TR2022010736A2 - ORAL DOSAGE FORMULATIONS CONTAINING EMPAGLIFLOZIN - Google Patents
ORAL DOSAGE FORMULATIONS CONTAINING EMPAGLIFLOZINInfo
- Publication number
- TR2022010736A2 TR2022010736A2 TR2022/010736 TR2022010736A2 TR 2022010736 A2 TR2022010736 A2 TR 2022010736A2 TR 2022/010736 TR2022/010736 TR 2022/010736 TR 2022010736 A2 TR2022010736 A2 TR 2022010736A2
- Authority
- TR
- Turkey
- Prior art keywords
- oral dosage
- empagliflozin
- dosage formulation
- formulation according
- particle size
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 47
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 38
- 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 37
- 238000009472 formulation Methods 0.000 claims abstract description 26
- 239000002245 particle Substances 0.000 claims abstract description 25
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000000945 filler Substances 0.000 claims abstract description 12
- 235000002639 sodium chloride Nutrition 0.000 claims description 18
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 16
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 14
- 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 description 12
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 10
- 229960004977 anhydrous lactose Drugs 0.000 claims description 10
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 10
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 10
- 239000008108 microcrystalline cellulose Substances 0.000 claims description 10
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 8
- 235000019359 magnesium stearate Nutrition 0.000 claims description 8
- 239000003826 tablet Substances 0.000 claims description 7
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 239000007941 film coated tablet Substances 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- 239000000314 lubricant Substances 0.000 claims description 5
- 229920001223 polyethylene glycol Polymers 0.000 claims description 5
- 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 4
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000004375 Dextrin Substances 0.000 claims description 4
- 229920001353 Dextrin Polymers 0.000 claims description 4
- 239000005913 Maltodextrin Substances 0.000 claims description 4
- 229920002774 Maltodextrin Polymers 0.000 claims description 4
- 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 description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims description 4
- 229920002472 Starch Polymers 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
- 239000011248 coating agent Substances 0.000 claims description 4
- 235000019425 dextrin Nutrition 0.000 claims description 4
- 229960001021 lactose monohydrate Drugs 0.000 claims description 4
- 239000000395 magnesium oxide Substances 0.000 claims description 4
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 4
- 235000012245 magnesium oxide Nutrition 0.000 claims description 4
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 4
- 229940035034 maltodextrin Drugs 0.000 claims description 4
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 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
- 238000000576 coating method Methods 0.000 claims description 3
- -1 dextrates Substances 0.000 claims description 3
- 235000000346 sugar Nutrition 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 235000012222 talc Nutrition 0.000 claims description 3
- 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 description 2
- 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 description 2
- OWEGMIWEEQEYGQ-UHFFFAOYSA-N 100676-05-9 Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC2C(OC(O)C(O)C2O)CO)O1 OWEGMIWEEQEYGQ-UHFFFAOYSA-N 0.000 claims description 2
- 241000416162 Astragalus gummifer Species 0.000 claims description 2
- 229920002261 Corn starch Polymers 0.000 claims description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 235000019739 Dicalciumphosphate Nutrition 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 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
- 229930091371 Fructose Natural products 0.000 claims description 2
- 239000005715 Fructose Substances 0.000 claims description 2
- 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 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 claims 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 claims description 2
- GUBGYTABKSRVRQ-PICCSMPSSA-N Maltose Natural products O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@@H]1O[C@@H]1[C@@H](CO)OC(O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-PICCSMPSSA-N 0.000 claims description 2
- 229930195725 Mannitol Natural products 0.000 claims description 2
- 229920000881 Modified starch Polymers 0.000 claims description 2
- 229920001100 Polydextrose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 2
- 229930006000 Sucrose Natural products 0.000 claims 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 claims description 2
- 229920001615 Tragacanth Polymers 0.000 claims description 2
- 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 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 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 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
- 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
- GUBGYTABKSRVRQ-QUYVBRFLSA-N beta-maltose Chemical compound OC[C@H]1O[C@H](O[C@H]2[C@H](O)[C@@H](O)[C@H](O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@@H]1O GUBGYTABKSRVRQ-QUYVBRFLSA-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
- 235000011132 calcium sulphate Nutrition 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 235000010980 cellulose Nutrition 0.000 claims description 2
- 229920002678 cellulose Polymers 0.000 claims description 2
- 239000001913 cellulose Substances 0.000 claims description 2
- 229920002301 cellulose acetate Polymers 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 239000008120 corn starch Substances 0.000 claims description 2
- 229940096516 dextrates Drugs 0.000 claims description 2
- 239000008121 dextrose Substances 0.000 claims description 2
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 claims description 2
- 229910000390 dicalcium phosphate Inorganic materials 0.000 claims description 2
- 229940038472 dicalcium phosphate Drugs 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- 229940009714 erythritol 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
- 229960004667 ethyl cellulose Drugs 0.000 claims description 2
- 239000007888 film coating Substances 0.000 claims description 2
- 238000009501 film coating Methods 0.000 claims description 2
- 229960001031 glucose Drugs 0.000 claims description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 claims description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 claims description 2
- 239000008101 lactose Substances 0.000 claims description 2
- 229960001375 lactose Drugs 0.000 claims description 2
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 claims description 2
- 239000001095 magnesium carbonate Substances 0.000 claims description 2
- 229910000021 magnesium carbonate Inorganic materials 0.000 claims description 2
- 229960001708 magnesium carbonate Drugs 0.000 claims description 2
- 229960000869 magnesium oxide Drugs 0.000 claims description 2
- 239000000391 magnesium silicate Substances 0.000 claims description 2
- 229910052919 magnesium silicate Inorganic materials 0.000 claims description 2
- 235000019792 magnesium silicate Nutrition 0.000 claims description 2
- 229960002160 maltose Drugs 0.000 claims description 2
- 239000000594 mannitol Substances 0.000 claims description 2
- 235000010355 mannitol Nutrition 0.000 claims description 2
- 239000000463 material Substances 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 238000000034 method Methods 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
- 235000013856 polydextrose Nutrition 0.000 claims description 2
- 239000001259 polydextrose Substances 0.000 claims description 2
- 229940035035 polydextrose Drugs 0.000 claims description 2
- 229920000193 polymethacrylate Polymers 0.000 claims description 2
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 claims description 2
- 239000000244 polyoxyethylene sorbitan monooleate Substances 0.000 claims description 2
- 229940068968 polysorbate 80 Drugs 0.000 claims description 2
- 229920000053 polysorbate 80 Polymers 0.000 claims description 2
- 238000003825 pressing Methods 0.000 claims description 2
- 239000000377 silicon dioxide Substances 0.000 claims description 2
- 235000012239 silicon dioxide Nutrition 0.000 claims description 2
- 235000010413 sodium alginate Nutrition 0.000 claims description 2
- 239000000661 sodium alginate Substances 0.000 claims description 2
- 229940005550 sodium alginate Drugs 0.000 claims description 2
- 239000011780 sodium chloride Substances 0.000 claims description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- 239000005720 sucrose Substances 0.000 claims description 2
- 229960004793 sucrose Drugs 0.000 claims description 2
- 229940097346 sulfobutylether-beta-cyclodextrin Drugs 0.000 claims description 2
- 235000010487 tragacanth Nutrition 0.000 claims description 2
- 239000000196 tragacanth Substances 0.000 claims description 2
- 229940116362 tragacanth Drugs 0.000 claims description 2
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 claims description 2
- 229940074410 trehalose Drugs 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
- 239000002552 dosage form Substances 0.000 claims 2
- YKTSYUJCYHOUJP-UHFFFAOYSA-N [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] Chemical compound [O--].[Al+3].[Al+3].[O-][Si]([O-])([O-])[O-] YKTSYUJCYHOUJP-UHFFFAOYSA-N 0.000 claims 1
- 238000010017 direct printing Methods 0.000 claims 1
- 229960002737 fructose Drugs 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
- 238000002360 preparation method Methods 0.000 claims 1
- 238000004519 manufacturing process Methods 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- UQSXHKLRYXJYBZ-UHFFFAOYSA-N Iron oxide Chemical compound [Fe]=O UQSXHKLRYXJYBZ-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 3
- 239000008194 pharmaceutical composition Substances 0.000 description 3
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 239000004349 Polyvinylpyrrolidone-vinyl acetate copolymer Substances 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
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- YKXCWZVUWWQSAV-BTVCFUMJSA-N (2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O YKXCWZVUWWQSAV-BTVCFUMJSA-N 0.000 description 1
- OBWASQILIWPZMG-UHFFFAOYSA-N Empagliflozin Chemical compound OC1C(O)C(O)C(CO)OC1C1=CC=C(Cl)C(CC=2C=CC(OC3COCC3)=CC=2)=C1 OBWASQILIWPZMG-UHFFFAOYSA-N 0.000 description 1
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- 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 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
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- 108090000088 Symporters Proteins 0.000 description 1
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- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
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- 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
- 239000003112 inhibitor Substances 0.000 description 1
- VBMVTYDPPZVILR-UHFFFAOYSA-N iron(2+);oxygen(2-) Chemical class [O-2].[Fe+2] VBMVTYDPPZVILR-UHFFFAOYSA-N 0.000 description 1
- 229940110665 jardiance Drugs 0.000 description 1
- 229960002397 linagliptin Drugs 0.000 description 1
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 239000007935 oral tablet Substances 0.000 description 1
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- 239000000049 pigment Substances 0.000 description 1
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- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 230000003389 potentiating effect Effects 0.000 description 1
- 238000007873 sieving Methods 0.000 description 1
- 229960002668 sodium chloride Drugs 0.000 description 1
- 239000007787 solid Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
Abstract
Mevcut buluş, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir dolgu maddesini içeren oral dozaj formülasyonları ile ilgili olup, burada Empagliflozin veya bunun farmasötik olarak kabul edilebilir tuzu 150 µm'den daha yüksek bir d (0.9) parçacık boyutuna sahiptir.The present invention relates to oral dosage formulations comprising Empagliflozin or a pharmaceutically acceptable salt thereof and at least one filler, wherein the Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) greater than 150 µm.
Description
TARIFNAME EMPAGLIFLOZIN IÇEREN ORAL DOZAJ FORMÜLASYONLARI Bulusun Alani Mevcut bulus, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir dolgu maddesini içeren oral dozaj formülasyonlari ile ilgili olup, Empagliflozin veya bunun farmasötik olarak kabul edilebilir tuzu 150 um'den daha yüksek bir d (0.9) parçacik boyutuna sahiptir. Bulusun Arka Plani Empagliflozin, bir sodyum-glukoz ko-transporter tip 2 (SGLT-Z) potent inhibitörüdür ve bu nedenle tip 2 diyabet tedavisinde kullanilir. Halihazirda tip 2 diyabet tedavisi ve kan sekeri kontrolünün iyilestirilmesi için onaylanmistir. Empagliflozin beyaz ila sarimsi higroskopik olmayan kristalin bir katidir, suda çok az çözünür (pH 1- 7.4), asetonitril ve etanolde az çözünür, metanolde eser miktarda çözünürdür ve toluende pratik olarak çözünmezdir. Empagliflozinin kimyasal adi (15)-1,5-anhidro-1-(4-kloro-3-{4-[(3S)- tetrahidrofuran-3-iloksi]benzil}fenil)-D-glusitol olup, kimyasal yapisi Formül I'de gösterilmistir. Formül I Empagliflozin piyasada bir serbest baz formunda mevcuttur ve Jardiance<® ticari adi altinda 10 mg ve 25 mg kuvvetlerde bir oral tablet olarak satilmaktadir. Ayrica piyasada Metformin ile bir kombinasyon ürünü ve Linagliptin ile bir kombinasyon ürünü olarak mevcuttur. Empagliflozinin üretimi ve sentezi için yöntemleri açiklamistir. Önceki teknikten ve literatürden açikça anlasilacagi gibi, Empagliflozin içerdigi rapor edilmis birkaç farmasötik kompozisyon bulunmaktadir. Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu içeren, iyi içerik tekdüzeligine, gelismis sikistirilabilirlige sahip olan ve güvenli, etkili, kolay üretim yöntemleriyle üretilmis oral dozaj formülasyonlarina yönelik mevcut ve sürekli bir ihtiyaç Bulusun Ayrintili Açiklamasi Mevcut bulusun ana amaci, terapötik olarak etkili bir miktarda Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu içeren, iyi içerik tekdüzeligine sahip olan oral dozaj formülasyonlari saglamaktir. Mevcut bulusun bir diger amaci, gelismis sikistirilabilirlik, akiskanlik ve yüksek stabiliteye sahip olan, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu içeren oral dozaj formülasyonlari saglamaktir. Mevcut bulusun bir diger amaci, basit, kolay, zaman kazandiran ve hizli imalat yöntemleriyle hazirlanan, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu içeren oral dozaj formülasyonlari saglamaktir. Bu bulusun bir düzenlemesine göre, oral dozaj formülasyonlari Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu ve en az bir dolgu maddesini içermekte olup, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu 150 um'den daha yüksek bir d (0.9) parçacik boyutuna sahiptir. Küçük parçaciklar oral dozaj formülasyonlari için önemli olabilir. Teknigin bilinen durumunda, küçük parçaciklar çözünme özelliklerini veya biyoyararlanimi etkilemeleri nedeniyle formülasyonlar için istenen bir seydir. Ancak küçük parçaciklar da formülasyonlari olumsuz etkileyebilir. Küçük parçacik boyutuna sahip Empagliflozinin problemler arz ettigini ve bunu içeren farmasötik kompozisyonlarin, örnegin yapisarak üretilebilirlik problemi gösterdigini ve küçük parçaciklarin farmasötik kompozisyonun içerik tekdüzeligini olumsuz etkiledigini bulduk. Daha da sasirtici bir sekilde, parçacik boyutunun d (0.9) 150 um'den daha yüksek oldugu Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzunu içeren oral dozaj kompozisyonlarinin, mükemmel içerik tekdüzeligi ve yüksek biyoyararlanim sergileyebilecegini bulduk. Asagida tercih edilen aralikta parçacik boyutu dagilimi açiklanmistir. Bu parçacik boyutu seçimi, yukarida açiklanan problemleri ortadan kaldirdi. Burada kullanildigi sekliyle "DX" terimi, bir kompozisyondaki (hacime dayali olarak) parçaciklarin "d90", parçaciklarin hacimce %90'inin daha ince oldugu boyutu ifade eder. Empagliflozin bilesiginin hacimsel ortalama parçacik boyutu, Malvern Mastersizer 2000 lazer kirinim parçacik boyutu analizörü kullanilarak belirlenir. Bu bulusun bir düzenlemesine göre, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu, 150 um'den daha yüksek bir d (0.9) parçacik boyutuna sahiptir. Bu parçacik boyutu, istenen içerik tekdüzeliginin saglanmasina yardimci olur. Bir düzenlemeye göre, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu, 250 um'den daha küçük bir d (0.9) parçacik boyutuna sahiptir. Bu düzenlemeye göre, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu, 150 um arasinda, 230 um ila 250 um arasinda bir d (0.9) parçacik boyutuna sahiptir. Bir düzenlemeye göre, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu, 350 um'den daha küçük bir d (0.9) parçacik boyutuna sahiptir. Bu düzenlemeye göre, Empagliflozin veya bunun farmasötik olarak kabul edilebilir bir tuzu, 250 um arasinda bir d (0.9) parçacik boyutuna sahiptir. Mevcut bulusun bir düzenlemesine göre, Empagliflozin miktari toplam kompozisyonda agirlikça %0.5 ile %25.0 arasindadir. Tercihen, Empagliflozin miktari, toplam kompozisyonda agirlikça %10.0 ile Uygun dolgu maddeleri, laktoz, laktoz monohidrat, spreyle kurutulmus laktoz monohidrat, susuz laktoz, mikrokristalin selüloz, önceden jelatinize edilmis nisasta, mannitol, misir nisastasi, maltodekstrin, dekstrin, dekstroz, eritritol, fruktoz, maltoz, sakaroz, ksilitol, dikalsiyum fosfat, hidroksipropil betadeks, amonyum aljinat, kalsiyum karbonat, kalsiyum fosfat, kalsiyum fosfat dehidrat, nötr peletler, kalsiyum sülfat, selüloz, selüloz asetat, dekstratlar, dekstrin, etilselüloz, gliseril palmitostearat, magnezyum karbonat, magnezyum oksit, maltodekstrin, orta zincirli trigliseritler, polidekstroz, polimetakrilatlar, sodyum aljinat, sodyum klorür, sorbitol, nisasta, seker küreleri, sülfobütileter beta-siklodekstrin, kitre, trehaloz, polisorbat 80 veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, dolgu maddelerinin miktari toplam kompozisyonda agirlikça Mevcut bulusun bir düzenlemesine göre dolgu maddesi mikrokristalin selülozdur. Mevcut bulusun bir düzenlemesine göre dolgu maddesi susuz laktozdur. Mevcut bulusun bir düzenlemesine göre dolgu maddeleri mikrokristalin selüloz ve susuz laktozdur. Mevcut bulusun bir düzenlemesine göre, oral dozaj kompozisyonlari ayrica en az bir glidant/lubrikant Uygun glidantlar/lubrikantlar, susuz kolloidal silikon dioksit, magnezyum stearat, sodyum stearil fumarat, magnezyum oksit, nisasta, silikon dioksit, talk, polietilen glikol, stearik asit, alüminyum silikat, magnezyum silikat, kolloidal silika veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre glidant/lubrikant, susuz kolloidal silikon dioksit veya magnezyum stearat veya bunlarin bir karisimidir. Bu eksipiyanlar karisimin akiskanligini saglar. Bir düzenlemede oral dozaj kompozisyonu, kapsül veya tablet veya film kapli tablet formundadir. Mevcut bulusun oral dozaj formülasyonu bir tablettir, özellikle bir film kapli tablettir ve direk baski ile hazirlanir. Mevcut bulusun bir düzenlemesine göre, oral dozaj formülasyonu sunlari içerir; a) Empagliflozin b) Mikrokristalin Selüloz c) Susuz Laktoz d) Susuz kolloidal silikon dioksit e) Magnezyum stearat f) Kaplama maddesi. Bu düzenlemeye göre, kaplama maddesi, hidroksipropil metil selüloz, hidroksipropil selüloz, polivinil alkol (PVA), polietilen glikol (PEG), gliserin, talk, polivinil alkol-polietilen glikol kopolimerleri (Kollicoat®), polivinilpirolidon, polivinilpirolidon-vinil asetat kopolimeri (PVP-VA), demir oksit sari, demir oksitler, tüm Opadry® türleri, pigmentler, boyalar, titanyum dioksit, boyar madde veya bunlarin karisimlarindan olusan gruptan seçilir. Mevcut bulusun bir düzenlemesine göre, oral dozaj formülasyonunun hazirlanmasina yönelik bir proses sunlari içerir; a) Empagliflozin, mikrokristalin selüloz, susuz laktoz ve susuz kolloidal silikon dioksitin karistirilmasi, b) Karisimin karistirilip elekten geçirilmesi, c) Magnezyum stearat ilave edilerek karistirilmasi, d) Karisimin tabletler halinde basilmasi, e) Tabletlerin film kaplama maddesi ile kaplanmasi. Örnek 1: Empagliflozin içeren film kapli tablet Miktar (toplam formülasyonun Bilesenler agirlikça %) Empagliflozin 0.5-25 Mikrokristalin Selüloz 5-70 Susuz laktoz 5-70 Susuz kolloidal silikon dioksit 0.1-10 Magnezyum stearat 0.1-10 TOPLAM 100 TR TR DESCRIPTION ORAL DOSAGE FORMULATIONS CONTAINING EMPAGLIFLOZIN Field of the Invention The present invention relates to oral dosage formulations containing Empagliflozin or a pharmaceutically acceptable salt thereof and at least one filler, wherein the Empagliflozin or its pharmaceutically acceptable salt has a concentration greater than 150 µm. It has a particle size of (0.9). Background of the Invention Empagliflozin is a potent inhibitor of sodium-glucose co-transporter type 2 (SGLT-Z) and is therefore used in the treatment of type 2 diabetes. It is currently approved to treat type 2 diabetes and improve blood sugar control. Empagliflozin is a white to yellowish non-hygroscopic crystalline solid, slightly soluble in water (pH 1-7.4), slightly soluble in acetonitrile and ethanol, sparingly soluble in methanol, and practically insoluble in toluene. The chemical name of empagliflozin is (15)-1,5-anhydro-1-(4-chloro-3-{4-[(3S)- tetrahydrofuran-3-yloxy]benzyl}phenyl)-D-glucitol and its chemical structure is Formula I It is shown in . Formula I Empagliflozin is commercially available in a free base form and is sold as an oral tablet in 10 mg and 25 mg strengths under the trade name Jardiance<®. It is also available on the market as a combination product with Metformin and a combination product with Linagliptin. Described methods for the production and synthesis of empagliflozin. It is clear from the prior art and literature that there are several pharmaceutical compositions reported to contain Empagliflozin. There is a current and continuing need for oral dosage formulations containing empagliflozin or a pharmaceutically acceptable salt thereof, having good content uniformity, improved compressibility, and produced by safe, effective, easy manufacturing methods. Detailed Description of the Invention The primary object of the present invention is to provide a therapeutically effective amount of To provide oral dosage formulations with good content uniformity containing empagliflozin or a pharmaceutically acceptable salt thereof. It is another object of the present invention to provide oral dosage formulations containing Empagliflozin or a pharmaceutically acceptable salt thereof, having improved compressibility, fluidity and high stability. Another object of the present invention is to provide oral dosage formulations containing Empagliflozin or a pharmaceutically acceptable salt thereof, prepared by simple, easy, time-saving and rapid manufacturing methods. According to one embodiment of the present invention, oral dosage formulations comprise Empagliflozin or a pharmaceutically acceptable salt thereof and at least one filler, the Empagliflozin or a pharmaceutically acceptable salt thereof having a particle size d (0.9) greater than 150 µm. . Small particles may be important for oral dosage formulations. In the prior art, small particles are desirable for formulations because they affect dissolution properties or bioavailability. However, small particles can also negatively affect formulations. We have found that Empagliflozin with a small particle size presents problems and that pharmaceutical compositions containing it exhibit manufacturability problems, for example by sticking, and that small particles negatively affect the content uniformity of the pharmaceutical composition. More surprisingly, we have found that oral dosage compositions containing Empagliflozin or a pharmaceutically acceptable salt thereof with particle size d (0.9) greater than 150 µm can exhibit excellent content uniformity and high bioavailability. Particle size distribution in the preferred range is described below. This choice of particle size eliminated the problems described above. The term "DX" as used herein refers to the "d90" size of the particles in a composition (based on volume) at which 90% of the particles are finer by volume. The volumetric average particle size of empagliflozin compound is determined using a Malvern Mastersizer 2000 laser diffraction particle size analyzer. According to one embodiment of the present invention, Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) greater than 150 µm. This particle size helps ensure the desired content uniformity. According to one embodiment, Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) of less than 250 µm. According to this embodiment, Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) between 230 µm and 250 µm, between 150 µm. According to one embodiment, Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) of less than 350 µm. According to this embodiment, Empagliflozin or a pharmaceutically acceptable salt thereof has a particle size d (0.9) of between 250 µm. According to one embodiment of the present invention, the amount of Empagliflozin is between 0.5% and 25.0% by weight in the total composition. Preferably, the amount of Empagliflozin is 10.0% by weight in the total composition. Suitable fillers include lactose, lactose monohydrate, spray-dried lactose monohydrate, anhydrous lactose, microcrystalline cellulose, pregelatinized starch, mannitol, corn starch, maltodextrin, dextrin, dextrose, erythritol, fructose. , maltose, sucrose, xylitol, dicalcium phosphate, hydroxypropyl betadex, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, neutral pellets, calcium sulfate, cellulose, cellulose acetate, dextrates, dextrin, ethylcellulose, glyceryl palmitostearate, magnesium carbonate, magnesium oxide, maltodextrin, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, or mixtures thereof. According to one embodiment of the present invention, the amount of fillers is by weight in the total composition. According to one embodiment of the present invention, the filler is microcrystalline cellulose. According to one embodiment of the present invention, the filler is anhydrous lactose. According to one embodiment of the present invention, the fillers are microcrystalline cellulose and anhydrous lactose. According to an embodiment of the present invention, oral dosage compositions further comprise at least one glidant/lubricant. Suitable glidants/lubricants include anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicon dioxide, talc, polyethylene glycol, stearic acid, aluminum. silicate, magnesium silicate, colloidal silica or mixtures thereof. According to one embodiment of the present invention, the glidant/lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or a mixture thereof. These excipients ensure the fluidity of the mixture. In one embodiment, the oral dosage composition is in capsule or tablet or film-coated tablet form. The oral dosage formulation of the present invention is a tablet, especially a film-coated tablet, and is prepared by direct compression. According to one embodiment of the present invention, the oral dosage formulation includes; a) Empagliflozin b) Microcrystalline Cellulose c) Anhydrous Lactose d) Anhydrous colloidal silicon dioxide e) Magnesium stearate f) Coating material. According to this regulation, the coating agent includes hydroxypropyl methyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, talc, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat®), polyvinylpyrrolidone, polyvinylpyrrolidone-vinyl acetate copolymer (PVP). -VA), iron oxide yellow, iron oxides, all types of Opadry®, pigments, dyes, titanium dioxide, dyestuff, or mixtures thereof. According to an embodiment of the present invention, a process for preparing an oral dosage formulation includes; a) Mixing empagliflozin, microcrystalline cellulose, anhydrous lactose and anhydrous colloidal silicon dioxide, b) Mixing and sieving the mixture, c) Adding magnesium stearate and mixing, d) Pressing the mixture into tablets, e) Coating the tablets with a film coating agent. Example 1: Film-coated tablet containing empagliflozin Quantity (Components % by weight of the total formulation) Empagliflozin 0.5-25 Microcrystalline Cellulose 5-70 Anhydrous lactose 5-70 Anhydrous colloidal silicon dioxide 0.1-10 Magnesium stearate 0.1-10 TOTAL 100 TR TR
Claims (11)
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/TR2023/050592 WO2024005756A1 (en) | 2022-06-29 | 2023-06-20 | Oral dosage formulations comprising empagliflozin |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| TR2022010736A2 true TR2022010736A2 (en) | 2023-08-21 |
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