WO2013077823A1 - Préparations à dispersion rapide contenant du natéglinide - Google Patents
Préparations à dispersion rapide contenant du natéglinide Download PDFInfo
- Publication number
- WO2013077823A1 WO2013077823A1 PCT/TR2012/000168 TR2012000168W WO2013077823A1 WO 2013077823 A1 WO2013077823 A1 WO 2013077823A1 TR 2012000168 W TR2012000168 W TR 2012000168W WO 2013077823 A1 WO2013077823 A1 WO 2013077823A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- formulation according
- nateglinide
- range
- formulation
- microcrystalline cellulose
- Prior art date
Links
- 229960000698 nateglinide Drugs 0.000 title claims abstract description 53
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 title claims abstract description 53
- 239000000203 mixture Substances 0.000 title claims description 112
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- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 5
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- 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 26
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- 239000007884 disintegrant Substances 0.000 claims description 21
- 239000013543 active substance Substances 0.000 claims description 20
- 238000000034 method Methods 0.000 claims description 17
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- 239000002552 dosage form Substances 0.000 claims description 12
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 claims description 11
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- 229960003105 metformin Drugs 0.000 claims description 7
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- 229910052623 talc Inorganic materials 0.000 claims description 7
- 235000012222 talc Nutrition 0.000 claims description 7
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 6
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- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 claims description 4
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- 239000000391 magnesium silicate Substances 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
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- 229960004329 metformin hydrochloride Drugs 0.000 claims description 4
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 claims description 4
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- 229960004034 sitagliptin Drugs 0.000 claims description 4
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 claims description 4
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- 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 3
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- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 claims description 3
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- FSBVERYRVPGNGG-UHFFFAOYSA-N dimagnesium dioxido-bis[[oxido(oxo)silyl]oxy]silane hydrate Chemical compound O.[Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O FSBVERYRVPGNGG-UHFFFAOYSA-N 0.000 claims description 3
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- NOOLISFMXDJSKH-UTLUCORTSA-N (+)-Neomenthol Chemical group CC(C)[C@@H]1CC[C@@H](C)C[C@@H]1O NOOLISFMXDJSKH-UTLUCORTSA-N 0.000 claims description 2
- TUAZNHHHYVBVBR-NHKADLRUSA-N (1s,3s,5s)-2-[(2s)-2-amino-2-(3-hydroxy-1-adamantyl)acetyl]-2-azabicyclo[3.1.0]hexane-3-carbonitrile;hydrochloride Chemical compound Cl.C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 TUAZNHHHYVBVBR-NHKADLRUSA-N 0.000 claims description 2
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 claims description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical group O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 claims description 2
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 claims description 2
- LLJFMFZYVVLQKT-UHFFFAOYSA-N 1-cyclohexyl-3-[4-[2-(7-methoxy-4,4-dimethyl-1,3-dioxo-2-isoquinolinyl)ethyl]phenyl]sulfonylurea Chemical compound C=1C(OC)=CC=C(C(C2=O)(C)C)C=1C(=O)N2CCC(C=C1)=CC=C1S(=O)(=O)NC(=O)NC1CCCCC1 LLJFMFZYVVLQKT-UHFFFAOYSA-N 0.000 claims description 2
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- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
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- XMSXOLDPMGMWTH-UHFFFAOYSA-N rivoglitazone Chemical compound CN1C2=CC(OC)=CC=C2N=C1COC(C=C1)=CC=C1CC1SC(=O)NC1=O XMSXOLDPMGMWTH-UHFFFAOYSA-N 0.000 claims description 2
- 229960004586 rosiglitazone Drugs 0.000 claims description 2
- 229960003271 rosiglitazone maleate Drugs 0.000 claims description 2
- SUFUKZSWUHZXAV-BTJKTKAUSA-N rosiglitazone maleate Chemical compound [H+].[H+].[O-]C(=O)\C=C/C([O-])=O.C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O SUFUKZSWUHZXAV-BTJKTKAUSA-N 0.000 claims description 2
- 150000003839 salts Chemical class 0.000 claims description 2
- 229960004937 saxagliptin Drugs 0.000 claims description 2
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 claims description 2
- 108010033693 saxagliptin Proteins 0.000 claims description 2
- 229960004973 saxagliptin hydrochloride Drugs 0.000 claims description 2
- 229940083037 simethicone Drugs 0.000 claims description 2
- 229960004115 sitagliptin phosphate Drugs 0.000 claims description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 claims description 2
- 239000004299 sodium benzoate Substances 0.000 claims description 2
- 235000010234 sodium benzoate Nutrition 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 229940032147 starch Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical group OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 2
- RTZRUVMEWWPNRR-UHFFFAOYSA-N tert-butyl n-(3-iodo-1h-pyrrolo[2,3-b]pyridin-5-yl)carbamate Chemical compound CC(C)(C)OC(=O)NC1=CN=C2NC=C(I)C2=C1 RTZRUVMEWWPNRR-UHFFFAOYSA-N 0.000 claims description 2
- 229960005371 tolbutamide Drugs 0.000 claims description 2
- 229960001641 troglitazone Drugs 0.000 claims description 2
- GXPHKUHSUJUWKP-UHFFFAOYSA-N troglitazone Chemical compound C1CC=2C(C)=C(O)C(C)=C(C)C=2OC1(C)COC(C=C1)=CC=C1CC1SC(=O)NC1=O GXPHKUHSUJUWKP-UHFFFAOYSA-N 0.000 claims description 2
- GXPHKUHSUJUWKP-NTKDMRAZSA-N troglitazone Natural products C([C@@]1(OC=2C(C)=C(C(=C(C)C=2CC1)O)C)C)OC(C=C1)=CC=C1C[C@H]1SC(=O)NC1=O GXPHKUHSUJUWKP-NTKDMRAZSA-N 0.000 claims description 2
- 229960001254 vildagliptin Drugs 0.000 claims description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 claims description 2
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 claims 2
- 240000007651 Rubus glaucus Species 0.000 claims 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 claims 1
- SNAAJJQQZSMGQD-UHFFFAOYSA-N aluminum magnesium Chemical compound [Mg].[Al] SNAAJJQQZSMGQD-UHFFFAOYSA-N 0.000 claims 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims 1
- 229960005168 croscarmellose Drugs 0.000 claims 1
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 claims 1
- ZADYMNAVLSWLEQ-UHFFFAOYSA-N magnesium;oxygen(2-);silicon(4+) Chemical compound [O-2].[O-2].[O-2].[Mg+2].[Si+4] ZADYMNAVLSWLEQ-UHFFFAOYSA-N 0.000 claims 1
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 3
- 239000003795 chemical substances by application Substances 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 239000006185 dispersion Substances 0.000 description 5
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- 238000005550 wet granulation Methods 0.000 description 5
- 239000011248 coating agent Substances 0.000 description 4
- 239000007888 film coating Substances 0.000 description 4
- 238000009501 film coating Methods 0.000 description 4
- 238000002360 preparation method Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000007906 compression Methods 0.000 description 3
- 230000006835 compression Effects 0.000 description 3
- 238000007907 direct compression Methods 0.000 description 3
- 238000007908 dry granulation Methods 0.000 description 3
- 229940117841 methacrylic acid copolymer Drugs 0.000 description 3
- 229920003145 methacrylic acid copolymer Polymers 0.000 description 3
- 235000000346 sugar Nutrition 0.000 description 3
- 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 3
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 2
- 229920001218 Pullulan Polymers 0.000 description 2
- 239000004373 Pullulan Substances 0.000 description 2
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 150000001252 acrylic acid derivatives Chemical class 0.000 description 2
- 229920003144 amino alkyl methacrylate copolymer Polymers 0.000 description 2
- 238000009826 distribution Methods 0.000 description 2
- 239000002702 enteric coating Substances 0.000 description 2
- 238000009505 enteric coating Methods 0.000 description 2
- 238000005469 granulation Methods 0.000 description 2
- 230000003179 granulation Effects 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 2
- 235000019423 pullulan Nutrition 0.000 description 2
- 229960004793 sucrose Drugs 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
- 244000215068 Acacia senegal Species 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 0.000 description 1
- 229920001479 Hydroxyethyl methyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 244000235659 Rubus idaeus Species 0.000 description 1
- 229920001800 Shellac Polymers 0.000 description 1
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- DHKHKXVYLBGOIT-UHFFFAOYSA-N acetaldehyde Diethyl Acetal Natural products CCOC(C)OCC DHKHKXVYLBGOIT-UHFFFAOYSA-N 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
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- PZZYQPZGQPZBDN-UHFFFAOYSA-N aluminium silicate Chemical compound O=[Al]O[Si](=O)O[Al]=O PZZYQPZGQPZBDN-UHFFFAOYSA-N 0.000 description 1
- 229910000323 aluminium silicate Inorganic materials 0.000 description 1
- 150000003862 amino acid derivatives Chemical class 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 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
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 235000015165 citric acid Nutrition 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 230000003111 delayed effect Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- XPNLOZNCOBKRNJ-UHFFFAOYSA-N ethyl prop-2-enoate;methyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C=C.COC(=O)C(C)=C XPNLOZNCOBKRNJ-UHFFFAOYSA-N 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 239000001530 fumaric acid Substances 0.000 description 1
- 235000011087 fumaric acid Nutrition 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 150000004677 hydrates Chemical class 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 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 1
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 1
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 1
- 229920000639 hydroxypropylmethylcellulose acetate succinate Polymers 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 235000001055 magnesium Nutrition 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
- 229940091250 magnesium supplement Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 239000005445 natural material Substances 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 239000008188 pellet Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 239000011736 potassium bicarbonate Substances 0.000 description 1
- 235000015497 potassium bicarbonate Nutrition 0.000 description 1
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- 235000011181 potassium carbonates Nutrition 0.000 description 1
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 1
- 229940086066 potassium hydrogencarbonate Drugs 0.000 description 1
- 239000004208 shellac Substances 0.000 description 1
- 229940113147 shellac Drugs 0.000 description 1
- 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 1
- 235000013874 shellac Nutrition 0.000 description 1
- 238000007086 side reaction Methods 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 235000017550 sodium carbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
-
- 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
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
- A61K9/0007—Effervescent
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
Definitions
- the present invention relates to pharmaceutical formulations comprising nateglinide that shall be used in the treatment of diabetes.
- Nateglinide was first disclosed in the application numbered EP 196222. In said document, it has been disclosed that nateglinide is effective in the treatment of diabetes.
- Nateglinide is available in 60, 120, 180 mg oral tablets on the market.
- Nateglinide is a low water-soluble active agent. Therefore, distribution of the formulations comprising this active agent in body takes long periods of time. However, nateglinide should act shortly after taken in order to reduce blood sugar level quickly which is elevated especially after meal. In this respect, there is need for development of nateglinide formulations which disperse in a short time.
- nateglinide is structurally an amino acid derivative.
- Such molecules cause formation of various by-products by reacting with some excipients which are used basically in pharmaceutical technology. Therefore, problems arise in selecting the excipient and there is need to develop pharmaceutical formulations which both have appropriate physical characteristics and are stable.
- one characteristic feature of the present invention is nateglinide formulations wherein a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium is used.
- microcrystalline cellulose one of the components in said disintegrant composition, and the weight ratio of microcrystalline cellulose to croscarmellose sodium, the other component in the disintegrant composition, are influential on dispersion of the dosage forms prepared with the formulation obtained in water.
- the inventors have found that use of macrocrystalline cellulose having a d 50 value in the range of 60 tolOO ⁇ , preferably in the range of 70 to 90 ⁇ ; a d 90 value in the range of 200 to 350 ⁇ , preferably in the range of 220 to 280 ⁇ gives positive results on dispersion of the formulation.
- d 50 signifies that half of the said substance by volume has a particle size over the value stated with d 50 and the other half of the substance by volume has a particle size below the value stated with dso.
- d 9 o signifies that 90% of the said substance by volume has a particle size below the stated value and 10% of the said substance by volume has a particle size over the stated value.
- the present invention relates to compositions comprising nateglinide as active agent wherein a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium is used and microcrystalline cellulose comprised in said composition has a d 50 value in the range of 60 to 100 ⁇ , a devalue in the range of 200 to 350 ⁇ .
- D 50 and d 90 values can be measured with one of the known measuring devices, for instance with a device which measures particle distribution by laser diffraction (for instance, Malvern Mastersizer etc.).
- a device which measures particle distribution by laser diffraction for instance, Malvern Mastersizer etc.
- pH value of microcrystalline cellulose used is also important for preventing side reactions that can occur with nateglinide.
- the inventors have seen that use of microcrystalline cellulose having a pH value in the range of 5 to 7.5 is important for preventing undesired reactions that can occur between nateglinide and microcrystalline cellulose.
- the present invention relates to compositions comprising nateglinide as active agent wherein a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium is used and microcrystalline cellulose comprised in said compositions has a pH value in the range of 5 to 7.5; a d 50 value in the range of 60 to 100 ⁇ ; a d 90 value in the range of 200 to 300 ⁇ .
- the inventors have seen that bulk density of microcrystalline cellulose used is effective on flow properties of the formulation obtained.
- the inventors have seen that the formulation obtained has a homogeneous flow in nateglinide formulations wherein microcrystalline cellulose has a bulk density in the range of 0.2 to 0.4 g cc is used.
- the present invention relates to compositions comprising nateglinide wherein a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium is used and microcrystalline cellulose comprised in said compositions has a pH value in the range of 5 to 7.5; a bulk density value in the range of 0.2 to 0.4; a d 50 value in the range of 60 to 100 ⁇ ; a d 90 value in the range of 200 to 300 ⁇ . It has been seen that other factors playing a role on dispersion of nateglinide formulations of the present invention in a short time as desired, for instance in less than 5 minutes, are the amount of the components composing disintegrant composition and the ratio of the components to each other.
- the ratio of microcrystalline cellulose to croscarmellose sodium composing the disintegrant composition is in the range of 5: 1 to 10: 1 by weight, preferably in the range of 6: 1 to 9: 1 by weight, more preferably in the range of 7:1 to 8.5: 1 by weight; dispersion of the dosage forms obtained from this formulation in water is performed in a short time.
- the formulations of the present invention comprise microcrystalline cellulose in the range of 5-10% by weight, croscarmellose sodium in the range of 0.5-5% by weight in proportion to total weight of the unit dosage form.
- the formulations prepared according to the present invention are in various dosage forms suitable for oral use, for instance in any of film coated tablet, prolonged release tablet, modified release tablet, capsule, dry powder for suspension preparation, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet, sachet forms.
- the formulations of the present invention are preferably in tablet or film coated tablet forms, more preferably in film coated tablet form.
- Nateglinide formulations of the present invention comprise at least one pharmaceutically acceptable excipient along with a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium.
- At least one pharmaceutically acceptable excipient that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention can be selected from a group comprising diluent, binder, lubricant, flavouring agent, effervescent acid, effervescent base, glidant.
- the binder that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising carboxymethyl cellulose sodium, ethyl cellulose, gelatine, hydroxyethyl cellulose, hydroxymethyl cellulose, hypromellose, magnesium aluminium silicate, maltodextrin, methyl cellulose, povidone, starch.
- the lubricant that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulphate, talc, stearic acid, zinc stearate.
- the diluent that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulphate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol.
- flavouring agent that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from menthol, lemon, orange, vanilla, strawberry, raspberry, caramel and similar flavours.
- the glidant that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising tribasic calcium phosphate, colloidal silicone dioxide, magnesium silicate, magnesium trisilicate, talc.
- the effervescent acid that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising organic acids such as malic acid, citric acid, tartaric acid, fumaric acid.
- the effervescent base that can be used in addition to a disintegrant combination comprising microcrystalline cellulose and croscarmellose sodium in nateglinide formulations of the present invention is selected from a group comprising the agents such as sodium carbonate, potassium carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate.
- the formulations of the present invention comprise nateglinide in the range of 5 to 35% by weight, preferably in the range of 10 to 30% by weight, more preferably in the range of 15 to 30%by weight in proportion to total weight of unit dosage amount.
- Nateglinide comprised in the formulations of the present invention can be in crystalline or amorphous forms and/or in the form of its hydrates, solvates or a combination thereof.
- the formulation can be produced by direct compression method or dry or wet granulation method or by using these methods consecutively in a combined form.
- the substances comprised in the formulations are measured one by one, and mixed.
- the dry powder obtained is compressed in tablet compression machine and formed into tablets.
- the other substances comprised in the formulation except for the lubricant are mixed and subjected to precompression process.
- the tablets obtained after said process are granulated in granulator. These granules are added into the lubricant granule, mixed and optionally tablet or pellet forms can be obtained.
- the formulations of the present invention are preferably prepared by wet granulation method and the formulation obtained is optionally filled into capsules or sachets or can be compressed in tablet form.
- the tablets can optionally be coated with film coating agents, for instance sugar based coating agents, water soluble film coating agents, enteric coating or modified release coating agents.
- nateglinide and at least one excipient are granulated and the granules obtained are mixed with at least one other excipient.
- the formulation obtained is compressed in tablet form and coated with a film coating agent.
- Saccharose can be used singly or optionally with any of the agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
- agents such as talc, calcium carbonate, calcium phosphate, calcium sulphate, gelatine, gum arabic, polyvinylpyrrolidone and pullulan or a combination thereof as the sugar based coating agent.
- the water soluble film coating agent can be selected from cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose; synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
- cellulose derivatives such as hydroxypropyl cellulose, hydroxypropyl methyl cellulose, hydroxyethyl cellulose, methyl hydroxyethyl cellulose and sodium carboxymethyl cellulose
- synthetic polymers such as polyvinyl acetal diethyl aminoacetate, aminoalkyl methacrylate copolymers and polyvinylpyrrolidone and polysaccharides such as pullulan or combinations thereof.
- the enteric coating agents can be selected from cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate; acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
- cellulose derivatives such as hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate, carboxymethyl ethyl cellulose, cellulose acetate phthalate
- acrylic acid derivatives such as methacrylic acid copolymer L, methacrylic acid copolymer LD and methacrylic acid copolymer S and natural substances such as shellac or combinations thereof.
- the delayed release coating agents can be selected from cellulose derivatives such as ethyl cellulose; acrylic acid derivatives such as aminoalkyl methacrylate copolymer RS, emulsion copolymer of ethyl acrylate-methyl methacrylate or combinations thereof.
- formulations can be used in the treatment of type 2 diabetes that cannot be controlled by diet and exercise.
- compositions of the present invention comprising nateglinide can comprise a second active agent in addition to nateglinide.
- Said second active agent can be selected from a group comprising meglinitides, alpha glucosidase inhibitors, sulfonylureas, tiazolidinediones, biguanides, dipeptidyl peptidase-4 inhibitors.
- said second active agent can be selected from a group comprising the agents such as repaglinide belonging to meglitinide group; alpha-glucosidase inhibitor acarbose; acetohexamide, glindeklamid, glibornuride, gliclazide, gliquidone, glimepiride, glipizide, chlorpropamide, tolbutamide belonging to sulfonylurea group; pioglitazone, rosiglitazone, rivoglitazone, rosiglitazone maleate, pioglitazone hydrochloride, troglitazone belonging to thiazolidinedione group; phenformin, metformin or a pharmaceutically acceptable salt thereof, for instance metformin hydrochloride belonging to biguanide group; dipeptidyl peptidase-4 inhibitors sitagliptin, vildagliptin, saxagliptin, saxagli
- nateglinide and the second active agent can be comprised in the same formulation while they can also be prepared in two different formulations. In the case that they are prepared in two different formulations, said formulations can be combined in a single dosage form or they can be in a treatment package form of independent but same or different dosage forms.
- the formulations comprising the second active agent can be in various dosage forms suitable for oral use, for instance in tablet, film coated tablet, prolonged release tablet, modified release tablet, capsule, dry powder to form suspension, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet, sachet forms.
- suitable for oral use for instance in tablet, film coated tablet, prolonged release tablet, modified release tablet, capsule, dry powder to form suspension, effervescent tablet, effervescent granule, orodispersible tablet, chewable tablet, sachet forms.
- the examples for the formulations of the present invention are given below.
- Example 1 Formulation and Production Method for Preparation of the Tablets Comprising Nateglinide.
- Each substance comprised in the formulation given above is measured one by one.
- Each substance measured is progressively mixed in said formulation obtained by direct compression method.
- the powder mixture obtained is compressed in tablet compression machine and formed into tablets.
- Example 2 Formulation for Preparation of Treatment Package Comprising Nateglinide and Metformin.
- the formulation comprising nateglinide given above is prepared by dry granulation method.
- the other excipients except from the lubricant in the formulation are mixed by an appropriate method and subjected to precompression process.
- the tablets obtained after precompression are granulated in granulator. These granules are added into the lubricant granule, mixed together and the tablet form is obtained.
- the formulation comprising metformin is prepared by wet granulation method and the first is step is mixing the active agent, the effervescent couple and the other excipients.
- the mixture obtained is subjected to granulation process. After the granules obtained are dried; sieving, adding the other excipients and mixing processes are performed respectively. Tablet compression is performed in the last step and effervescent tablets are obtained.
- Example 3 Formulation for Preparation of Tablets Comprising Nateglinide and Metformin.
- the formulation comprising the excipients given above has been prepared by wet granulation method.
- wet granulation nateglinide and metformin are wet sieved after being granulated with the granulation solution comprising the binder and dried in fluid bed dryer.
- the mixture obtained is mixed I with the other excipients and homogenized.
- the lubricant is added in the last step of the mixture.
- the formulation is formed into tablets after this step.
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Abstract
Cette invention concerne des préparations pharmaceutiques comprenant du natéglinide qui sont utilisées pour le traitement du diabète.
Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| TR201111590 | 2011-11-23 | ||
| TR2011/11590 | 2011-11-23 | ||
| TR201112200 | 2011-12-09 | ||
| TR2011/12200 | 2011-12-09 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2013077823A1 true WO2013077823A1 (fr) | 2013-05-30 |
Family
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/TR2012/000168 WO2013077823A1 (fr) | 2011-11-23 | 2012-10-04 | Préparations à dispersion rapide contenant du natéglinide |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2013077823A1 (fr) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105534931A (zh) * | 2015-12-25 | 2016-05-04 | 安徽环球药业股份有限公司 | 那格列奈片及直接压片法制备那格列奈片的方法 |
| CN108451923A (zh) * | 2018-05-31 | 2018-08-28 | 常州兰陵制药有限公司 | 盐酸二甲双胍速释胶囊及其制备方法 |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2002072146A2 (fr) * | 2001-03-12 | 2002-09-19 | Novartis Ag | Combinaison de composes organiques |
| US20030162816A1 (en) * | 1999-09-17 | 2003-08-28 | Gatlin Marjorie Regan | Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes |
| WO2005051360A1 (fr) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Compositions pharmaceutiques comprenant de la nateglinide et un agent tensioactif |
-
2012
- 2012-10-04 WO PCT/TR2012/000168 patent/WO2013077823A1/fr active Application Filing
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20030162816A1 (en) * | 1999-09-17 | 2003-08-28 | Gatlin Marjorie Regan | Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes |
| WO2002072146A2 (fr) * | 2001-03-12 | 2002-09-19 | Novartis Ag | Combinaison de composes organiques |
| WO2005051360A1 (fr) * | 2003-11-28 | 2005-06-09 | Ranbaxy Laboratories Limited | Compositions pharmaceutiques comprenant de la nateglinide et un agent tensioactif |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105534931A (zh) * | 2015-12-25 | 2016-05-04 | 安徽环球药业股份有限公司 | 那格列奈片及直接压片法制备那格列奈片的方法 |
| CN108451923A (zh) * | 2018-05-31 | 2018-08-28 | 常州兰陵制药有限公司 | 盐酸二甲双胍速释胶囊及其制备方法 |
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