TR2021021295A2 - A PHARMACEUTICAL COMPOSITION CONTAINING EMPAGLIFLOZIN AND LINAGLIPTIN PREPARED BY HOT MEL EXTRUSION - Google Patents
A PHARMACEUTICAL COMPOSITION CONTAINING EMPAGLIFLOZIN AND LINAGLIPTIN PREPARED BY HOT MEL EXTRUSIONInfo
- Publication number
- TR2021021295A2 TR2021021295A2 TR2021/021295 TR2021021295A2 TR 2021021295 A2 TR2021021295 A2 TR 2021021295A2 TR 2021/021295 TR2021/021295 TR 2021/021295 TR 2021021295 A2 TR2021021295 A2 TR 2021021295A2
- Authority
- TR
- Turkey
- Prior art keywords
- pharmaceutical composition
- composition according
- salts
- empagliflozin
- sodium
- Prior art date
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 34
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 28
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 title claims abstract description 26
- 229960002397 linagliptin Drugs 0.000 title claims abstract description 15
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 title claims abstract description 13
- 238000001125 extrusion Methods 0.000 title description 4
- 150000003839 salts Chemical class 0.000 claims abstract description 27
- 239000008187 granular material Substances 0.000 claims abstract description 19
- 238000009474 hot melt extrusion Methods 0.000 claims abstract description 9
- 239000000203 mixture Substances 0.000 claims description 31
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 claims description 10
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 10
- 229940095079 dicalcium phosphate anhydrous Drugs 0.000 claims description 10
- 239000000945 filler Substances 0.000 claims description 10
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 9
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 9
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 9
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 9
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 9
- 239000002775 capsule Substances 0.000 claims description 7
- 239000000314 lubricant Substances 0.000 claims description 7
- 238000000034 method Methods 0.000 claims description 7
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- -1 polyoxyglycerides Chemical compound 0.000 claims description 6
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 claims description 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 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 claims description 4
- 239000002202 Polyethylene glycol Substances 0.000 claims description 4
- 239000001506 calcium phosphate Substances 0.000 claims description 4
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 4
- 235000011010 calcium phosphates Nutrition 0.000 claims description 4
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 claims description 4
- DOIRQSBPFJWKBE-UHFFFAOYSA-N dibutyl phthalate Chemical compound CCCCOC(=O)C1=CC=CC=C1C(=O)OCCCC DOIRQSBPFJWKBE-UHFFFAOYSA-N 0.000 claims description 4
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 claims description 4
- 235000019329 dioctyl sodium sulphosuccinate Nutrition 0.000 claims description 4
- GLDOVTGHNKAZLK-UHFFFAOYSA-N octadecan-1-ol Chemical compound CCCCCCCCCCCCCCCCCCO GLDOVTGHNKAZLK-UHFFFAOYSA-N 0.000 claims description 4
- 229920001223 polyethylene glycol Polymers 0.000 claims description 4
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 claims description 4
- 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 claims description 4
- GVJHHUAWPYXKBD-IEOSBIPESA-N α-tocopherol Chemical compound OC1=C(C)C(C)=C2O[C@@](CCC[C@H](C)CCC[C@H](C)CCCC(C)C)(C)CCC2=C1C GVJHHUAWPYXKBD-IEOSBIPESA-N 0.000 claims description 4
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 claims description 3
- 238000001816 cooling Methods 0.000 claims description 3
- 238000007580 dry-mixing Methods 0.000 claims description 3
- 238000010438 heat treatment Methods 0.000 claims description 3
- 238000002360 preparation method Methods 0.000 claims description 3
- APSBXTVYXVQYAB-UHFFFAOYSA-M sodium docusate Chemical compound [Na+].CCCCC(CC)COC(=O)CC(S([O-])(=O)=O)C(=O)OCC(CC)CCCC APSBXTVYXVQYAB-UHFFFAOYSA-M 0.000 claims description 3
- 239000001069 triethyl citrate Substances 0.000 claims description 3
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 claims description 3
- 235000013769 triethyl citrate Nutrition 0.000 claims description 3
- QMMJWQMCMRUYTG-UHFFFAOYSA-N 1,2,4,5-tetrachloro-3-(trifluoromethyl)benzene Chemical compound FC(F)(F)C1=C(Cl)C(Cl)=CC(Cl)=C1Cl QMMJWQMCMRUYTG-UHFFFAOYSA-N 0.000 claims description 2
- 239000000263 2,3-dihydroxypropyl (Z)-octadec-9-enoate Substances 0.000 claims description 2
- RZRNAYUHWVFMIP-GDCKJWNLSA-N 3-oleoyl-sn-glycerol Chemical compound CCCCCCCC\C=C/CCCCCCCC(=O)OC[C@H](O)CO RZRNAYUHWVFMIP-GDCKJWNLSA-N 0.000 claims description 2
- QZCLKYGREBVARF-UHFFFAOYSA-N Acetyl tributyl citrate Chemical compound CCCCOC(=O)CC(C(=O)OCCCC)(OC(C)=O)CC(=O)OCCCC QZCLKYGREBVARF-UHFFFAOYSA-N 0.000 claims description 2
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.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 WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 claims description 2
- 239000004375 Dextrin Substances 0.000 claims description 2
- 229920001353 Dextrin Polymers 0.000 claims description 2
- 239000001856 Ethyl cellulose Substances 0.000 claims description 2
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 claims description 2
- FPVVYTCTZKCSOJ-UHFFFAOYSA-N Ethylene glycol distearate Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCCOC(=O)CCCCCCCCCCCCCCCCC FPVVYTCTZKCSOJ-UHFFFAOYSA-N 0.000 claims description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229940087168 alpha tocopherol Drugs 0.000 claims description 2
- 235000010407 ammonium alginate Nutrition 0.000 claims description 2
- 239000000728 ammonium alginate Substances 0.000 claims description 2
- KPGABFJTMYCRHJ-YZOKENDUSA-N ammonium alginate Chemical compound [NH4+].[NH4+].O1[C@@H](C([O-])=O)[C@@H](OC)[C@H](O)[C@H](O)[C@@H]1O[C@@H]1[C@@H](C([O-])=O)O[C@@H](O)[C@@H](O)[C@H]1O KPGABFJTMYCRHJ-YZOKENDUSA-N 0.000 claims description 2
- CADWTSSKOVRVJC-UHFFFAOYSA-N benzyl(dimethyl)azanium;chloride Chemical class [Cl-].C[NH+](C)CC1=CC=CC=C1 CADWTSSKOVRVJC-UHFFFAOYSA-N 0.000 claims 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 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 235000010216 calcium carbonate Nutrition 0.000 claims description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 claims description 2
- 235000013539 calcium stearate Nutrition 0.000 claims description 2
- 239000008116 calcium stearate Substances 0.000 claims description 2
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 239000004359 castor oil Substances 0.000 claims description 2
- 235000019438 castor oil Nutrition 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 229940096516 dextrates Drugs 0.000 claims description 2
- 235000019425 dextrin Nutrition 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- HTDKEJXHILZNPP-UHFFFAOYSA-N dioctyl hydrogen phosphate Chemical compound CCCCCCCCOP(O)(=O)OCCCCCCCC HTDKEJXHILZNPP-UHFFFAOYSA-N 0.000 claims description 2
- 229960000878 docusate sodium Drugs 0.000 claims description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 claims description 2
- 235000019325 ethyl cellulose Nutrition 0.000 claims description 2
- 229920001249 ethyl cellulose Polymers 0.000 claims description 2
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 2
- 229940075507 glyceryl monostearate Drugs 0.000 claims description 2
- 235000013773 glyceryl triacetate Nutrition 0.000 claims description 2
- 239000001087 glyceryl triacetate Substances 0.000 claims description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 claims description 2
- 229960001021 lactose monohydrate Drugs 0.000 claims description 2
- 229940059904 light mineral oil Drugs 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000002480 mineral oil Substances 0.000 claims description 2
- 235000010446 mineral oil Nutrition 0.000 claims description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 claims description 2
- RZRNAYUHWVFMIP-UHFFFAOYSA-N monoelaidin Natural products CCCCCCCCC=CCCCCCCCC(=O)OCC(O)CO RZRNAYUHWVFMIP-UHFFFAOYSA-N 0.000 claims description 2
- GOQYKNQRPGWPLP-UHFFFAOYSA-N n-heptadecyl alcohol Natural products CCCCCCCCCCCCCCCCCO GOQYKNQRPGWPLP-UHFFFAOYSA-N 0.000 claims description 2
- 230000007935 neutral effect Effects 0.000 claims description 2
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 claims description 2
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 150000003904 phospholipids Chemical class 0.000 claims description 2
- 229920001983 poloxamer Polymers 0.000 claims description 2
- 229920000136 polysorbate Polymers 0.000 claims description 2
- 229940068965 polysorbates Drugs 0.000 claims description 2
- RMGVATURDVPNOZ-UHFFFAOYSA-M potassium;hexadecyl hydrogen phosphate Chemical compound [K+].CCCCCCCCCCCCCCCCOP(O)([O-])=O RMGVATURDVPNOZ-UHFFFAOYSA-M 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
- BTURAGWYSMTVOW-UHFFFAOYSA-M sodium dodecanoate Chemical compound [Na+].CCCCCCCCCCCC([O-])=O BTURAGWYSMTVOW-UHFFFAOYSA-M 0.000 claims description 2
- RYYKJJJTJZKILX-UHFFFAOYSA-M sodium octadecanoate Chemical compound [Na+].CCCCCCCCCCCCCCCCCC([O-])=O RYYKJJJTJZKILX-UHFFFAOYSA-M 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 229960000984 tocofersolan Drugs 0.000 claims description 2
- 229960002622 triacetin Drugs 0.000 claims description 2
- WEAPVABOECTMGR-UHFFFAOYSA-N triethyl 2-acetyloxypropane-1,2,3-tricarboxylate Chemical compound CCOC(=O)CC(C(=O)OCC)(OC(C)=O)CC(=O)OCC WEAPVABOECTMGR-UHFFFAOYSA-N 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
- 235000004835 α-tocopherol Nutrition 0.000 claims description 2
- 239000002076 α-tocopherol Substances 0.000 claims description 2
- DLRVVLDZNNYCBX-UHFFFAOYSA-N Polydextrose Polymers OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(O)O1 DLRVVLDZNNYCBX-UHFFFAOYSA-N 0.000 claims 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims 2
- HDTRYLNUVZCQOY-UHFFFAOYSA-N α-D-glucopyranosyl-α-D-glucopyranoside Natural products OC1C(O)C(O)C(CO)OC1OC1C(O)C(O)C(O)C(CO)O1 HDTRYLNUVZCQOY-UHFFFAOYSA-N 0.000 claims 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 claims 1
- NZAQRZWBQUIBSF-UHFFFAOYSA-N 4-(4-sulfobutoxy)butane-1-sulfonic acid Chemical compound OS(=O)(=O)CCCCOCCCCS(O)(=O)=O NZAQRZWBQUIBSF-UHFFFAOYSA-N 0.000 claims 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 claims 1
- 241000416162 Astragalus gummifer Species 0.000 claims 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 claims 1
- 239000001836 Dioctyl sodium sulphosuccinate Substances 0.000 claims 1
- 239000005715 Fructose Substances 0.000 claims 1
- 229930091371 Fructose Natural products 0.000 claims 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 claims 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 claims 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims 1
- 239000005913 Maltodextrin Substances 0.000 claims 1
- 229920002774 Maltodextrin Polymers 0.000 claims 1
- 229930195725 Mannitol Natural products 0.000 claims 1
- 229920001100 Polydextrose Polymers 0.000 claims 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 claims 1
- 229920001615 Tragacanth Polymers 0.000 claims 1
- HDTRYLNUVZCQOY-WSWWMNSNSA-N Trehalose Natural products O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-WSWWMNSNSA-N 0.000 claims 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims 1
- HDTRYLNUVZCQOY-LIZSDCNHSA-N alpha,alpha-trehalose Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 HDTRYLNUVZCQOY-LIZSDCNHSA-N 0.000 claims 1
- AMTWCFIAVKBGOD-UHFFFAOYSA-N dioxosilane;methoxy-dimethyl-trimethylsilyloxysilane Chemical compound O=[Si]=O.CO[Si](C)(C)O[Si](C)(C)C AMTWCFIAVKBGOD-UHFFFAOYSA-N 0.000 claims 1
- 229960004667 ethyl cellulose Drugs 0.000 claims 1
- 229960002737 fructose Drugs 0.000 claims 1
- 229960001031 glucose Drugs 0.000 claims 1
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims 1
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims 1
- 239000008101 lactose Substances 0.000 claims 1
- 229960001375 lactose Drugs 0.000 claims 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims 1
- 239000001095 magnesium carbonate Substances 0.000 claims 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims 1
- 229960001708 magnesium carbonate Drugs 0.000 claims 1
- 239000000395 magnesium oxide Substances 0.000 claims 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims 1
- 229960000869 magnesium oxide Drugs 0.000 claims 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims 1
- 229940035034 maltodextrin Drugs 0.000 claims 1
- 239000000594 mannitol Substances 0.000 claims 1
- 235000010355 mannitol Nutrition 0.000 claims 1
- 229960001855 mannitol Drugs 0.000 claims 1
- 229940057917 medium chain triglycerides Drugs 0.000 claims 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims 1
- 235000013856 polydextrose Nutrition 0.000 claims 1
- 239000001259 polydextrose Substances 0.000 claims 1
- 229940035035 polydextrose Drugs 0.000 claims 1
- 229920000193 polymethacrylate Polymers 0.000 claims 1
- 229940083037 simethicone Drugs 0.000 claims 1
- 239000011734 sodium Substances 0.000 claims 1
- 229910052708 sodium Inorganic materials 0.000 claims 1
- 235000010413 sodium alginate Nutrition 0.000 claims 1
- 239000000661 sodium alginate Substances 0.000 claims 1
- 229940005550 sodium alginate Drugs 0.000 claims 1
- 239000011780 sodium chloride Substances 0.000 claims 1
- 229960002668 sodium chloride Drugs 0.000 claims 1
- 239000000454 talc Substances 0.000 claims 1
- 229910052623 talc Inorganic materials 0.000 claims 1
- 229940033134 talc Drugs 0.000 claims 1
- 235000010487 tragacanth Nutrition 0.000 claims 1
- 239000000196 tragacanth Substances 0.000 claims 1
- 229940116362 tragacanth Drugs 0.000 claims 1
- 229940074410 trehalose Drugs 0.000 claims 1
- 239000000811 xylitol Substances 0.000 claims 1
- 235000010447 xylitol Nutrition 0.000 claims 1
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Abstract
Mevcut buluş, empagliflozin veya tuzlarını ve linagliptin veya tuzlarını veya kristalinpolimorfuna sahip bir granülat içeren bir farmasötik kompozisyon ile ilgili olup, özelliği, granülatın sıcak eriyik ekstrüzyonla elde edilmesidirThe present invention relates to a pharmaceutical composition comprising empagliflozin or its salts and linagliptin or its salts or a granulate having its crystalline polymorph, characterized in that the granulate is obtained by hot melt extrusion.
Description
TARIFNAME SICAK ERIYIK EKSTRÜZYON iLE HAZIRLANAN EMPAGLIFLOZIN VE LINAGLIPTIN IÇEREN BIR FARMASÖTIK KOMPOZISYON Bulusun Alani Mevcut bulus, empagliflozin veya onun tuzlarini ve Iinagliptin veya onun tuzlarini veya kristalin polimorfuna sahip bir granülat içeren bir farmasötik kompozisyon ile ilgili olup, granülat sicak eriyik ekstrüzyonla elde edilir. Bulusun Geçmisi Diabetes mellitus, bozulmus sekresyon, azalmis insülin aktivitesi veya her iki faktörün bir kombinasyonu nedeniyle insülin aksiyonunun azaldigi veya hiç bulunmadigi bir grup karbonhidrat metabolizmasi bozuklugudur. Iki baslica diyabet tipi vardir; Tip 1 ve Tip 2: Tip 1 diyabet, pankreasin insülin üreten hücrelerinin (beta hücreleri) hasar görmesi nedeniyle olusur. Tip 1 diyabette pankreas çok az insülin yapar veya hiç insülin yapmaz, bu nedenle seker enerji olarak kullanilmak üzere vücudun hücrelerine giremez. Tip 1 diyabetli kisiler kan glikozunu kontrol etmek için insülin enjeksiyonlari kullanmalidir. Tip 2 diyabette pankreas insülin üretir ancak ya yeterince üretemez ya da insülin görevini düzgün sekilde yerine getiremez. Bu diyabet en sik 40 yas üstü ve asiri kilolu kisilerde görülür. Tip 2 diyabet bazen birdiyet, kilo yönetimi ve egzersiz kombinasyonu ile kontrol altina alinabilir. Bununla birlikte, tedavi ayrica oral glikoz düsürücü ilaçlari veya insülin enjeksiyonlarini da içerebilmektedir. Linagliptin, tip 2 veya insüline bagimli olmayan diyabet için kullanilir. Glisemik kontrolü iyilestirmek için diyet ve egzersize ek olarak kullanilan seçici, oral yoldan uygulanan, ksantin bazli bir dipeptidil peptidaz-4 (DPP-4) inhibitörüdür. DPP-4 inhibitörleri, hormon inkretinini yok eden bir enzim olan DPP-4'ün aksiyonunu bloke ederek çalisirlar. Vücutta glukagon benzeri peptit-1 (GLP-i) ve glikoz bagimli insülinotropik peptit (GIP) olarak adlandirilan iki tür inkretin hormonu bulunur. Bu hormonlar vücut tarafindan gida alimina tepki olarak dogal sekilde üretilir. islevleri, vücudun yalnizca gerektiginde daha fazla insülin üretmesine yardimci olmak ve gerekmediginde karaciger tarafindan üretilen glikoz miktarini azaltmaktir. Linagliptin, DPP- 4'e baglanarak ve onun GLP-i'i ve GIP'yi parçalamasini önleyerek çalisir. Bu, vücuttaki bu hormonlarin seviyelerini arttirirve böylece kan sekerini kontrol etme üzerindeki etkilerini arttirir. metilkinazolin-2-il)metiI]-3,7-dihidr0-1H-purin-2,6-dion olup, kimyasal yapisi Formül I'de gösterilmistir. Formül I Empagliflozin, tip 2 diyabetli hastalarda glisemik kontrolde tedavi veya iyilestirme için tarif edilen, bilinen bir SGLT2 inhibitörüdür. Empagliflozinin kimyasal adi 1-klor0-4-(3-D- glukopiranos-1 -il)- 2-[4-((S)-tetrahidrofuran-3-iIoksi)-benziI]-benzen olup, kimyasal yapisi Formül Il'de gösterilmistir. Formülll Oral uygulama için Iinagliptin ile kombinasyon halinde empagliflozin tabletleri su anda Amerika Birlesik Devletleri'nde Boehringer Ingelheim tarafindan üretilen Glyxambi® adi altinda pazarlanmakta olup, tip 2 diyabetli yetiskinlerde glisemik kontrolü iyilestirmek için diyet ve egzersize tamamlayici olarak belirtilmektedir ve tek katmanli tabletler olarak sirasiyla 1D mg/5 mg ve 25 mg/5 mg olmak üzere iki dozaj gücünde mevcuttur. hazirlanmasini ve tip 1 diyabet ve tip 2 diyabet tedavisinde kullanimlarini açiklar. katmanli farmasötik kompozisyonlari açiklar. Önceki teknikte, oral farmasötik dozaj formlarinda empagliflozin veya tuzlarini ve Iinagliptin veya tuzlarini veya kristalin polimorfunu içeren bir farmasötik kompozisyonu açiklayan birkaç patent de bulunmaktadir. Teknikte halen, yüksek çözünürlüge, çözünme hizina ve istenen içerik tekdüzeligine sahip olan ve ayrica etkili bir proses kullanarak elde edilen, empagliflozin veya tuzlarini ve Iinagliptin veya tuzlarini veya kristalin polimorfun içeren bir farmasötik kompozisyondan olusan gelismis bir farmasötik kompozisyon saglanmasina ihtiyaç vardir. Bulusun Ayrintili Açiklamasi Mevcut bulusun temel amaci, eksipiyanlarin seçiminin yardimiyla istenen içerik tekdüzeligine ve istenen çözünme profiline sahip olan, etkili bir proses kullanan ve ilgili önceki teknige avantajlar getiren, empagliflozin veya tuzlarini ve linagliptin veya tuzlarini veya kristalin polimorfunu içeren bir farmasötik kompozisyon saglamaktir. Düsük dozlu ilaçlarin dozaj formlarindaki içerik tekdüzeligi kalite güvencesi için çok önemlidir. Mevcut bulusun avantajlari daha da önemlidir çünkü homojenlik probleminin, iki etkin madde bir nihai dozaj formuna dahil edildiginde, özellikle miktar bakimindan çok farkli iki etkin madde kullanildiginda ortaya çikma ihtimali daha da fazladir. Gelismis içerik tekdüzeligi, biyoyararlanimda belirgin bir artisa verimli bir sekilde katkida bulunur. Gelismis içerik tekdüzeligi ayrica ilaç maddesi miktarinin çok yüksek olacagi aksi olasi duruma karsi toksisiteyi önlemeye de yardimci olur. Linagliptin, formülasyon prosesi boyunca önemli problemlere yol açabilecek küçük oranlarda kullanilir. Bu, içerik tekdüzelik problemlerine neden olur ve bu da çözünme problemine neden olur. Bu bulusta, sicak eriyik ekstrüzyon prosesinin kullanilmasi, üretim sirasinda Iinagliptin veya eksipiyanlarda kayiplara yol açmayacak homojenlik ve içerik tekdüzeligi saglar. Mevcut bulusun bir düzenlemesine göre, bir farmasötik kompozisyon, empagliflozin veya tuzlarini ve linagliptin veya tuzlarini veya kristalin polimorfuna sahip granülatlari içermekte olup, granülatlar sicak eriyik ekstrüzyonla elde edilir. Mevcut bulusun bir baska düzenlemesine göre, sicak eriyik ekstrüzyonun sonunda, ekstrüdat formunun granüllere dönüstürülmesiyle granüller elde edilir. Mevcut bulusun bir baska düzenlemesine göre, sicak eriyik ekstrüzyon kullanilarak elde edilen ekstrüdatin bir d (0.9) partikül boyutu 250 pm'den az, daha tercihen 200 pm'den azdir. Ekstrüdatin boyutu sasirtici sekilde daha iyi çözünürlük ve stabilite saglar. Bu bulusun bir düzenlemesine göre, empagliflozin veya tuzlarinin toplam miktari, toplam kompozisyonun agirlikça %5.0 ile %30.0'u arasindadir. Bu bulusun bir düzenlemesine göre, empagliflozin veya tuzlarinin toplam miktari, toplam Bu bulusun bir düzenlemesine göre, Iinagliptin veya tuzlarinin veya kristalin polimorfunun toplam miktari, toplam kompozisyonun agirlikça %05 ile %8.0'i arasindadir. Bu bulusun bir düzenlemesine göre, Iinagliptin veya tuzlarinin veya kristalin polimorfunun toplam miktari, toplam kompozisyonun agirlikça %13 ila %60'si veya %20 ile %50'i arasindadir. Empagliflozin, yaklasik 145°C ila 160°C araliginda erime noktalarina sahiptir. Tercihen empagliflozinin erime noktalari 153°C'dir. Linagliptin, yaklasik 198°C ila 206°C araliginda erime noktalarina sahiptir. Tercihen empagliflozinin erime noktalari 202°C'dir. Mevcut bulusun bir düzenlemesine göre, granülatlar ayrica en az bir dolgu maddesi içerir. Uygun dolgu maddeleri, polivinilpirolidon, dibazik kalsiyum fosfat, mikrokristalin selüloz, Iaktoz monohidrat, amonyum aljinat, kalsiyum karbonat, kalsiyum fosfat, kalsiyum fosfat dehidrat, nötr peletler, kalsiyum sülfat, selüloz, selüloz asetat, basilabilir seker, dekstratlar, dekstrin, dekstroz, etilselüloz, fruktoz, gliseril palmitostearat, Iaktoz, mannitol, magnezyum karbonat, magnezyum oksit, maltodekstrin, orta Zincirli trigliseritler, polidekstroz, polimetakrilatlar, simetikon, sodyum aljinat, sodyum klorür, seker küreleri, sülfobütileter beta-talktrin, talk, kitre, trehaloz, ksilitol veya bunlarin karisimlarini içeren gruptan seçilir. Bu bulusun bir düzenlemesine göre, dolgu maddesi, polivinilpirolidon ya da dibazik kalsiyum fosfat ya da bunlarin karisimlaridir. Bu bulusun bir düzenlemesine göre, dolgu maddesinin miktari toplam kompozisyonun agirlikça Bu bulusun bir düzenlemesine göre, dolgu maddesinin miktari toplam kompozisyonun agirlikça Bu bulusun bir düzenlemesine göre farmasötik kompozisyon sunlari içerir; A. Granül miktari, toplam kompozisyonun agirlikça en az %95.0'idir ve granülat sunlari - Empagliflozin veya tuzlari - Linagliptin veya tuzlari veya kristalin polimorfu - En az bir dolgu maddesi B. Farmasötik olarak kabul edilebilir en az bir eksipiyanin miktari, toplam kompozisyonun agirlikça %005 ila %5.0'i arasindadir. Mevcut bulusun bir düzenlemesine göre farmasötik kompozisyon, granülatlar ve glidantlar, lubrikantlar veya bunlarin karisimlarindan olusan gruptan seçilen farmasötik olarak kabul edilebilir en az bir eksipiyan içerir. Uygun glidantlar, koloidal silikon dioksit, polietilen glikol, triasetin, alfa tokoferol, dokusat sodyum, gliseril monooleat, gliseril monostearat, fosfolipidlei, polioksigliseritler, trietil sitrat, tributil sitrat, asetil trietil sitrat, asetil tributil sitrat, butil stearat, stearil alkol, propilen glikol, dietil ftalat, dibutil ftalat, dioktil fosfat, sodyum lauril sülfat, potasyum setilfosfat, etilen glikol distearat, sodyum dodekanoat, dioktil sodyum sülfosüksinat, sodyum stearat, benzalkonyum klorürler, polisorbatlar, poloksamerler veya bunlarin karisimlarini içeren gruptan seçilir. Bu bulusun bir düzenlemesine göre, glidant koloidal silikon dioksittir. Bu bulusun bir düzenlemesine göre, glidantin miktari toplam kompozisyonun agirlikça %0.05 ila %3.0'ü arasindadir. Uygun Iubrikantlar, magnezyum stearat, stearik asit, kalsiyum stearat, çinko stearat, sodyum stearil fumarat, hidrojene hint yagi, hidrojene bitkisel yag, hafif mineral yag, mineral yag, polietilen glikol, sodyum benzoat veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre Iubrikant, magnezyum stearattir. Bu bulusun bir düzenlemesine göre, lubrikantin miktari toplam kompozisyonun agirlikça %002 ila %2.0'si arasindadir. Bu bulusun bir düzenlemesine göre farmasötik kompozisyon, kapsül veya tablet formundadir. Bu bulusun bir düzenlemesine göre, farmasötik kompozisyon, basilmis tabletler, kaplanmis veya kaplanmamis tabletler, çok katmanli tabletler, mini tabletler, iki katmanli tabletler, bukkal tabletler, dil alti tabletler, efervesan tabletler, film kapli tabletler, agizda dagilan tabletler, çignenebilir tablet, dispersiyon tableti, Iozengeler veya pastiller dahil tabletler olarak formüle Bu bulusun bir düzenlemesine göre farmasötik kompozisyon, film kapli tablet olarak formüle Bu bulusun bir düzenlemesine göre farmasötik kompozisyon, kapsül olarak formüle edilir. Sasirtici bir sekilde, sicak eriyik ekstrüzyonda asagidaki adimlar uygulandiginda mükemmel içerik tekdüzelige, iyi akiskanliga sahip olan ve gelismis çözünme gösteren bir farmasötik kompozisyonun elde edilebilecegi bulunmustur, bu nedenle istenen çözünme profili, akiskanlik, içerik tekdüzeligi gözlemlenmistir. Farmasötik kompozisyonun hazirlanmasina yönelik bir proses, asagidaki adimlari içeren empagliflozin veya tuzlarini ve Iinagliptin veya tuzlarini veya kristalin polimorfunu içerir: Empagliflozin, Iinagliptin ve polivinilpirolidonun kuru karistirilmasi, Adim (a)'da hazirlanan karisimin isitilarak bir ekstrüdat olusturulmasi, ) Adim (b)'deki ekstrüdatin sogutulmasi, ) Ekstrüdat formlarinin granüle dönüstürülmesi, Dibazik kalsiyum fosfat ve kolloidal silikon dioksit ilave edilerek karistirilmasi, Magnezyum stearat ilave edilerek karistirilmasi, g) Ardindan, istege bagli olarak tablet olusturmak için basilmasi veya kapsüllere doldurulmasi. Örnek 1: Sicak eriyik ekstrüzyonla hazirlanan bir tablet veya kapsül Bilesenler Miktar (toplam formülasyonun agirlikça %) Empagliflozin 5.0 - 30.0 Linagliptin 0.5 - 8.0 Dibazik kalsiyum fosfat 10.0 - 30.0 Kolloidal silikon dioksit 0.1 - 5.0 Magnezyum stearat 0.05 - 3.0 TOPLAM 100 Örnek 2: Sicak eriyik ekstrüzyonla hazirlanan bir tablet Bilesenler Miktar (toplam formülasyonun agirlikça %) Empagliflozin 16.7 Linagliptin 3.3 Polivinilpirolidon 60.0 Dibazik kalsiyum fosfat 19.3 Kolloidal silikon dioksit 0.6 Magnezyum stearat 0.07 TOPLAM 100 Örnek 3: Sicak eriyik ekstrüzyonla hazirlanan bir tablet Bilesenler Miktar (toplam formülasyonun agirlikça %) Empagliflozin 7.41 Linagliptin 3.70 Polivinilpirolidon 66.67 Dibazik kalsiyum fosfat 21.48 Magnezyum stearat 0.07 TOPLAM 100 Örnek 1 veya 2 veya 3 için bir proses; Empagliflozin, Iinagliptin ve polivinilpirolidonun kuru karistirilmasi, Adim (a)'da hazirlanan karisimin isitilarak bir ekstrüdat olusturulmasi, c) Adim (b)'deki ekstrüdatin sogutulmasi, ) Ekstrüdat formlarinin granüle dönüstürülmesi, Dibazik kalsiyum fosfat ve kolloidal silikon dioksit ilave edilerek karistirilmasi, f) Magnezyum stearat ilave edilerek karistirilmasi, g) Ardindan, istege bagli olarak tablet olusturmak için basilmasi veya kapsüllere doldurulmasi. TR TR DESCRIPTION A PHARMACEUTICAL COMPOSITION CONTAINING EMPAGLIFLOZIN AND LINAGLIPTIN PREPARED BY HOT MEL EXTRUSION Field of the Invention The present invention relates to a pharmaceutical composition comprising empagliflozin or its salts and Iinagliptin or its salts or a granulate having a crystalline polymorph thereof, the granulate being hot melt It is obtained by extrusion. Background of the Invention Diabetes mellitus is a group of disorders of carbohydrate metabolism in which insulin action is reduced or absent due to impaired secretion, decreased insulin activity, or a combination of both factors. There are two main types of diabetes; Type 1 and Type 2: Type 1 diabetes occurs due to damage to the insulin-producing cells (beta cells) of the pancreas. In type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot enter the body's cells to be used as energy. People with type 1 diabetes must use insulin injections to control blood glucose. In type 2 diabetes, the pancreas produces insulin, but it either does not produce enough or insulin cannot perform its function properly. This diabetes is most common in people over the age of 40 and in people who are overweight. Type 2 diabetes can sometimes be controlled with a combination of diet, weight management and exercise. However, treatment may also include oral glucose-lowering medications or insulin injections. Linagliptin is used for type 2 or non-insulin-dependent diabetes. It is a selective, orally administered, xanthine-based dipeptidyl peptidase-4 (DPP-4) inhibitor used as an adjunct to diet and exercise to improve glycemic control. DPP-4 inhibitors work by blocking the action of DPP-4, an enzyme that destroys the hormone incretin. There are two types of incretin hormones in the body called glucagon-like peptide-1 (GLP-i) and glucose-dependent insulinotropic peptide (GIP). These hormones are naturally produced by the body in response to food intake. Their function is to help the body produce more insulin only when needed and to reduce the amount of glucose produced by the liver when it is not needed. Linagliptin works by binding to DPP-4 and preventing it from cleaving GLP-i and GIP. This increases the levels of these hormones in the body, thus increasing their effect on controlling blood sugar. methylquinazolin-2-yl)methyl]-3,7-dihydrO-1H-purine-2,6-dione and its chemical structure is shown in Formula I. Formula I Empagliflozin is a known SGLT2 inhibitor described for the treatment or improvement of glycemic control in patients with type 2 diabetes. The chemical name of empagliflozin is 1-chloro0-4-(3-D-glucopyranos-1-yl)-2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is in Formula II. has been shown. Formula II Empagliflozin tablets in combination with Iinagliptin for oral administration are currently marketed in the United States under the name Glyxambi®, manufactured by Boehringer Ingelheim, and are indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes and as monolayer tablets 1D mg respectively. It is available in two dosage strengths: /5 mg and 25 mg/5 mg. Explains its preparation and use in the treatment of type 1 diabetes and type 2 diabetes. Explain layered pharmaceutical compositions. There are also several patents in the prior art that disclose a pharmaceutical composition comprising empagliflozin or its salts and Iinagliptin or its salts or its crystalline polymorph in oral pharmaceutical dosage forms. There is still a need in the art to provide an improved pharmaceutical composition comprising a pharmaceutical composition comprising empagliflozin or its salts and Iinagliptin or its salts or crystalline polymorphine, having high solubility, dissolution rate and desired content uniformity and also obtained using an efficient process. Detailed Description of the Invention The essential object of the present invention is to provide a pharmaceutical composition comprising empagliflozin or its salts and linagliptin or its salts or its crystalline polymorph, which, with the aid of the selection of excipients, has the desired content uniformity and the desired dissolution profile, uses an efficient process and brings advantages to the relevant prior art. Content uniformity in dosage forms of low-dose drugs is very important for quality assurance. The advantages of the present invention are even more significant because the problem of homogeneity is even more likely to arise when two active substances are incorporated into a final dosage form, especially when two active substances that are very different in quantity are used. The improved content uniformity efficiently contributes to a significant increase in bioavailability. Improved content uniformity also helps prevent toxicity in the unlikely event that the amount of drug substance is too high. Linagliptin is used in small amounts that can cause significant problems throughout the formulation process. This causes content uniformity problems, which in turn causes the dissolution problem. In this invention, the use of the hot melt extrusion process provides homogeneity and content uniformity that will not result in losses of Iinagliptin or excipients during production. According to an embodiment of the present invention, a pharmaceutical composition comprises empagliflozin or its salts and linagliptin or its salts or granulates having its crystalline polymorph, the granulates being obtained by hot melt extrusion. According to another embodiment of the present invention, at the end of hot melt extrusion, granules are obtained by converting the extrudate form into granules. According to another embodiment of the present invention, the extrudate obtained using hot melt extrusion has a d (0.9) particle size of less than 250 pm, more preferably less than 200 pm. The size of the extrudate surprisingly provides better solubility and stability. According to one embodiment of the present invention, the total amount of empagliflozin or its salts is between 5.0% and 30.0% by weight of the total composition. According to one embodiment of this invention, the total amount of empagliflozin or its salts is between 05% and 8.0% by weight of the total composition. According to one embodiment of the present invention, the total amount of Iinagliptin or its salts or crystalline polymorph is between 13% and 60% or 20% and 50% by weight of the total composition. Empagliflozin has melting points ranging from approximately 145°C to 160°C. Preferably, empagliflozin has melting points of 153°C. Linagliptin has melting points ranging from approximately 198°C to 206°C. Preferably, empagliflozin has a melting point of 202°C. According to one embodiment of the present invention, the granulates further include at least one filler. Suitable fillers are polyvinylpyrrolidone, dibasic calcium phosphate, microcrystalline cellulose, lactose monohydrate, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, ethylcellulose. or is selected from the group containing mixtures thereof. According to one embodiment of the present invention, the filler is polyvinylpyrrolidone or dibasic calcium phosphate, or mixtures thereof. According to an embodiment of the present invention, the amount of the filler is the total composition by weight. According to an embodiment of the present invention, the amount of the filler is the total composition by weight. According to an embodiment of the present invention, the pharmaceutical composition includes; A. The amount of granules is at least 95.0% by weight of the total composition and the granulate is - Empagliflozin or its salts - Linagliptin or its salts or its crystalline polymorph - At least one filler B. The amount of at least one pharmaceutically acceptable excipient is 95.0% by weight of the total composition It is between 005 and 5.0%. According to an embodiment of the present invention, the pharmaceutical composition comprises at least one pharmaceutically acceptable excipient selected from the group consisting of granulates and glidants, lubricants, or mixtures thereof. Suitable glidants are colloidal silicon dioxide, polyethylene glycol, triacetin, alpha tocopherol, docusate sodium, glyceryl monooleate, glyceryl monostearate, phospholipids, polyoxyglycerides, triethyl citrate, tributyl citrate, acetyl triethyl citrate, acetyl tributyl citrate, butyl stearate, stearyl alcohol, propylene glycol. , diethyl phthalate, dibutyl phthalate, dioctyl phosphate, sodium lauryl sulfate, potassium cetylphosphate, ethylene glycol distearate, sodium dodecanoate, dioctyl sodium sulfosuccinate, sodium stearate, benzalkonium chlorides, polysorbates, poloxamers, or mixtures thereof. According to one embodiment of the present invention, the glidant is colloidal silicon dioxide. According to one embodiment of the present invention, the amount of glidantin is between 0.05% and 3.0% by weight of the total composition. Suitable lubricants are selected from the group consisting of magnesium stearate, stearic acid, calcium stearate, zinc stearate, sodium stearyl fumarate, hydrogenated castor oil, hydrogenated vegetable oil, light mineral oil, mineral oil, polyethylene glycol, sodium benzoate, or mixtures thereof. According to one embodiment of the present invention, the lubricant is magnesium stearate. According to one embodiment of the present invention, the amount of lubricant is between 0.2% and 2.0% by weight of the total composition. According to one embodiment of the present invention, the pharmaceutical composition is in capsule or tablet form. According to one embodiment of this invention, the pharmaceutical composition includes pressed tablets, coated or uncoated tablets, multilayer tablets, mini-tablets, bilayer tablets, buccal tablets, sublingual tablets, effervescent tablets, film-coated tablets, orodispersible tablets, chewable tablets, dispersion. The pharmaceutical composition according to one embodiment of the present invention is formulated as a film-coated tablet. The pharmaceutical composition according to one embodiment of the present invention is formulated as a capsule. Surprisingly, it was found that when the following steps are applied in hot melt extrusion, a pharmaceutical composition having excellent content uniformity, good flowability and improved dissolution can be obtained, thus the desired dissolution profile, fluidity, content uniformity is observed. A process for the preparation of the pharmaceutical composition includes empagliflozin or its salts and Iinagliptin or its salts or crystalline polymorph, comprising the following steps: dry mixing empagliflozin, Iinagliptin and polyvinylpyrrolidone, heating the mixture prepared in step (a) to form an extrudate, ) cooling of the extrudate, ) Converting the extrudate forms into granules, mixing by adding dibasic calcium phosphate and colloidal silicon dioxide, mixing by adding magnesium stearate, g) Then, optionally, pressing to form tablets or filling into capsules. Example 1: A tablet or capsule prepared by hot melt extrusion Ingredients Amount (% by weight of total formulation) Empagliflozin 5.0 - 30.0 Linagliptin 0.5 - 8.0 Dibasic calcium phosphate 10.0 - 30.0 Colloidal silicon dioxide 0.1 - 5.0 Magnesium stearate 0.05 - 3.0 TOTAL 1 00 Example 2: Hot A tablet prepared by melt extrusion Components Quantity (wt% of total formulation) Empagliflozin 16.7 Linagliptin 3.3 Polyvinylpyrrolidone 60.0 Dibasic calcium phosphate 19.3 Colloidal silicon dioxide 0.6 Magnesium stearate 0.07 TOTAL 100 Example 3: A tablet prepared by hot melt extrusion essenler Amount (% by weight of total formulation) Empagliflozin 7.41 Linagliptin 3.70 Polyvinylpyrrolidone 66.67 Dibasic calcium phosphate 21.48 Magnesium stearate 0.07 TOTAL 100 A process for Example 1 or 2 or 3; Dry mixing of empagliflozin, Iinagliptin and polyvinylpyrrolidone, Forming an extrudate by heating the mixture prepared in step (a), c) Cooling the extrudate in step (b), ) Converting the extrudate forms into granules, Mixing by adding dibasic calcium phosphate and colloidal silicon dioxide, f) ) Adding magnesium stearate and mixing, g) Then, optionally, pressing to form tablets or filling into capsules. TR TR
Claims (1)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2022/051598 WO2023129050A1 (en) | 2021-12-28 | 2022-12-26 | A pharmaceutical composition of empagliflozin and linagliptin processed with hot-melt extrusion |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2021021295A2 true TR2021021295A2 (en) | 2023-07-21 |
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