EP3856162A1 - Pharmazeutische zusammensetzung mit vildagliptin und metformin und verfahren zur herstellung davon - Google Patents
Pharmazeutische zusammensetzung mit vildagliptin und metformin und verfahren zur herstellung davonInfo
- Publication number
- EP3856162A1 EP3856162A1 EP19790134.1A EP19790134A EP3856162A1 EP 3856162 A1 EP3856162 A1 EP 3856162A1 EP 19790134 A EP19790134 A EP 19790134A EP 3856162 A1 EP3856162 A1 EP 3856162A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- metformin
- vildagliptin
- pharmaceutical composition
- pharmaceutically acceptable
- lubricant
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 48
- 229960003105 metformin Drugs 0.000 title claims abstract description 46
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 title claims abstract description 44
- 229960001254 vildagliptin Drugs 0.000 title claims abstract description 43
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 17
- 238000000034 method Methods 0.000 title claims description 31
- 238000002360 preparation method Methods 0.000 title claims description 9
- 150000003839 salts Chemical class 0.000 claims abstract description 18
- 239000007787 solid Substances 0.000 claims abstract description 4
- 239000000203 mixture Substances 0.000 claims description 79
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 29
- 239000008187 granular material Substances 0.000 claims description 28
- 239000000314 lubricant Substances 0.000 claims description 22
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 20
- 238000005550 wet granulation Methods 0.000 claims description 20
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 18
- 230000008569 process Effects 0.000 claims description 17
- 238000002156 mixing Methods 0.000 claims description 16
- 238000007906 compression Methods 0.000 claims description 13
- 230000006835 compression Effects 0.000 claims description 13
- 235000019359 magnesium stearate Nutrition 0.000 claims description 10
- 229920001577 copolymer Polymers 0.000 claims description 7
- 239000003085 diluting agent Substances 0.000 claims description 7
- 239000007884 disintegrant Substances 0.000 claims description 7
- 229940075614 colloidal silicon dioxide Drugs 0.000 claims description 6
- 239000011248 coating agent Substances 0.000 claims description 5
- 238000000576 coating method Methods 0.000 claims description 5
- 238000001035 drying Methods 0.000 claims description 5
- 239000007864 aqueous solution Substances 0.000 claims description 4
- 238000011282 treatment Methods 0.000 abstract description 7
- 208000001072 type 2 diabetes mellitus Diseases 0.000 abstract description 7
- 239000003826 tablet Substances 0.000 description 45
- 238000009472 formulation Methods 0.000 description 39
- 239000011230 binding agent Substances 0.000 description 22
- 238000004519 manufacturing process Methods 0.000 description 18
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 18
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 17
- 229910002012 Aerosil® Inorganic materials 0.000 description 16
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 16
- 238000005469 granulation Methods 0.000 description 13
- 230000003179 granulation Effects 0.000 description 13
- 229940079593 drug Drugs 0.000 description 11
- 239000003814 drug Substances 0.000 description 11
- 238000007907 direct compression Methods 0.000 description 10
- 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 10
- 239000002904 solvent Substances 0.000 description 10
- 229920003083 Kollidon® VA64 Polymers 0.000 description 9
- 239000004480 active ingredient Substances 0.000 description 9
- 239000002552 dosage form Substances 0.000 description 9
- 238000004090 dissolution Methods 0.000 description 8
- 239000000126 substance Substances 0.000 description 8
- 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 7
- 239000012535 impurity Substances 0.000 description 7
- 238000007909 melt granulation Methods 0.000 description 7
- 239000000843 powder Substances 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 6
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 6
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 6
- 239000013543 active substance Substances 0.000 description 6
- 238000013461 design Methods 0.000 description 6
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 6
- 239000004615 ingredient Substances 0.000 description 6
- 238000005461 lubrication Methods 0.000 description 6
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 6
- 239000000047 product Substances 0.000 description 6
- 102000004877 Insulin Human genes 0.000 description 5
- 108090001061 Insulin Proteins 0.000 description 5
- 230000015572 biosynthetic process Effects 0.000 description 5
- 229940088679 drug related substance Drugs 0.000 description 5
- 239000008103 glucose Substances 0.000 description 5
- 229940125396 insulin Drugs 0.000 description 5
- 239000008108 microcrystalline cellulose Substances 0.000 description 5
- 229940016286 microcrystalline cellulose Drugs 0.000 description 5
- 239000002245 particle Substances 0.000 description 5
- 239000007916 tablet composition Substances 0.000 description 5
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 4
- 235000005911 diet Nutrition 0.000 description 4
- 230000037213 diet Effects 0.000 description 4
- 239000007941 film coated tablet Substances 0.000 description 4
- 239000003112 inhibitor Substances 0.000 description 4
- 229920002785 Croscarmellose sodium Polymers 0.000 description 3
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 3
- 229920002472 Starch Polymers 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 230000015556 catabolic process Effects 0.000 description 3
- 238000012512 characterization method Methods 0.000 description 3
- 239000007891 compressed tablet Substances 0.000 description 3
- 238000006731 degradation reaction Methods 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- 239000000945 filler Substances 0.000 description 3
- 238000012395 formulation development Methods 0.000 description 3
- 230000002209 hydrophobic effect Effects 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 3
- 239000000463 material Substances 0.000 description 3
- 238000005457 optimization Methods 0.000 description 3
- 230000000704 physical effect Effects 0.000 description 3
- 229940069328 povidone Drugs 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- 235000019698 starch Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- UOXXTZDTECBLDK-FRWZKJFKSA-N 3-(diaminomethylidene)-1,1-dimethylguanidine (2R)-1-[2-[(3-hydroxy-1-adamantyl)amino]acetyl]pyrrolidine-2-carbonitrile Chemical compound CN(C)C(=N)N=C(N)N.OC12CC3CC(C1)CC(C3)(C2)NCC(=O)N1CCC[C@@H]1C#N UOXXTZDTECBLDK-FRWZKJFKSA-N 0.000 description 2
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 description 2
- 229940123208 Biguanide Drugs 0.000 description 2
- 229920003081 Povidone K 30 Polymers 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 239000000853 adhesive Substances 0.000 description 2
- 230000001070 adhesive effect Effects 0.000 description 2
- 238000013459 approach Methods 0.000 description 2
- 239000001913 cellulose Substances 0.000 description 2
- 235000010980 cellulose Nutrition 0.000 description 2
- 229920002678 cellulose Polymers 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- 239000013066 combination product Substances 0.000 description 2
- 229940127555 combination product Drugs 0.000 description 2
- 239000001767 crosslinked sodium carboxy methyl cellulose Substances 0.000 description 2
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 2
- 239000008121 dextrose Substances 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 229940126534 drug product Drugs 0.000 description 2
- 239000002706 dry binder Substances 0.000 description 2
- 238000007908 dry granulation Methods 0.000 description 2
- 238000007580 dry-mixing Methods 0.000 description 2
- 238000003055 full factorial design Methods 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 229940035752 metformin and vildagliptin Drugs 0.000 description 2
- 229940124531 pharmaceutical excipient Drugs 0.000 description 2
- 239000000825 pharmaceutical preparation Substances 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920003124 powdered cellulose Polymers 0.000 description 2
- 235000019814 powdered cellulose Nutrition 0.000 description 2
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 2
- 238000012545 processing Methods 0.000 description 2
- 230000002035 prolonged effect Effects 0.000 description 2
- 230000004044 response Effects 0.000 description 2
- 125000000467 secondary amino group Chemical group [H]N([*:1])[*:2] 0.000 description 2
- 238000005204 segregation Methods 0.000 description 2
- 238000009491 slugging Methods 0.000 description 2
- 239000007909 solid dosage form Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 235000012222 talc Nutrition 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- ZOBPZXTWZATXDG-UHFFFAOYSA-N 1,3-thiazolidine-2,4-dione Chemical compound O=C1CSC(=O)N1 ZOBPZXTWZATXDG-UHFFFAOYSA-N 0.000 description 1
- -1 3-hydroxy- l-adamantyl Chemical group 0.000 description 1
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 description 1
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- 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 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 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 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 description 1
- 101800000224 Glucagon-like peptide 1 Proteins 0.000 description 1
- 229920002907 Guar gum Polymers 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 206010052341 Impaired insulin secretion Diseases 0.000 description 1
- 229940123993 Incretin mimetic Drugs 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 102000036770 Islet Amyloid Polypeptide Human genes 0.000 description 1
- 108010041872 Islet Amyloid Polypeptide Proteins 0.000 description 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 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 229920003080 Povidone K 25 Polymers 0.000 description 1
- 102100040918 Pro-glucagon Human genes 0.000 description 1
- 229940100389 Sulfonylurea Drugs 0.000 description 1
- 229940123464 Thiazolidinedione Drugs 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 235000010443 alginic acid Nutrition 0.000 description 1
- 229920000615 alginic acid Polymers 0.000 description 1
- 239000003888 alpha glucosidase inhibitor Substances 0.000 description 1
- CEGOLXSVJUTHNZ-UHFFFAOYSA-K aluminium tristearate Chemical compound [Al+3].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CEGOLXSVJUTHNZ-UHFFFAOYSA-K 0.000 description 1
- 229940063655 aluminum stearate Drugs 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 150000004283 biguanides Chemical class 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 1
- 239000008116 calcium stearate Substances 0.000 description 1
- 235000013539 calcium stearate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 238000006243 chemical reaction Methods 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 239000011247 coating layer Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 238000005056 compaction Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 239000000470 constituent Substances 0.000 description 1
- 229920001531 copovidone Polymers 0.000 description 1
- 229960005168 croscarmellose Drugs 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229920006037 cross link polymer Polymers 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 206010012601 diabetes mellitus Diseases 0.000 description 1
- GXGAKHNRMVGRPK-UHFFFAOYSA-N dimagnesium;dioxido-bis[[oxido(oxo)silyl]oxy]silane Chemical compound [Mg+2].[Mg+2].[O-][Si](=O)O[Si]([O-])([O-])O[Si]([O-])=O GXGAKHNRMVGRPK-UHFFFAOYSA-N 0.000 description 1
- 208000016097 disease of metabolism Diseases 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 239000000890 drug combination Substances 0.000 description 1
- 230000009977 dual effect Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000002124 endocrine Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- 239000013020 final formulation Substances 0.000 description 1
- 239000013022 formulation composition Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- 208000004104 gestational diabetes Diseases 0.000 description 1
- 230000004110 gluconeogenesis Effects 0.000 description 1
- 229940095884 glucophage Drugs 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 230000002641 glycemic effect Effects 0.000 description 1
- 239000003979 granulating agent Substances 0.000 description 1
- 239000000665 guar gum Substances 0.000 description 1
- 235000010417 guar gum Nutrition 0.000 description 1
- 229960002154 guar gum Drugs 0.000 description 1
- 230000002440 hepatic effect Effects 0.000 description 1
- 238000009474 hot melt extrusion Methods 0.000 description 1
- 239000012943 hotmelt Substances 0.000 description 1
- 230000007062 hydrolysis Effects 0.000 description 1
- 238000006460 hydrolysis reaction Methods 0.000 description 1
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000010348 incorporation Methods 0.000 description 1
- 230000005764 inhibitory process Effects 0.000 description 1
- 229910052500 inorganic mineral Inorganic materials 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 238000004898 kneading Methods 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000011866 long-term treatment Methods 0.000 description 1
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 1
- 239000001095 magnesium carbonate Substances 0.000 description 1
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 1
- 239000000395 magnesium oxide Substances 0.000 description 1
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 description 1
- 239000000391 magnesium silicate Substances 0.000 description 1
- 229910000386 magnesium trisilicate Inorganic materials 0.000 description 1
- 235000019793 magnesium trisilicate Nutrition 0.000 description 1
- 229940099273 magnesium trisilicate Drugs 0.000 description 1
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical compound [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 235000012054 meals Nutrition 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- 239000000155 melt Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 description 1
- 238000003801 milling Methods 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 239000011812 mixed powder Substances 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 230000005876 negative regulation of fatty acid oxidation Effects 0.000 description 1
- 229940127017 oral antidiabetic Drugs 0.000 description 1
- 210000000496 pancreas Anatomy 0.000 description 1
- 230000007310 pathophysiology Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 230000010399 physical interaction Effects 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 230000000291 postprandial effect Effects 0.000 description 1
- 238000009725 powder blending Methods 0.000 description 1
- 239000012254 powdered material Substances 0.000 description 1
- 208000037821 progressive disease Diseases 0.000 description 1
- 230000001681 protective effect Effects 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 230000000979 retarding effect Effects 0.000 description 1
- 238000009490 roller compaction Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 230000035945 sensitivity Effects 0.000 description 1
- 239000003421 short acting drug Substances 0.000 description 1
- 238000009097 single-agent therapy Methods 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 description 1
- 230000001629 suppression Effects 0.000 description 1
- 239000006188 syrup Substances 0.000 description 1
- 235000020357 syrup Nutrition 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 229920001169 thermoplastic Polymers 0.000 description 1
- 239000004416 thermosoftening plastic Substances 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 238000004078 waterproofing Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
- 238000009736 wetting Methods 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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- 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)
Definitions
- the present invention relates to a solid pharmaceutical formulation of Vildagliptin or a pharmaceutically acceptable salt thereof in combination with Metformin or a pharmaceutically acceptable salt thereof, to be used for the treatment of Type 2 diabetes.
- the main objective of the present invention is to provide a formulation that is stable and robust and it overcomes the difficulties encountered in formulating combination products.
- Diabetes mellitus is a common disorder with higher prevalence in developed countries. It is considered a metabolic disease wherein the patient has high blood sugar level over a prolonged period of time.
- the disease has three different types. Type 1 diabetes, wherein the pancreas fails to produce enough insulin, therefore it requires immediate and life-long treatment with insulin.
- Type 2 diabetes a chronic and progressive disease with a complex pathophysiology involving the dual endocrine defects of insulin resistance and impaired insulin secretion. Typical treatment begins with diet and exercise, however, it will be followed by oral antidiabetic monotherapy, before moving into a combination regime. Most patients find it hard to sufficiently control glycaemia during long-term treatment with diet and exercise alone.
- gestational diabetes occurs when pregnant women develop high blood sugar levels and is treated with diet and exercise and in some cases insulin.
- Drugs of choice for therapy include biguanides, Dipepidyl peptidase-IV (DPP-IV) inhibitors, sulfonylurea, thiazolidinedione, alphaglucosidase inhibitor, amylin analog, glucagon-like peptide- 1 (GLP-l) or incretin mimetic, meglitinide and insulin.
- DPP-IV inhibitors represent a class of agents that are being developed for the treatment or improvement in glycemic control in patients with type 2 diabetes.
- Vildagliptin also known as LAF-237 is the generic name for (S)-l -[(3-hydroxy- l-adamantyl)amino]acetyl-2-cyano-pyrrolidine has been disclosed specifically in US patent no 6,166,063; it was introduced in 2006, it is easy to use and does not require regular glucose monitoring or dose adjustments.
- Vildagliptin has been found to reduce fasting glucose and postprandial glucose excursion in association with significantly reduced HbAu levels. It is well known in the art that DPP-IV inhibitors with primary or secondary amino group show incompatibilities, degradation problems or extraction problems with some excipients especially excipients that have acidic properties.
- Vildagliptin has also a secondary amino group on its chemical structure. In solid dosage forms, it may react with many excipients or impurities of excipients, although it is very stable it has high susceptibility to air and humidity. This leads to formation of impurities and incorporation of undesired components into the composition.
- EP 2468361 discloses a pharmaceutical composition, comprising Vildagliptin granules which are coated with at least one coating layer and one or more than one excipients.
- direct compression is used to develop tablet formulation of DPP-IV inhibitor compounds, especially Vildagliptin or an acid addition salt thereof.
- Metformin has also been widely prescribed for lowering blood glucose in patients with Type 2 diabetes and is marketed in 500, 750, 850 and 1000 mg strengths. However, because it is a short acting drug, metformin requires twice-daily or three- times-daily dosing (500 - 850 mg tab 2-3/day or 1000 mg bid with meals). Metformin is disclosed in U.S. 3,174,901 is currently marketed in the U.S. in the form of its hydrochloride salt (Glucophage ® , BMS), The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art and was disclosed first by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1922, 1790-1794 .
- Metformin increases the sensitivity to insulin in peripheral tissues of the hosts and it is also involved in inhibition of glucose absorption from the intestine, suppression of hepatic gluconeogenesis, and inhibition of fatty acid oxidation.
- Suitable dosage regimens of Metformin include unit doses of 500 mg two to three time's daily and can even be build up to five times daily or 850 mg once or twice daily.
- Combination products offer several advantages. First, they have concentrations for the active agents that are consistently maintained within an optimal therapeutic range for both active agents. Second, combination products have been shown to improve patient compliance. Most healthcare practitioners now agree that within an ageing population, compliance becomes less certain and, therefore, more important. Third, particularly for treatment of Type 2 diabetes where single treatment along with diet and exercise fails quickly a combination product can have more advantages.
- the present invention relates to a combination product comprising Vildagliptin and Metformin that overcomes the difficulties in the manufacturing process of such product, and a process for preparation thereof
- an object of the present invention to provide an immediate release pharmaceutical formulation comprising a combination of Vildagliptin or a pharmaceutically acceptable salt thereof and Metformin or pharmaceutically acceptable salt thereof
- a further object of the present invention is to provide a manufacturing process that is easy and cost effective and overcomes the added problems of impurities due to reaction of Vildagliptin with excipients present in the formulation.
- Metformin granules are formed after granulation with an appropriate binder and Vildagliptin is then added in order to avoid formation of impurities.
- the main objective of the present invention is to provide a composition comprising the combination of Vildagliptin or pharmaceutical acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof, prepared by a suitable manufacturing process in order to obtain a stable and efficacious dosage form with good physicochemical characteristics.
- a process for the preparation of a stable dosage form of Vildagliptin and Metformin comprising the following steps:
- the dry granulation method may be used where one of the constituents, either the drug or the diluent, has sufficient cohesive properties to be tableted.
- the method consists of blending, slugging the ingredients, dry screening, lubrication and compression.
- the wet granulation method is used to convert a powder mixture into granules having suitable flow and cohesive properties for tableting.
- the procedure consists of mixing the powders in a suitable blender followed by adding the granulating solution under shear to the mixed powders to obtain a granulation.
- the damp mass is then screened through a suitable screen and dried by tray drying or fluidized bed drying. Alternately, the wet mass may be dried and passed through a mill.
- the overall process includes weighing, dry powder blending, wet granulating, drying, milling, blending lubrication and compression.
- powders do not have sufficient adhesive or cohesive properties to form hard, strong granules.
- a binder is usually required to bond the powder particles together due to the poor cohesive properties of most powders.
- Heat and moisture sensitive drugs cannot usually be manufactured using wet granulation. The large number of processing steps and time create problems due to high level manufacturing costs.
- Wet granulation has also been known to reduce the compressibility of some pharmaceutical excipients, such as microcrystalline cellulose.
- Direct compression is regarded as a relatively quick process where the powdered materials are compressed directly without changing the physical and chemical properties of the drug.
- the active ingredient(s), direct compression excipients and other auxiliary substances, such as a glidant and lubricant are blended in a twin shell blender or similar low shear apparatus before being compressed into tablets.
- lubricants are usually added to a granulation by gentle mixing. It is also believed that prolonged blending of a lubricant with a granulation can materially affect hardness and disintegration time for the resulting tablets. Excessive blending of lubricants with the granulate ingredients can cause water proofing of the granule and reduces tablet hardness or strength of the compressed tablet. For these reasons, high-shear mixing conditions have not been used to prepare direct compression dosage forms.
- wet granulation provides the material to be compressed with better wetting properties, particularly in the case of hydrophobic drug substances.
- hydrophilic excipients makes the surface of the hydrophobic drug more hydrophilic, reducing disintegration and dissolution problems.
- the content uniformity of the solid dosage form is generally improved with wet granulation because all of the granules usually contain the same amount of drug. easily, the segregation of drug(s) from excipients is avoided.
- Segregation could be a potential problem with direct compression.
- the size and shape of particles comprising the granulate to be compressed are optimized through the wet granulation process. This is because when a dry solid is wet granulated the binder "glues" particles together, so that they agglomerate into spherical granules.
- the size and shape of the resulting tablet should be considered since an easy oral administration to a patient is required, as well as an easy tablet manufacturing process which meets all the herein described requirements.
- the high-dose Vildagliptin and Metformin tablets have to meet all the herein listed requirements with preferably a limited number and amount of pharmaceutical excipients to reduce the size of the tablet.
- Pre-formulation testing was the first step in the development of dosage forms for the drug substance. The physical and chemical properties of the drug substance combined with excipients were investigated. Pre-formulation testing generated useful information in developing stable and bioavailable dosage forms that can be scaled up. Based on compatibility and pre-formulation studies the selected commonly used Ph.Eur grade excipients were shown compatible with the active substance.
- the main objective of the present invention is to develop a robust and stable immediate release film-coated tablet comprising Vildagliptin/Metformin HC1 in two strengths 50/850mg and 50/l000mg respectivelly.
- the excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the APIs.
- Binders such as Hydroxypropylcellulose, Hydroxypropylmethylcellulose Copovidone, vinylpyrrolidone-vinyl acetate copolymer and Povidone were tested in order to promote granules during granulation and to provide mechanical strength to the tablet.
- Colloidal silicon dioxide was tested as glidant to improve the flow property of the formulation due to the reduction of the friction between the particles during granulation and compaction.
- Magnesium Stearate was used in formulations as lubricant to prevent any sticking during compression. Wet (aqueous and solvent) granulation and melt granulation were tested in manufacturing process.
- Formulation trials were performed in order to study the physicochemical properties of the tablets as well as dissolution properties and result in the final drug product with the optimum quality.
- the target characteristics were set to hardness from 150 to 25 ON, disintegration time from 12 ⁇ 0” to 17 ⁇ 0” and dissolution was set to >85% at 30 minutes.
- the preferred formulation of this invention comprises the following: Vildagliptin and Metformin HC1 as the active ingredients, one or more binders, optionally a diluent, one or more lubricants, optionally a disintegrant and a lubricant which is magnesium stearate.
- the excipients have been carefully selected after many optimization steps.
- Binder excipients are formulated to act as an adhesive, to literally“bind together” powders, granules and other dry ingredients to impart to the product the necessary mechanical strength. Binders are added to create a more effective and predictable granule formation.
- pharmaceutically acceptable binders include, but are not limited to, starches; celluloses and derivatives thereof, e.g., vinylpyrrolidone-vinyl acetate copolymer, microcrystalline cellulose, hydroxypropyl cellulose hydroxylethyl cellulose and hydroxylpropylmethyl cellulose; sucrose; dextrose; com syrup; polysaccharides; and gelatin.
- the binder e.g., may be present in an amount from about 10% to about 40% by weight of the composition.
- Polyvinylpyrrolidone VA64 (PVP VA64), also known as Kollidon® VA 64, is a vinylpyrrolidone-vinyl acetate copolymer. It is used in a variety of manufacturing processes such as a dry binder for direct compression, as s granulating agent, as s retarding and as a film forming agent as well as in taste-masking applications. Kollidon® VA 64 can be used as a dry binder for direct compression tableting and as a soluble binder for granulation and it is ideal as a solubilizer in hot-melt extrusion processes because of its excellent binding capacity. Another important property of Kollidon® VA 64 is the plasticity, which distinguishes the products from povidone (e.g.
- Kollidon® 30 This property often gives granules and mixtures that are less susceptible to capping during tableting, and tablets that are less brittle. These properties in total make it an attractive and cost-effective alternative to natural binders. In addition,. Kollidon® VA 64 is especially suitable for processes with higher humidity exposure.
- Kollidon® VA 64 is an excellent binder in wet granulation for the production of tablets and granules, since it is readily soluble in all the usual solvents. It can then be added either as a solution during granulation, or dry to the other ingredients, in which case the solvent is added alone during granulation. Trials so far conducted with both methods, using equal quantities of liquid, produced tablets of much the same hardness. A combination of the two methods, i.e. mixing some of the Kollidon® VA 64 with the active ingredient, and dissolving the rest in the solvent, sometimes gives the best results. This is particularly recommended if the active ingredient does not readily absorb the solvent. Since it is less hygroscopic than povidone (e.g. Kollidon® 25 or Kollidon® 30), Kollidon® VA 64 gives granules that have less tendency to stick to the punches of the tableting machine, when operating under humid conditions.
- povidone e.g. Kollidon® 25 or Kollidon® 30
- Kollidon VA64 as binder showed the best results when used in an amount from about 5% to about 25% by weight of the composition, more preferably from about 10% to about 20%.
- Aerosil ® when added during the external phase protects Vildagliptin and minimizes its degradation. This is most likely due to the formation of a protective film around Vildagliptin and minimization of its interaction with the Metformin granules.
- the preferred amount of Aerosil ® in the present invention is from about 0.1% to about 7% of the total weight of the composition and most preferably from about 1% to about 5% of the total weight of the composition.
- the formulation may contain diluents.
- diluents include, but are not limited to, confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, powdered cellulose, sorbitol, sucrose and talc.
- the filler and/or diluent may be present in an amount from about 15% to about 40% by weight of the composition.
- the preferred diluent is microcrystalline cellulose which is manufactured by the controlled hydrolysis of alpha- cellulose, obtained as a pulp from fibrous plant materials, with dilute mineral acid solutions.
- a disintegrant is also an optional but useful component of the tablet formulation. Disintegrants are included to ensure that the tablet has an acceptable rate of disintegration. One, two, three or more disintegrants can be selected.
- examples of pharmaceutically acceptable disintegrants include, but are not limited to, starches; clays; celluloses; alginates; gums; cross-linked polymers, e.g., cross-linked calcium carboxymethylcellulose and cross-linked sodium carboxymethylcellulose (croscarmellose sodium or croscarmellose); soy polysaccharides; and guar gum, sodium starch glycolate.
- the disintegrant may be present preferably in an amount from about 2% to about 20%, more preferably from about 5% to about 10%, and most preferably from 7% to about 9% by weight of the composition.
- Lubricants are typically added to prevent the tableting materials from sticking to punches, minimize friction during tablet compression and allow for removal of the compressed tablet from the die. Such lubricants are commonly included in the final tablet mix in amounts usually less than 1% by weight.
- the lubricant component may be hydrophobic or hydrophilic. One, two, three or more lubricants can be selected.
- Examples of pharmaceutically acceptable lubricants and pharmaceutically acceptable glidants include, but are not limited to, colloidal silica, magnesium trisilicate, starches, talc, tribasic calcium phosphate, magnesium stearate, aluminum stearate, calcium stearate, magnesium carbonate, magnesium oxide, polyethylene glycol, powdered cellulose and microcrystalline cellulose.
- the lubricant may be present in an amount preferably from about 0.1% to about 5% by weight of the composition and most preferably from about 0.1% to about 2% by weight of the composition.
- Magnesium stearate was the choice for the present invention. It reduces the friction between the die wall and tablet mix during the compression and ejection of the tablets. It helps prevent adhesion of tablets to the punches and dies. Magnesium stearate also aids in the flow of the powder in the hopper and into the die. It has a particle size range of 450-550 microns and a density range of 1.00-1.80 g/mL. It is stable and does not polymerize within the tableting mix.
- the inventors of the invention have surprisingly found that it is possible to formulate a stable pharmaceutical composition comprising a combination of Vildagliptin or pharmaceutically acceptable salt thereof and Metformin or a pharmaceutically acceptable salt thereof, which can exhibit superior chemical and physical stability by wet granulation, a manufacturing process that is easy and cost effective.
- the tablet as described in the present invention is obtained by wet granulation of the Metformin granules in the presence of a binder, drying and subsequent addition of a lubricant and Vildagliptin and optionally at least one pharmaceutically acceptable excipient.
- the tablet as described in the present invention comprises as active ingredients,
- the process for the preparation of a stable dosage form of Vildagliptin and Metformin HC1 comprising the following steps:
- a lubricant which is Magnesium stearate and mixing
- the main objective of the present invention was to develop a robust and stable immediate release film-coated tablet comprising Vildagliptin/Metformin HC1 in two strengths 50/850mg and 50/1000 mg with respect to both active ingredients.
- excipients were selected to enhance dissolution, physicochemical properties and stability of drug substances in the finished dosage form and thus were subjected to compatibility study with the active ingredients.
- Formulation trials were performed in order to study the physicochemical properties of the tablets as well as dissolution properties and result in the final drug product with the optimum quality below.
- compositions 1.2 - 1.4 show a rather stable behavior except from formulation 1.3 with the ethanol granulation where the total impurities after the six months are above the limit. Based upon the stability data and the physical attributes of the studied compositions, the manufacturing process of formulation 1.3 was not further utilized, while the process of formulations 1.2 and 1.4 were qualified as more appropriate for the development.
- melt granulation is a standard and cost-effective manufacturing process that incorporates common raw materials and requires standard equipment.
- melt granulation may require non-typical equipment i.e. hot melt extruder (HME) which means that the potential excipients for such process are limited. For that reason, melt granulation was not further utilized and wet granulation remained as the prevalent manufacturing process
- the next step of the formulation development incorporated the use of alternative excipients (PVP/K30, PVP/VA64, MCC, Aerosil and HPMC) with different proportions in each composition, in order to study any effect on the physical attributes of the final tablet.
- Wet granulation in a high shear granulator performed as the selected manufacturing process to form metformin granulates for all formulations.
- the composition, for each compression mixture categorized by the binder type and the internal phase excipients, is tabulated below (Table 4). Hardness and disintegration time for each formulation after compression and coating were measured and listed in Table 4.
- Formulations 2.5, 2.6 and 2.7 presented the best hardness value in combination with an acceptable disintegration time for a high load drug combination. Flowability of the said formulations 2.5, 2.6 and 2.7 was measured by the Carr’s index and found to be 26, 19 and 23, respectively. In conclusion, PVP/VA64 performed well as a binding agent, to form a Metformin granulate that provides adequate physical properties to the final tablet.
- the in-vitro Vildagliptin and Metformin release from film-coated tablets was evaluated using apparatus II (rotating paddle method) of the USP 2 on a dissolution tester.
- the test for the film- coated tablets was performed at 37 ⁇ 0.5°C with a rotation speed of 100 rpm using as dissolution medium 900 mL of buffer solution at pH 6.8 for 60 mins.
- Formulation 2.6.1 with 8.4% PVP/VA64 and 2% Aerosil showed Metformin and Vildagliptin release rates that were satisfying. Although, Metformin release rate for formulations 3.6.1 and 3.7.1 exhibited similar behaviour, the respective Vildagliptin release rate showed a slower profile.
- the Carr’s index for formulations 2.6.1 and 3.7.1 characterized the bulk flowability as good and for formulation 3.6.1 as poor.
- Example 6 According to the results from the previous experiments the inventors determined that the PVP/VA64 and Aerosil percentages are defined at around 15.5% and 3.4%, respectively. Finally, formulation 4.5 was tested that was manufactured according to these findings shown in table 12.
- the manufacturing process comprises wet granulation of Metformin HC1 with a kneading aqueous solution of PVP/VA64. Then, for the external phase Vildagliptin and Aerosil are added successively and Magnesium Stearate for the lubrication.
- the drug release profile is similar for formulations 4.5 compared to 2.6.1, a fact that underlines the unchangeable in-vitro behaviour even in case of different final tablet weight.
- the 6 months stability data for the final composition 4.5 are shown below in Table 13 and 14. Regarding the final composition 4.5, the stability data are within the specified limits for both active ingredients Table 13. Vildagliptin stability data in zero time and after 6 months for Comp 4.5
- Metformin HC1 and Vildagliptin sustain their crystallinity form after the manufacturing process.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GR20180100438A GR1009644B (el) | 2018-09-25 | 2018-09-25 | Φαρμακευτικο σκευασμα που περιλαμβανει βιλνταγλιπτινη και μετφορμινη και μεθοδος για την παρασκευη αυτου |
PCT/EP2019/025314 WO2020064145A1 (en) | 2018-09-25 | 2019-09-24 | Pharmaceutical composition comprising vildagliptin and metformin and method of preparation thereof |
Publications (1)
Publication Number | Publication Date |
---|---|
EP3856162A1 true EP3856162A1 (de) | 2021-08-04 |
Family
ID=68290196
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19790134.1A Pending EP3856162A1 (de) | 2018-09-25 | 2019-09-24 | Pharmazeutische zusammensetzung mit vildagliptin und metformin und verfahren zur herstellung davon |
Country Status (3)
Country | Link |
---|---|
EP (1) | EP3856162A1 (de) |
GR (1) | GR1009644B (de) |
WO (1) | WO2020064145A1 (de) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TR202009949A1 (tr) * | 2020-06-25 | 2022-01-21 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | Vi̇ldagli̇pti̇n ve metformi̇n hci i̇çeren bi̇r fi̇lm kapli tablet |
WO2022211762A1 (en) * | 2021-03-29 | 2022-10-06 | Sanovel Ilac Sanayi Ve Ticaret Anonim Sirketi | The film coated tablet of vildagliptin and metformin hydrochloride |
CN114886862B (zh) * | 2022-05-17 | 2024-02-02 | 北京悦康科创医药科技股份有限公司 | 一种复方降糖药物制剂及其制备方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3174901A (en) | 1963-01-31 | 1965-03-23 | Jan Marcel Didier Aron Samuel | Process for the oral treatment of diabetes |
CO5150173A1 (es) | 1998-12-10 | 2002-04-29 | Novartis Ag | Compuestos n-(glicilo sustituido)-2-cianopirrolidinas inhibidores de peptidasa de dipeptidilo-iv (dpp-iv) los cuales son efectivos en el tratamiento de condiciones mediadas por la inhibicion de dpp-iv |
LT3366283T (lt) | 2004-01-20 | 2021-12-10 | Novartis Ag | Tiesioginio presavimo formulė ir procesas |
GT200600008A (es) | 2005-01-18 | 2006-08-09 | Formulacion de compresion directa y proceso | |
JOP20180109A1 (ar) * | 2005-09-29 | 2019-01-30 | Novartis Ag | تركيبة جديدة |
PE20140960A1 (es) * | 2008-04-03 | 2014-08-15 | Boehringer Ingelheim Int | Formulaciones que comprenden un inhibidor de dpp4 |
SI2459531T1 (sl) * | 2009-07-31 | 2020-02-28 | Krka, D.D., Novo Mesto | Granulat, ki obsega vildagliptin, in postopek njegove priprave |
TR201010683A1 (tr) | 2010-12-21 | 2012-07-23 | Sanovel İlaç San. Ve Ti̇c. A.Ş. | Vildagliptin formülasyonları. |
WO2014101986A1 (en) * | 2012-12-27 | 2014-07-03 | Zentiva Sağlik Ürünleri San. Ve Tic. A.Ş. | Dry granulation process for producing tablet compositions of metformin and compositions thereof |
SI3086781T1 (sl) * | 2013-12-23 | 2023-12-29 | Krka D. D., Novo Mesto | Farmacevtski sestavek zaviralca dpp-iv v kombinaciji z metforminom |
-
2018
- 2018-09-25 GR GR20180100438A patent/GR1009644B/el active IP Right Grant
-
2019
- 2019-09-24 EP EP19790134.1A patent/EP3856162A1/de active Pending
- 2019-09-24 WO PCT/EP2019/025314 patent/WO2020064145A1/en unknown
Also Published As
Publication number | Publication date |
---|---|
WO2020064145A1 (en) | 2020-04-02 |
GR1009644B (el) | 2019-11-12 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
ES2377572T5 (es) | Formulación que comprende metformina y vildagliptina | |
JP6041919B2 (ja) | 8−[{1−(3,5−ビス−(トリフルオロメチル)フェニル)−エトキシ}−メチル]−8−フェニル−1,7−ジアザ−スピロ[4.5]デカン−2−オンの塩を含む錠剤処方物およびそれから作製される錠剤 | |
AU2010212866B2 (en) | Pharmaceutical composition comprising linagliptin and optionally a SGLT2 inhibitor, and uses thereof | |
JP5826830B2 (ja) | ピオグリタゾンとリナグリプチンを含む医薬製剤 | |
JP4848558B2 (ja) | 塩酸メトホルミン含有速放性錠剤 | |
WO2020064145A1 (en) | Pharmaceutical composition comprising vildagliptin and metformin and method of preparation thereof | |
EP2242483B1 (de) | Raloxifen-zusammensetzung | |
EP3313187B1 (de) | Formulierung mit verzögerter freisetzung und daraus hergestellte tabletten | |
WO2021176096A1 (en) | Pharmaceutical composition comprising sglt2 inhibitor | |
US20220362235A1 (en) | Pharmaceutical compositions of cabozantinib | |
US11590122B2 (en) | Pharmaceutical compositions of cabozantinib | |
US20240131018A1 (en) | Pharmaceutical compositions of cabozantinib | |
US20030104059A1 (en) | Controlled release tablets of metformin | |
WO2021076066A1 (en) | Oral formulations comprising sitagliptin hci monohydrate with improved pharmaceutical characteristics | |
CN103251594B (zh) | 瑞格列奈二甲双胍的片剂 | |
EP3697392B1 (de) | Tabletten mit tamsulosin und solifenacin | |
KR20210045404A (ko) | 다낭성 난소 증후군 치료에 유용한 활성 약학적 성분들의 삼중 조합의 즉시 방출 제제 | |
EP3511001B1 (de) | Pirfenidonhaltige tablette und kapselformulierung | |
CN110913843B (zh) | 药物组合物 | |
WO2021107967A1 (en) | Pharmaceutical compositions of lurasidone | |
EP3691614B1 (de) | Pharmazeutische zusammensetzung mit vildagliptin und verfahren zur herstellung davon | |
US20140044783A1 (en) | Pharmaceutical composition comprising a thiazolidinedione | |
US20090068260A1 (en) | Beta-1-selective adrenoceptor blocking agent compositions and methods for their preparation | |
WO2022042646A1 (zh) | 盐酸鲁拉西酮组合物及其制备方法 | |
WO2023012817A1 (en) | A pharmaceutical composition comprising combination of dapagliflozin and sitagliptin |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: UNKNOWN |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE |
|
PUAI | Public reference made under article 153(3) epc to a published international application that has entered the european phase |
Free format text: ORIGINAL CODE: 0009012 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE |
|
17P | Request for examination filed |
Effective date: 20210422 |
|
AK | Designated contracting states |
Kind code of ref document: A1 Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR |
|
DAV | Request for validation of the european patent (deleted) | ||
DAX | Request for extension of the european patent (deleted) | ||
P01 | Opt-out of the competence of the unified patent court (upc) registered |
Effective date: 20230526 |
|
STAA | Information on the status of an ep patent application or granted ep patent |
Free format text: STATUS: EXAMINATION IS IN PROGRESS |
|
17Q | First examination report despatched |
Effective date: 20240118 |