WO2023234900A1 - A tablet comprising empagliflozin and metformin hydrochloride - Google Patents
A tablet comprising empagliflozin and metformin hydrochloride Download PDFInfo
- Publication number
- WO2023234900A1 WO2023234900A1 PCT/TR2023/050470 TR2023050470W WO2023234900A1 WO 2023234900 A1 WO2023234900 A1 WO 2023234900A1 TR 2023050470 W TR2023050470 W TR 2023050470W WO 2023234900 A1 WO2023234900 A1 WO 2023234900A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- film coated
- coated tablet
- tablet according
- empagliflozin
- hydroxypropyl
- Prior art date
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin hydrochloride Natural products CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 31
- 229960003345 empagliflozin Drugs 0.000 title claims abstract description 26
- 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
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 229960004329 metformin hydrochloride Drugs 0.000 title claims abstract description 16
- 239000000203 mixture Substances 0.000 claims abstract description 40
- 239000007941 film coated tablet Substances 0.000 claims abstract description 31
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims abstract description 15
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims abstract description 15
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims abstract description 13
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims abstract description 13
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims abstract description 13
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims abstract description 13
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000011230 binding agent Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000003826 tablet Substances 0.000 claims abstract description 12
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 18
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 15
- 229960003105 metformin Drugs 0.000 claims description 15
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 11
- 239000000314 lubricant Substances 0.000 claims description 11
- 239000003085 diluting agent Substances 0.000 claims description 10
- 229920002261 Corn starch Polymers 0.000 claims description 9
- 239000008120 corn starch Substances 0.000 claims description 9
- 235000019359 magnesium stearate Nutrition 0.000 claims description 9
- 239000002202 Polyethylene glycol Substances 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000007888 film coating Substances 0.000 claims description 6
- 238000009501 film coating Methods 0.000 claims description 6
- 238000002156 mixing Methods 0.000 claims description 6
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000002904 solvent Substances 0.000 claims description 6
- 239000008187 granular material Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 229920002472 Starch Polymers 0.000 claims description 4
- 239000011248 coating agent Substances 0.000 claims description 4
- 238000000576 coating method Methods 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
- 229960000869 magnesium oxide Drugs 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
- 239000008107 starch Substances 0.000 claims description 4
- 235000019698 starch Nutrition 0.000 claims description 4
- 229940032147 starch Drugs 0.000 claims description 4
- 238000001035 drying Methods 0.000 claims description 3
- 239000000454 talc Substances 0.000 claims description 3
- 229910052623 talc Inorganic materials 0.000 claims description 3
- 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
- GUBGYTABKSRVRQ-DCSYEGIMSA-N Beta-Lactose 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-DCSYEGIMSA-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
- 239000005913 Maltodextrin Substances 0.000 claims description 2
- 229920002774 Maltodextrin Polymers 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
- 229920000168 Microcrystalline cellulose Polymers 0.000 claims description 2
- 235000021355 Stearic acid Nutrition 0.000 claims description 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 description 2
- 229960004977 anhydrous lactose Drugs 0.000 claims description 2
- XAAHAAMILDNBPS-UHFFFAOYSA-L calcium hydrogenphosphate dihydrate Chemical compound O.O.[Ca+2].OP([O-])([O-])=O XAAHAAMILDNBPS-UHFFFAOYSA-L 0.000 claims description 2
- 239000008119 colloidal silica Substances 0.000 claims description 2
- 229940099112 cornstarch Drugs 0.000 claims description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 claims description 2
- VLCINIKIVYNLPT-UHFFFAOYSA-J dicalcium;hydrogen phosphate Chemical compound [Ca+2].[Ca+2].OP(O)([O-])=O.[O-]P([O-])([O-])=O VLCINIKIVYNLPT-UHFFFAOYSA-J 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
- 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
- HCWCAKKEBCNQJP-UHFFFAOYSA-N magnesium orthosilicate Chemical compound [Mg+2].[Mg+2].[O-][Si]([O-])([O-])[O-] HCWCAKKEBCNQJP-UHFFFAOYSA-N 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
- 229940057948 magnesium stearate Drugs 0.000 claims description 2
- 229940035034 maltodextrin Drugs 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
- 229960001855 mannitol Drugs 0.000 claims description 2
- 229940057917 medium chain triglycerides Drugs 0.000 claims description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 claims description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 claims description 2
- 239000008108 microcrystalline cellulose Substances 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
- 229940045902 sodium stearyl fumarate Drugs 0.000 claims description 2
- 239000008117 stearic acid Substances 0.000 claims description 2
- MLCUESNGPCTHAL-UHFFFAOYSA-H tricalcium diphosphate trihydrate Chemical compound O.O.O.[Ca++].[Ca++].[Ca++].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O MLCUESNGPCTHAL-UHFFFAOYSA-H 0.000 claims description 2
- 238000004090 dissolution Methods 0.000 abstract description 9
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 description 18
- 102000004877 Insulin Human genes 0.000 description 9
- 108090001061 Insulin Proteins 0.000 description 9
- 229940125396 insulin Drugs 0.000 description 9
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 5
- 238000009472 formulation Methods 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 239000000126 substance Substances 0.000 description 4
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-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
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 3
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 3
- 239000013543 active substance Substances 0.000 description 3
- 206010012601 diabetes mellitus Diseases 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 210000000496 pancreas Anatomy 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 2
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 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 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
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- 210000004027 cell Anatomy 0.000 description 2
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- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 235000013980 iron oxide Nutrition 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 239000008194 pharmaceutical composition Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 239000007916 tablet composition Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- 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 description 1
- XMSXQFUHVRWGNA-UHFFFAOYSA-N Decamethylcyclopentasiloxane Chemical compound C[Si]1(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O[Si](C)(C)O1 XMSXQFUHVRWGNA-UHFFFAOYSA-N 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 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 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000654 additive Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- 230000003178 anti-diabetic effect Effects 0.000 description 1
- 210000000227 basophil cell of anterior lobe of hypophysis Anatomy 0.000 description 1
- 150000004283 biguanides Chemical group 0.000 description 1
- 230000000903 blocking effect Effects 0.000 description 1
- 230000023852 carbohydrate metabolic process Effects 0.000 description 1
- 235000021256 carbohydrate metabolism Nutrition 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 229940000425 combination drug Drugs 0.000 description 1
- 239000013066 combination product Substances 0.000 description 1
- 229940127555 combination product Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229920001577 copolymer Polymers 0.000 description 1
- 229940086555 cyclomethicone Drugs 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 230000037213 diet Effects 0.000 description 1
- 235000005911 diet Nutrition 0.000 description 1
- 230000003292 diminished effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 239000000975 dye Substances 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 230000010030 glucose lowering effect Effects 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 235000011187 glycerol Nutrition 0.000 description 1
- 208000035474 group of disease Diseases 0.000 description 1
- 238000009776 industrial production Methods 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
- 210000003734 kidney Anatomy 0.000 description 1
- 229960001021 lactose monohydrate Drugs 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 238000002483 medication Methods 0.000 description 1
- WVDDGKGOMKODPV-ZQBYOMGUSA-N phenyl(114C)methanol Chemical compound O[14CH2]C1=CC=CC=C1 WVDDGKGOMKODPV-ZQBYOMGUSA-N 0.000 description 1
- 239000000049 pigment Substances 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 229940002737 synjardy Drugs 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- 210000002700 urine Anatomy 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000037221 weight management Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
-
- 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
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- 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
- 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
- A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
Definitions
- the present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof, the tablet provides pharmacotechnical properties and the desired dissolution profile.
- the present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.
- Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered secretion, decreased insulin activity or a combination of both factors.
- Type 1 diabetes occurs because the insulin-producing cells of the pancreas (beta cells) are damaged.
- Type 1 diabetes the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy.
- People with Type 1 diabetes must use insulin injections to control their blood glucose.
- Type 2 diabetes the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweighed.
- Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
- Metformin is antidiabetics having an orally-administrated biguanide structure.
- Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform.
- Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
- metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
- Empagliflozin is a known SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus.
- the chemical name of empagliflozin is 1 - chloro-4-(3-D-glucopyranos-l -yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is shown in the Formula II.
- Combination product of empagliflozin and metformin hydrochloride is marketed under the trademark Synjardy®.
- the combination is to help control blood glucose in people with T2D.
- Empagliflozin a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney.
- SGLT2 sodium glucose co-transporter-2
- Active ingredients have some disadvantages in the formulation and process.
- the main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times.
- metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile.
- WO2011039337 (Al) application discloses pharmaceutical compositions comprising fixed dose combinations of a SGLT-2 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.
- CN104586834 (A) application discloses a pharmaceutical composition of empagliflozin and metformin, a preparation method and application thereof.
- the composition comprises the following components: i.) empagliflozin; ii.) metformin hydrochloride; and one or more fillers; one or more adhesives; one or more flow aids and one or more lubricants.
- the main object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having the desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
- Another object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having high stability.
- Another object of the present invention is to provide a process for preparing a film coated tablet comprising empagliflozin and metformin hydrochloride.
- the process is a simple, rapid, cost effective, time-saving, and industrially convenient method.
- a film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof.
- the film coated tablet is obtained which provides the desired dissolution profile, and good flowability of the powder/granules.
- This choice of binder eliminates the disadvantages of both active agents and provides an effective tablet formulation.
- the binder is hydroxypropyl methyl cellulose.
- the binder is hydroxypropyl cellulose.
- the amount of binders is 5.0% to 20.0% by weight in the total composition.
- the amount of binders is 5.0% to 13.0% by weight in the total composition.
- the amount of metformin hydrochloride is 70.0% to 90.0% by weight in the total composition.
- the amount of empagliflozin is 0.1% to 5.0% by weight in the total composition.
- the film coated tablet further comprises at least one diluent and at least one glidant/lubricant.
- Suitable diluents are selected from the group comprising corn starch, microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
- the diluent is corn starch.
- the filler provides flowability and compressibility of the powder mixture.
- the amount of diluents is 1.0% to 15.0% by weight in the total composition.
- the amount of diluents is 1.0% to 10.0% by weight in the total composition.
- Suitable glidants/lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.
- the glidant/lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof. These excipients provide the flowability of the powder mixture.
- the amount of glidants/lubricants is 0.2% to 4.0% by weight in the total composition.
- the amount of glidants/lubricants is 0.5% to 2.5% by weight in the total composition.
- the amount of glidants/lubricants used helps to provide the desired flowability and compressibility of tablet.
- the amount of anhydrous colloidal silicon dioxide used helps to provide the desired flowability and compressibility of tablet, the amount of anhydrous colloidal silicon dioxide is 0.1% to 2.0% by weight in the total composition.
- the film coated tablet is coated with at least one film coating agent.
- HPMC-based coating is used.
- Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxides, all kinds of Opadry®, pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.
- the film coated tablet comprises; a) Metformin HCI b) Empagliflozin c) Corn starch d) Hydroxypropyl Cellulose or hydroxypropyl methylcellulose e) Anhydrous colloidal silicon dioxide f) Magnesium stearate
- the film coated tablet of the present invention is prepared wet granulation.
- a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, corn starch and hydroxypropyl Cellulose or hydroxypropyl methylcellulose, b) Granulating the mixture with a solvent, c) Drying the wet granules, d) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, e) Compressing the mixture into the tablet, f) Coating the tablets with film coating agent.
- a solvent is used at wet granulation.
- Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, cyclomethicone or mixtures thereof.
- the solvent is water.
- Example 1 The tablet formulation
- a solvent for example; pure water
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Abstract
The present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof, the tablet provides pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.
Description
A TABLET COMPRISING EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE
Field of the Invention
The present invention relates to a film coated tablet comprising empagliflozin and metformin hydrochloride, wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof, the tablet provides pharmacotechnical properties and the desired dissolution profile. The present invention also relates to a simple, rapid, cost effective, time-saving and industrially convenient method of preparing the tablet.
Background of the Invention
Diabetes mellitus is a group of disorders of carbohydrate metabolism in which the action of insulin is diminished or absent through altered 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 because the insulin-producing cells of the pancreas (beta cells) are damaged. In Type 1 diabetes, the pancreas makes little or no insulin, so sugar cannot get into the body's cells for use as energy. People with Type 1 diabetes must use insulin injections to control their blood glucose. In Type 2 diabetes, the pancreas makes insulin, but it either doesn't produce enough, or the insulin does not work properly. This diabetes occurs most often in people who are over 40 years old and overweighed. Type 2 diabetes may sometimes be controlled with a combination of diet, weight management, and exercise. However, treatment also may include oral glucose-lowering medications or insulin injections.
Metformin is antidiabetics having an orally-administrated biguanide structure. Metformin hydrochloride is a white to off-white crystalline compound and it is freely soluble in water and practically insoluble in acetone, ether and chloroform. Oral doses of metformin are generally recommended in the range of 500 to 2500 mg a day and a single dose may vary from 500 to 850 mg. It is used singly or in combination with sulfonylureas, alpha-glucosidase inhibitors, or insulin.
The chemical name of metformin hydrochloride is 1,1-dimethylbiguanide hydrochloride, has the following chemical structure of Formula I.
Formula I
Empagliflozin is a known SGLT2 inhibitor that is described for the treatment or improvement in glycemic control in patients with type 2 diabetes mellitus. The chemical name of empagliflozin is 1 - chloro-4-(3-D-glucopyranos-l -yl)- 2-[4-((S)-tetrahydrofuran-3-yloxy)-benzyl]-benzene and its chemical structure is shown in the Formula II.
Formula II
Combination product of empagliflozin and metformin hydrochloride is marketed under the trademark Synjardy®. The combination is to help control blood glucose in people with T2D. Empagliflozin, a sodium glucose co-transporter-2 (SGLT2) inhibitor, removes excess glucose through the urine by blocking glucose re-absorption in the kidney.
Active ingredients have some disadvantages in the formulation and process. The main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times. Furthermore, metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile.
WO2011039337 (Al) application discloses pharmaceutical compositions comprising fixed dose combinations of a SGLT-2 inhibitor drug and a partner drug, processes for the preparation thereof, and their use to treat certain diseases.
CN104586834 (A) application discloses a pharmaceutical composition of empagliflozin and metformin, a preparation method and application thereof. The composition comprises the following components: i.) empagliflozin; ii.) metformin hydrochloride; and one or more fillers; one or more adhesives; one or more flow aids and one or more lubricants.
In the prior art, there are also several patents which disclose empagliflozin and metformin hydrochloride in oral pharmaceutical dosage forms. However, because of the dissolution problem of empagliflozin, and the poorly compressible of metformin, an effective formulation and method has not been disclosed.
There still remains a need in the art to provide an improved a film coated tablet comprising empagliflozin and metformin hydrochloride having high solubility, excellent pharmacomechanic
properties and accordingly a high bioavailability and a long-term stability which is also obtained by using an effective process.
Detailed Description of the Invention
The main object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having the desired level of dissolution rate and excellent physicochemical properties, such as flowability, compressibility, homogeneity, and content uniformity which overcomes the above-described problems in the prior art and have additive advantages over them.
Another object of the present invention is to provide a film coated tablet comprising empagliflozin and metformin hydrochloride with having high stability.
Another object of the present invention is to provide a process for preparing a film coated tablet comprising empagliflozin and metformin hydrochloride. The process is a simple, rapid, cost effective, time-saving, and industrially convenient method.
The main problem encountered when preparing formulations comprising empagliflozin is low solubility, leading to difficulties with disintegration and dissolution times. Furthermore, metformin is a very poorly compressible active substance and metformin presents in high amounts in a composition. This causes some problems for examples; homogeneity, flowability and dissolution profile. Therefore, the excipients and process steps used are very important. We found that especially using hydroxypropyl methyl cellulose or hydroxypropyl cellulose eliminated the described above problems.
According to an embodiment of the present invention, a film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof. The film coated tablet is obtained which provides the desired dissolution profile, and good flowability of the powder/granules. This choice of binder eliminates the disadvantages of both active agents and provides an effective tablet formulation.
According to an embodiment of the present invention, the binder is hydroxypropyl methyl cellulose.
According to an embodiment of the present invention, the binder is hydroxypropyl cellulose.
According to an embodiment of the present invention, the amount of binders is 5.0% to 20.0% by weight in the total composition. Preferably, the amount of binders is 5.0% to 13.0% by weight in the total composition.
According to an embodiment of the present invention, the amount of metformin hydrochloride is 70.0% to 90.0% by weight in the total composition.
According to an embodiment of the present invention, the amount of empagliflozin is 0.1% to 5.0% by weight in the total composition.
Encountered while developing formulations is the flowability-problem and compressibility of metformin HCI, which makes the production difficult. It has been observed that this problem is overcome by using at least one diluent.
According to an embodiment of the present invention, the film coated tablet further comprises at least one diluent and at least one glidant/lubricant.
Suitable diluents are selected from the group comprising corn starch, microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
According to an embodiment of the present invention, the diluent is corn starch. The filler provides flowability and compressibility of the powder mixture.
According to an embodiment of the present invention, the amount of diluents is 1.0% to 15.0% by weight in the total composition. Preferably, the amount of diluents is 1.0% to 10.0% by weight in the total composition.
Suitable glidants/lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.
According to an embodiment of the present invention, the glidant/lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof. These excipients provide the flowability of the powder mixture.
According to an embodiment of the present invention, the amount of glidants/lubricants is 0.2% to 4.0% by weight in the total composition. Preferably, the amount of glidants/lubricants is 0.5% to 2.5% by weight in the total composition. The amount of glidants/lubricants used helps to provide the desired flowability and compressibility of tablet. Especially, the amount of anhydrous colloidal silicon dioxide used helps to provide the desired flowability and compressibility of tablet, the amount of anhydrous colloidal silicon dioxide is 0.1% to 2.0% by weight in the total composition.
According to an embodiment of the present invention, the film coated tablet is coated with at least one film coating agent. Especially, HPMC-based coating is used.
Suitable film coating agents are selected from the group comprising polymethacrylates, hydroxypropyl methylcellulose, lactose monohydrate, talc, hydroxypropyl cellulose, polyvinyl alcohol (PVA), polyethylene glycol (PEG), glycerin, polyvinyl alcohol-polyethylene glycol copolymers (Kollicoat® IR), ethylcellulose dispersions (Surelease®), polyvinylprolidone, polyvinylprolidone-vinyl acetate copolymer (PVP-VA), iron oxide yellow, iron oxides, all kinds of Opadry®, pigments, dyes, titanium dioxide, coloring agent or mixtures thereof.
According to an embodiment of the present invention, the film coated tablet comprises; a) Metformin HCI b) Empagliflozin c) Corn starch d) Hydroxypropyl Cellulose or hydroxypropyl methylcellulose e) Anhydrous colloidal silicon dioxide f) Magnesium stearate
The film coated tablet of the present invention is prepared wet granulation.
According to one embodiment of the present invention, a process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, corn starch and hydroxypropyl Cellulose or hydroxypropyl methylcellulose, b) Granulating the mixture with a solvent, c) Drying the wet granules, d) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, e) Compressing the mixture into the tablet, f) Coating the tablets with film coating agent.
According to this embodiment of the present invention, a solvent is used at wet granulation.
Suitable solvents are selected from the group comprising pure water, dichloromethane, 0.1N HCI, methanol, ethanol, isopropyl alcohol, benzyl alcohol, propylene glycol, polyethylene glycol, cyclomethicone or mixtures thereof. Preferably, the solvent is water.
In this present invention, a desired compressibility and a desired content uniformity of the film coated tablet is obtained and it has a simple and low-cost preparation process, in favor of industrial production.
A process for example 1; a) Sieving metformin HCI through 2 mm, b) Mixing Metformin HCI, empagliflozin, corn starch and hydroxypropyl Cellulose or hydroxypropyl methylcellulose, c) Granulating the mixture with a solvent (for example; pure water) d) Sieving the wet granule through 8 mm, e) Drying the wet granules at 50 °C and sieving through 1.5 mm, f) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, g) Compressing the mixture into the tablet, h) Coating the tablets with film coating agent.
Claims
1) A film coated tablet comprises metformin hydrochloride and empagliflozin wherein comprising at least one binder which is hydroxypropyl methyl cellulose or hydroxypropyl cellulose or mixtures thereof.
2) The film coated tablet according to claim 1, wherein the binder is hydroxypropyl methyl cellulose.
3) The film coated tablet according to claim 1, wherein the binder is hydroxypropyl cellulose.
4) The film coated tablet according to claim 1, wherein the amount of binders is 5.0% to 20.0% by weight in the total composition.
5) The film coated tablet according to claim 1, wherein the film coated tablet further comprises at least one diluent and at least one glidant/lubricant.
6) The film coated tablet according to claim 5, wherein diluents are selected from the group comprising corn starch, microcrystalline cellulose, lactose, anhydrous lactose, starch, mannitol, calcium hydrogen phosphate dihydrate, dicalcium hydrogen phosphate anhydrate, calcium phosphate trihydrate, neutral pellets, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides or mixtures thereof.
7) The film coated tablet according to claim 5, wherein the diluent is corn starch.
8) The film coated tablet according to claim 5, wherein the amount of diluents is 1.0% to 15.0% by weight in the total composition.
9) The film coated tablet according to claim 5, wherein glidants/lubricants are selected from the group comprising anhydrous colloidal silicon dioxide, magnesium stearate, sodium stearyl fumarate, magnesium oxide, starch, silicone dioxide, talc, polyethylene glycol, stearic acid, aluminum silicate, magnesium silicate, colloidal silica or mixtures thereof.
10) The film coated tablet according to claim 5, wherein the glidant/lubricant is anhydrous colloidal silicon dioxide or magnesium stearate or mixtures thereof.
11) The film coated tablet according to claim 5, wherein the amount of glidants/lubricants is 0.2% to 4.0% by weight in the total composition.
) The film coated tablet according to claim 1, wherein the film coated tablet is coated with at least one film coating agent which is HPMC-based. ) The film coated tablet according to claim 1, wherein the film coated tablet comprises; a) Metformin HCI b) Empagliflozin c) Corn starch d) Hydroxypropyl Cellulose or hydroxypropyl methylcellulose e) Anhydrous colloidal silicon dioxide f) Magnesium stearate ) A process for the preparation of the film coated tablet comprises the following steps: a) Mixing Metformin HCI, empagliflozin, corn starch and hydroxypropyl Cellulose or hydroxypropyl methylcellulose, b) Granulating the mixture with a solvent, c) Drying the wet granules, d) Adding anhydrous colloidal silicon dioxide and magnesium stearate and then mixing, e) Compressing the mixture into the tablet, f) Coating the tablets with film coating agent.
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TR2022008869 | 2022-05-31 | ||
TR2022/008869 TR2022008869A1 (en) | 2022-05-31 | A TABLET CONTAINING EMPAGLIFLOZIN AND METFORMIN HYDROCHLORIDE |
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Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO2017093419A1 (en) * | 2015-12-04 | 2017-06-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
KR20210084053A (en) * | 2019-12-27 | 2021-07-07 | (주)휴온스 | Pharmaceutical composite formulation comprising empagliflozin and metformin and method for manufacturing the same |
CN114404436A (en) * | 2022-02-24 | 2022-04-29 | 北京百奥药业有限责任公司 | Metformin empagliflozin composition and preparation method thereof |
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2023
- 2023-05-25 WO PCT/TR2023/050470 patent/WO2023234900A1/en unknown
Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2017093419A1 (en) * | 2015-12-04 | 2017-06-08 | Boehringer Ingelheim International Gmbh | Pharmaceutical composition, methods for treating and uses thereof |
KR20210084053A (en) * | 2019-12-27 | 2021-07-07 | (주)휴온스 | Pharmaceutical composite formulation comprising empagliflozin and metformin and method for manufacturing the same |
CN114404436A (en) * | 2022-02-24 | 2022-04-29 | 北京百奥药业有限责任公司 | Metformin empagliflozin composition and preparation method thereof |
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