling polymer may be present in the pharmaceutical composition at a concentration of from about 20% to about 90% by weight.
- the enteric polymer may include one or more of hydroxylpropylmethyl cellulose phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate copolymer. h particular, the enteric polymer may include one or more of methacrylic acid and ethyl acrylate copolymer.
- the wax may include one or more of hydro genated vegetable oils, esters of long chain fatty acids, long chain fatty acids, and mixtures thereof. The wax may include one or more of glyceryl monos.tearate and stearic acid.
- the water soluble polymer may include one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethylcellulose sodium, liydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
- the water insoluble polymer may include one or more of ethyl cellulose, cellulose acetate, methacrylic acid-acrylic acid copolymers with quaternary ammonium groups, and mixtures thereof.
- the alkaline metal salts of higher fatty acid may include one or more of magnesium stearate, zinc stearate, calcium stearate, and mixtures thereof.
- the alkaline metal salt of higher fatty acid may include magnesium stearate.
- the spheroid core may include one or more of pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients may include one or more of plasticizers, diluents, colorants and flavoring agents.
- the enteric coating may include one or more of hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic and methacrylic acid and mixtures thereof.
- the enteric coating may also have one or more of alkalizing agents, plasticizer, tack-modifiers and opacifiers.
- the pharmaceutical composition may be formulated into capsules, sachets, and tablets.
- a process for the preparation of a controlled release pharmaceutical composition of tamsulosin includes providing spherical cores that includes tamsulosin, a spheronizing agent and one or more of rate controlling polymers; and coating the spheroid cores with an enteric polymer.
- the core may be prepared by extrusion-spheronization.
- the extrasion-spheronization process may include granulating tamsulosin, spheronizing agent and one or more rate controlling polymers, extruding the granulated mixture to obtain extrudates, spheronizing the extradates to obtain spherical cores, drying the spheroid cores; and coating the spheroid cores with an enteric polymer.
- the tamsulosin may include one or more of free base, pharmaceutically acceptable salts and isomers of tamsulosin.
- the pharmaceutically acceptable salts of tamsulosin maybe one or more of hydrochloride, hydroiodide, hydrobromide, hydrogen fumarate, and the like.
- the pharmaceutically acceptable salt of tamsulosin may be hydrochloride.
- the pharmaceutical composition may contain a concentration of from about 0.03% to about 0.33% by weight of tamsulosin.
- the rate controlling agent may include one or more of enteric polymers, water insoluble polymers, water-soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof at a concentration of from about 20% to about 90% by weight of the composition.
- the enteric polymer may include one or more of hydroxylpropylmethyl cellulose phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate copolymer. h particular, the enteric polymer may include one or more of methacrylic acid and ethyl acrylate copolymer.
- the wax may include one or more of hydro genated vegetable oils, esters of long chain fatty acids, long chain fatty acids, and mixtures thereof. In particular, the wax may include one or more of glyceryl monostearate and stearic acid.
- the water soluble polymers may include one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethylcellulose sodium, liydroxypropylmethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
- the water insoluble polymers may include one or more of ethyl cellulose, cellulose acetate, methacrylic acid-acrylic acid copolymers with quaternary arrimonium groups, and mixtures thereof.
- the alkaline metal salts of higher fatty acid may include one or more of magnesium stearate, zinc stearate, calcium stearate and mixtures thereof.
- the alkaline metal salt of higher fatty acid may include magnesium stearate.
- the spheroid core may include one or more of pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients may include one or more of plasticizers, diluents, colorants and flavoring agents.
- the enteric coating may include one or more of hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic and methacrylic acid and mixtures thereof.
- the enteric coating may also have one or more of alkalizing agents, plasticizer, tack-modifiers and opacifiers.
- the pharmaceutical composition may be formulated into capsules, sachets, and tablets. hi another general aspect there is provided a process for the preparation of a controlled release pharmaceutical composition of tamsulosin.
- the process includes granulating tamsulosin and spheronizing agent with dispersion of one or more of rate controlling polymers, extruding the granulates to form extrudates using an extruder, spheronizing the extrudates until spherical cores are formed; and coating the spheroid cores with an enteric polymer.
- the tamsulosin may include one or more of free base, pharmaceutically acceptable salts and isomers of tamsulosin.
- the pharmaceutically acceptable salts of tamsulosin may be one or more of hydrochloride, hydroiodide, hydrobromide, hydrogen fumarate, and the like.
- the pharmaceutically acceptable salt of tamsulosin may be hydrochloride.
- the pharmaceutical composition may contain a concentration of from about 0.03% to about 0.33% by weight of tamsulosin.
- the rate controlling agent may include one or more of enteric polymers, water insoluble polymers, water-soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof at a concentration of from about 20% to about 90%> by weight of the composition.
- the enteric polymer may include one or more of hydroxylpropylmethyl cellulose phthalate, cellulose acetate phthalate, methacrylic acid, and ethyl acrylate copolymer. i particular, the enteric polymer may include one or more of methacrylic acid and ethyl acrylate copolymer.
- the wax may include one or more of hydro genated vegetable oils, esters of long chain fatty acids, long chain fatty acids, and mixtures thereof.
- the wax may include one or more of glyceryl monostearate and stearic acid.
- the water soluble polymers may include one or more of polyvinylpyrrolidone, hydroxypropyl cellulose, carboxymethylcellulose sodium, hydroxypropyhnethyl cellulose, hydroxyethyl cellulose, methyl cellulose, and mixtures thereof.
- the water insoluble polymers may include one or more of ethyl cellulose, cellulose acetate, methacrylic acid-acrylic acid copolymers with quaternary arrrmonium groups, and mixtures thereof.
- the alkaline metal salts of higher fatty acid may include one or more of magnesium stearate, zinc stearate, calcium stearate and mixtures thereof.
- the alkaline metal salt of higher fatty acid may include magnesium stearate.
- the spheroid core may include one or more of pharmaceutically acceptable excipients.
- the pharmaceutically acceptable excipients may include one or more of plasticizers, diluents, colorants and flavoring agents.
- the enteric coating may include one or more of hydroxypropyl methylcellulose phthalate, polyvinyl phthalate, cellulose acetate phthalate, copolymers of acrylic and methacrylic acid and mixtures thereof.
- the enteric coating may also have one or more of alkalizing agents, plasticizer, tack-modifiers and opacifiers.
- the pharmaceutical composition may be formulated into capsules, sachets, and tablets.
- a method for preparing a controlled release pharmaceutical composition includes providing a core having a coating, forming individual units, and forming the dosage form by combining one or more individual units.
- Embodiments of the method of preparing a controlled release multiple unit dosage form may include one or more of the following features, including any one or more of the features described above.
- Combining one or more individual units may include filling the individual units into a capsule or sachet or compressing the individual units into a tablet.
- a method of treating symptoms of benign prostatic hyperplasia includes administering a controlled-release pharmaceutical composition of tamsulosin, which includes a spheroid core.
- This core includes tamsulosin, about 10% to about 45% w/w of a spheronizing agent, and one or more ratecontrolling polymers.
- the core is then coated by an enteric coating.
- Embodiments of the method may contain any one or more features described above.
- the details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
- the present invention relates to controlled release individual unit or multiple unit formulation comprising an enteric coated spherical core, wherein the core comprises tamsulosin, about 10% to about 45% w/w of a spheronizing agent and rate controlling polymers.
- Tamsulosin may comprise free base, pharmaceutically acceptable salts or isomers of tamsulosin thereof.
- the pharmaceutically acceptable salts may include hydrochloride, hydroiodide, hydrobromide, hydrogen fumarate, and the like. Tamsulosin constitutes about 0.03 to about 0.33% by weight of the formulation.
- the spheronizing agent may comprise any pharmaceutically acceptable material, which may be spheronized together with the active ingredient to form spheroid cores.
- the most commonly used spheronizing agent is microcrystalline cellulose.
- the microcrystalline cellulose employed may be, for example, Avicel® PH 101 or Avicel® PH 102 commercially available from FMC Corporation.
- the spheronizing agent may be present in an amount ranging from about 10% to about 45% by weight of the formulation.
- the rate controlling agent may include one or more of enteric polymers, water insoluble polymers, water-soluble polymers, alkaline metal salts of a higher fatty acid, waxes, and mixtures thereof.
- Suitable enteric polymers include those known in the art, such as hydroxypropyl methyl cellulose acetate phthalate, hydroxypropyl methyl cellulose acetate succinate, polyvinyl acetate phthalate, polymethylacrylates and copolymers of acrylic and methacrylic acid (commercially available under the trade name of Eudragit®), for example, Eudragit L30D-55 (anionic aqueous polymer dispersion of methacrylic acid - ethyl acrylate copolymer), Eudragit L100-55 (Spray-dried Eudragit L30D-55 which can be reconstituted as aqueous dispersion), Eudragit LI 00 (anionic polymer powder solubilizing above pH 6.0) and Eudragit S100 (anionic polymer powder solubilizing above pH 7.0).
- Eudragit L30D-55 anionic aqueous polymer dispersion of methacrylic acid - ethyl acrylate copolymer
- Suitable waxes include one or more of hydrogenated vegetable oils, esters of long chain fatty acids, long chain fatty acids such as stearic acid and oleic acid, and mixtures thereof.
- Suitable water-insoluble polymers include one or more of ethyl cellulose, cellulose acetate, copolymers of polyethylene and vinyl acetate, methacrylic acid methyl methacrylate copolymers with quaternary ammonium groups such as those sold under the trade name Eudragit® RL, Eudragit® RS and Eudragit® NE, and the like.
- Suitable examples of the alkaline metal salts of a higher fatty acid include one or more of magnesium stearate, zinc stearate, calcium stearate, and the like.
- Suitable water-soluble polymers may include one or more of polyvinylpyrrolidone, carboxymethylcellulose sodium, hydroxylpropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, methylcellulose, and mixtures thereof.
- the rate controlling polymers may comprise about 20 to about 90% by weight of the formulation.
- the rate controlling polymers in accordance with this invention may also act as binder and may be added as such or dissolved or dispersed in an appropriate solvent system and the resulting solution or dispersion is then used to granulate the active agent. The resulting granulated mass may then be subjected to extrusion and spheronization. This method of incorporation allows the rate controlling polymers to more effectively retard drug release.
- the spheroid cores may also contain other pharmaceutically acceptable excipients.
- the other pharmaceutically acceptable excipients as used herein include plasticizers, diluents, colorants, and flavoring agents.
- Suitable diluents include one or more of lactose, starch, sugar alcohols, sucrose and mixtures thereof.
- the controlled release composition according to this invention may be prepared by: a. granulating tamsulosin, spheronizing agent and rate controlling polymers with water, b. extruding the granulated mixture to give extrudates; and c. spheronizing the extrudates until spherical cores are formed.
- granulation according to step a) may be carried out with a dispersion of rate controlling polymers.
- Extrusion maybe carried out in any of the extruders such as screw-feed extruders and gravity-feed extruders such as cylindrical roll or gear roll and piston-feed extruders.
- the pharmaceutical composition according to the present invention further includes an enteric coating over the spheroid core.
- This coating will substantially eliminate dissolution in the acidic environment of the stomach but will dissolve sufficiently to permit release in a controlled manner over an extended period in the intestine.
- enteric coatings include one or more of neutralized hydroxypropyl methylcellulose phthalate (HPMCP) coating, beeswax, glyceryl monostearate, shellac and cellulose, shellac and stearic acid; neutral copolymer of methacrylic acid and methacrylic acid methyl ester (Eudragit®) or a neutral copolymer of polymethacrylic acid esters containing metallic stearates.
- HPMCP neutralized hydroxypropyl methylcellulose phthalate
- beeswax glyceryl monostearate
- shellac and cellulose shellac and stearic acid
- EUdragit® neutral copolymer of methacrylic acid and methacrylic acid methyl ester
- the other enteric coating polymers known in the art may also be employed, including one or more of polyvinyl acetate phthalate, cellulose acetate phthalate, cellulose acetate succinate and the like.
- enteric coating materials are acidic in nature and hence may cause chemical instability when in contact with active ingredient. However, this can be avoided by using suitable alkalizing agents like sodium hydroxide, potassium hydroxide, calcium carbonate, sodium carboxymethylcellulose, magnesium oxide and magnesium hydroxide.
- the enteric coating may also contain a plasticizer, which may be one or more of citrate, triacetin, diethyl phthalate, dibutyl phthalate, polyethylene glycol, propylene glycol, glycerol, tributyl citrate, and the like.
- the enteric coating may also include anti-adherent or tack-modifiers as an inert aid in the stability of coating process. Suitable tack-modifier may include one or more of talc, kaolin or colloidal anhydrous silica.
- the coating may also include an opacifier such as titanium dioxide.
- the enteric coating layer can be formed on the surface of the spheroid cores, using conventional coating methods, such as fluidized or pan coating.
- compositions prepared according to the invention may be filled into capsules, sachets or compressed into tablets using conventional pharmaceutical techniques.
- Tamsulosin hydrochloride is dissolved in water and the solution is used to granulate microcrystalline cellulose, in a mixer.
- step 1 Granulate of step 1 is dried in a fluidized bed dryer at 60°C and sieved to a particle size of less than about 600 ⁇ . 3.
- Magnesium stearate/ glyceryl mono stearate/ stearic acid and starch are sieved to a particle size of less than about 600 ⁇ and mixed with granulate of step 2 in a mixer.
- step 3 is granulated with the dispersion of methacrylic acid-ethyl acrylate copolymer (Eudragit L30D 55) in a rotary mixer grinder. In Example 3, same blend is further granulated by 10% solution of povidone in water. 5. Granulate of Step 4 is extruded through a bore of inner diameter of 1mm.
- step 5 The extrudates of step 5 are spheronized-using spheronizer fitted with plate of 3.25 mm pitch.
- Spherical cores obtained in step 6 are dried in fluidized bed dryer at 60°C for one hour.
- Enteric coating dispersion of Eudragit L100: 55 is prepared by dispersing enteric coating materials in water.
- the spherical cores of step 7 are coated with the dispersion of step 8, to a weight gain of about 3.33%> w/w. 10.
- the coated cores of step 9 are filled in capsules.
- Example 1 The resulting capsules of Example 1 were compared with FLOMAX capsules (containing 0.4mg tamsulosin marketed by Boehringer Ingelheim) for in vitro release of tamsulosin.
- the dissolution studies were performed using USP Apparatus II at 50 rpm in 500ml phosphate buffer pH 6.8. The results are shown in Table 1.
- Table 1 Comparative in vitro release data of tamsulosin from capsules (of Example 1) and FLOMAX capsules (of Boehringer Ingelheim) using USP dissolution apparatus 11/ 500 ml/ pH 6.8 phosphate buffer/ 50 rpm
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Medicinal Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Cardiology (AREA)
- Epidemiology (AREA)
- Heart & Thoracic Surgery (AREA)
- Hospice & Palliative Care (AREA)
- Urology & Nephrology (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN1292DE2002 IN192381B (de) | 2002-12-20 | 2002-12-20 | |
INDE12922002 | 2002-12-20 | ||
PCT/IB2003/006072 WO2004056354A1 (en) | 2002-12-20 | 2003-12-18 | Controlled release pharmaceutical compositions of tamsulosin |
Publications (1)
Publication Number | Publication Date |
---|---|
EP1596849A1 true EP1596849A1 (de) | 2005-11-23 |
Family
ID=32676755
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP03780445A Withdrawn EP1596849A1 (de) | 2002-12-20 | 2003-12-18 | Pharmazeutische zusammensetzungen zur kontrollierten freisetzung von tamsulosin |
Country Status (9)
Country | Link |
---|---|
EP (1) | EP1596849A1 (de) |
JP (1) | JP2006512358A (de) |
CN (1) | CN1744889A (de) |
AU (1) | AU2003288604A1 (de) |
BR (1) | BR0317567A (de) |
CA (1) | CA2511208A1 (de) |
IN (1) | IN192381B (de) |
RU (1) | RU2005121999A (de) |
WO (1) | WO2004056354A1 (de) |
Families Citing this family (21)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CA2515585A1 (en) * | 2003-01-27 | 2004-08-12 | Yoji Tanijiri | Enteric sustained-release fine particles for tamsulosin or its salt and manufacturing method thereof |
EP2112920B1 (de) | 2003-06-26 | 2018-07-25 | Intellipharmaceutics Corp. | Protonenpumpeninhibitoren enthaltende kapseln, die verschieden aufgebaute untereinheiten zur verzögerten wirkstofffreisetzung enthalten |
US8394409B2 (en) | 2004-07-01 | 2013-03-12 | Intellipharmaceutics Corp. | Controlled extended drug release technology |
SI1618873T1 (sl) * | 2004-07-14 | 2007-10-31 | Siegfried Generics Int Ag | Granulat za kontrolirano sproščanje tamsulozina, ki vsebuje alginat |
US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
JP5457830B2 (ja) | 2006-04-03 | 2014-04-02 | オディディ,イサ | オルガノゾル被膜を含む制御放出送達デバイス |
US20190083399A9 (en) * | 2006-04-03 | 2019-03-21 | Isa Odidi | Drug delivery composition |
US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
WO2008089593A1 (fr) * | 2007-01-18 | 2008-07-31 | Standard Chem. & Pharm. Co., Ltd. | Preparation de tamsulosine a liberation prolongee et procede de production associe |
WO2010001574A1 (ja) * | 2008-07-01 | 2010-01-07 | 沢井製薬株式会社 | タムスロシン塩酸塩を含有する球形微粒子の製造方法 |
CN101695478B (zh) * | 2009-10-23 | 2012-01-18 | 江苏大学 | 盐酸坦索罗辛缓释微丸制剂及其制备方法 |
KR101423237B1 (ko) | 2010-05-04 | 2014-07-30 | 주식회사 삼양바이오팜 | 탐스로신 또는 이의 약학적으로 허용 가능한 염을 포함하는 방출 제어용 약학 조성물, 및 이를 포함하는 경구용 제제 |
CN103315962A (zh) * | 2013-02-01 | 2013-09-25 | 北京科信必成医药科技发展有限公司 | 一种坦索罗辛缓释微丸制剂及其制备方法 |
CN103142492A (zh) * | 2013-02-01 | 2013-06-12 | 北京科信必成医药科技发展有限公司 | 一种缓释微丸制剂及其制备方法 |
CN103919735B (zh) * | 2014-05-04 | 2018-04-17 | 翰宇药业(武汉)有限公司 | 一种盐酸坦索罗辛缓释微丸及其制备方法 |
ES2555485T1 (es) | 2014-05-26 | 2016-01-04 | Galenicum Health S.L. | Composiciones farmacéuticas que contienen un agente activo |
CN109562071A (zh) * | 2016-05-04 | 2019-04-02 | 艾森潘帕克制药股份有限公司 | 延迟释放口服盐酸坦索罗辛 |
EP3473245A1 (de) | 2017-10-20 | 2019-04-24 | Veru Inc. | Orales tamsulosinhydrochlorid mit kontrollierter freisetzung |
EP3473244A1 (de) | 2017-10-20 | 2019-04-24 | Veru Inc. | Orales tamsulosinhydrochlorid mit kontrollierter freisetzung |
KR20200078146A (ko) * | 2018-12-21 | 2020-07-01 | 한미약품 주식회사 | 내산성이 우수한 탐수로신 염산염 함유 제약 조성물 및 이의 제조방법 |
Family Cites Families (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5158777A (en) * | 1990-02-16 | 1992-10-27 | E. R. Squibb & Sons, Inc. | Captopril formulation providing increased duration of activity |
US6248363B1 (en) * | 1999-11-23 | 2001-06-19 | Lipocine, Inc. | Solid carriers for improved delivery of active ingredients in pharmaceutical compositions |
EP1064938A1 (de) * | 1999-06-28 | 2001-01-03 | Sanofi-Synthelabo | Pharmazeutische Dosierungsformen zur kontrollierte Wirkstoffabgabe mit mindenstens ein pulsierendem Zeitverlauf |
DE60210315T2 (de) * | 2001-11-07 | 2006-11-02 | Synthon B.V. | Tamsulosin tabletten |
-
2002
- 2002-12-20 IN IN1292DE2002 patent/IN192381B/en unknown
-
2003
- 2003-12-18 WO PCT/IB2003/006072 patent/WO2004056354A1/en not_active Application Discontinuation
- 2003-12-18 RU RU2005121999/15A patent/RU2005121999A/ru not_active Application Discontinuation
- 2003-12-18 BR BR0317567-7A patent/BR0317567A/pt not_active Application Discontinuation
- 2003-12-18 EP EP03780445A patent/EP1596849A1/de not_active Withdrawn
- 2003-12-18 CN CNA2003801094133A patent/CN1744889A/zh active Pending
- 2003-12-18 AU AU2003288604A patent/AU2003288604A1/en not_active Abandoned
- 2003-12-18 JP JP2004561893A patent/JP2006512358A/ja not_active Withdrawn
- 2003-12-18 CA CA002511208A patent/CA2511208A1/en not_active Abandoned
Non-Patent Citations (1)
Title |
---|
See references of WO2004056354A1 * |
Also Published As
Publication number | Publication date |
---|---|
IN192381B (de) | 2004-04-10 |
AU2003288604A1 (en) | 2004-07-14 |
CN1744889A (zh) | 2006-03-08 |
WO2004056354A1 (en) | 2004-07-08 |
RU2005121999A (ru) | 2006-01-20 |
BR0317567A (pt) | 2005-11-22 |
CA2511208A1 (en) | 2004-07-08 |
JP2006512358A (ja) | 2006-04-13 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
EP1596849A1 (de) | Pharmazeutische zusammensetzungen zur kontrollierten freisetzung von tamsulosin | |
JP4789806B2 (ja) | パントプラゾール多粒子処方 | |
RU2240786C2 (ru) | Пероральные лекарственные формы пролонгированного действия | |
JP6169411B2 (ja) | ゾニサミドの徐放性製剤 | |
US6660382B2 (en) | Process for manufacturing coated granules with masked taste and immediate release of the active principle | |
US6638535B2 (en) | Modified release formulations containing a hypnotic agent | |
JP2720932B2 (ja) | 経口投与用アセトアミノフエン錠剤の製造法及びアセトアミノフエン二層錠剤 | |
JP2001172201A (ja) | 経口投与形のための味をマスキングするコーティングとしてのフィルム被覆の使用、経口投与形及びその製造法 | |
CN1356102A (zh) | 掩味药物颗粒 | |
IL175860B2 (en) | A method of creating a solid pharmaceutical preparation for oral administration | |
JPH05201866A (ja) | 配合製剤 | |
CN101977593A (zh) | 包含弱碱性药物以及有机酸的给药*** | |
JP3134187B2 (ja) | 放出制御組成物 | |
JP2011522050A (ja) | バルサルタンのパルス放出 | |
JP3677156B2 (ja) | 医薬 | |
WO2005009416A1 (en) | Modified release compositions for minocycline | |
JP5664225B2 (ja) | 不快味マスキング粒子及びこれを含有する経口製剤 | |
ES2516693T3 (es) | Esferoides farmacéuticos | |
JP3929522B2 (ja) | 難水溶性薬物の徐放性製剤 | |
JPWO2004066991A1 (ja) | タムスロシンまたはその塩の腸溶性徐放微粒子およびその製造法 | |
WO2005051362A2 (en) | Oral benzimidazole compositions comprising an active core, an optional separating layer and an enteric coating | |
EP2736496B1 (de) | Pharmazeutische zusammensetzung mit einem antimuskarinischen wirkstoff und herstellungsverfahren dafür | |
JP2021084905A (ja) | 経口医薬製剤およびその製造方法 | |
Rhee et al. | Controlled-release pelletized dosage forms using the extrusion-spheronization process |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
17P | Request for examination filed |
Effective date: 20050720 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HU IE IT LI LU MC NL PT RO SE SI SK TR |
|
AX | Request for extension of the european patent |
Extension state: AL LT LV MK |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE APPLICATION IS DEEMED TO BE WITHDRAWN |
|
18D | Application deemed to be withdrawn |
Effective date: 20070703 |