WO2024043358A1 - Oral composite formulation comprising evogliptin and metformin and method for preparing same - Google Patents
Oral composite formulation comprising evogliptin and metformin and method for preparing same Download PDFInfo
- Publication number
- WO2024043358A1 WO2024043358A1 PCT/KR2022/012670 KR2022012670W WO2024043358A1 WO 2024043358 A1 WO2024043358 A1 WO 2024043358A1 KR 2022012670 W KR2022012670 W KR 2022012670W WO 2024043358 A1 WO2024043358 A1 WO 2024043358A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- metformin
- evogliptin
- sustained
- release granules
- weight
- Prior art date
Links
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 title claims abstract description 156
- 229960003105 metformin Drugs 0.000 title claims abstract description 138
- LCDDAGSJHKEABN-MLGOLLRUSA-N Evogliptin Chemical compound C1CNC(=O)[C@@H](COC(C)(C)C)N1C(=O)C[C@H](N)CC1=CC(F)=C(F)C=C1F LCDDAGSJHKEABN-MLGOLLRUSA-N 0.000 title claims abstract description 128
- 229950011259 evogliptin Drugs 0.000 title claims abstract description 127
- 239000000203 mixture Substances 0.000 title claims abstract description 40
- 238000000034 method Methods 0.000 title claims abstract description 31
- 238000009472 formulation Methods 0.000 title claims abstract description 21
- 239000002131 composite material Substances 0.000 title claims abstract description 19
- 239000008187 granular material Substances 0.000 claims abstract description 158
- 238000013268 sustained release Methods 0.000 claims abstract description 114
- 239000012730 sustained-release form Substances 0.000 claims abstract description 114
- 238000004090 dissolution Methods 0.000 claims abstract description 53
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 23
- 238000002360 preparation method Methods 0.000 claims description 94
- 239000012729 immediate-release (IR) formulation Substances 0.000 claims description 71
- 150000003839 salts Chemical class 0.000 claims description 34
- 238000004519 manufacturing process Methods 0.000 claims description 27
- OETHQSJEHLVLGH-UHFFFAOYSA-N metformin hydrochloride Chemical compound Cl.CN(C)C(=N)N=C(N)N OETHQSJEHLVLGH-UHFFFAOYSA-N 0.000 claims description 24
- 229960004329 metformin hydrochloride Drugs 0.000 claims description 21
- 239000007884 disintegrant Substances 0.000 claims description 20
- 239000011230 binding agent Substances 0.000 claims description 12
- 239000000314 lubricant Substances 0.000 claims description 12
- 239000003085 diluting agent Substances 0.000 claims description 10
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 10
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 10
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 10
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 7
- 229920002125 Sokalan® Polymers 0.000 claims description 7
- 229960001631 carbomer Drugs 0.000 claims description 7
- 238000007908 dry granulation Methods 0.000 claims description 7
- 238000005550 wet granulation Methods 0.000 claims description 7
- 229920002785 Croscarmellose sodium Polymers 0.000 claims description 6
- 239000000654 additive Substances 0.000 claims description 6
- 229960001681 croscarmellose sodium Drugs 0.000 claims description 6
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 claims description 6
- 229960003943 hypromellose Drugs 0.000 claims description 6
- 229920003145 methacrylic acid copolymer Polymers 0.000 claims description 6
- 229940117841 methacrylic acid copolymer Drugs 0.000 claims description 6
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 claims description 5
- 238000007922 dissolution test Methods 0.000 claims description 5
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 claims description 5
- 239000003086 colorant Substances 0.000 claims description 4
- 229960000913 crospovidone Drugs 0.000 claims description 4
- 239000002270 dispersing agent Substances 0.000 claims description 4
- 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 description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 claims description 4
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 claims description 4
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 3
- 230000000996 additive effect Effects 0.000 claims 2
- 229940090124 dipeptidyl peptidase 4 (dpp-4) inhibitors for blood glucose lowering Drugs 0.000 abstract description 16
- 239000004480 active ingredient Substances 0.000 abstract description 10
- 206010012601 diabetes mellitus Diseases 0.000 abstract description 9
- 238000011282 treatment Methods 0.000 abstract description 7
- 230000001747 exhibiting effect Effects 0.000 abstract description 3
- 229940123208 Biguanide Drugs 0.000 abstract description 2
- 150000004283 biguanides Chemical group 0.000 abstract 1
- 239000003826 tablet Substances 0.000 description 50
- 230000000052 comparative effect Effects 0.000 description 48
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 23
- 238000011156 evaluation Methods 0.000 description 16
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 13
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 13
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 13
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 13
- 235000019359 magnesium stearate Nutrition 0.000 description 12
- 230000000694 effects Effects 0.000 description 9
- RBBXDAJRSNHIJZ-DLDKMZOSSA-N (3R)-4-[(3R)-3-amino-4-(2,4,5-trifluorophenyl)butanoyl]-3-[(2-methylpropan-2-yl)oxymethyl]piperazin-2-one (2R,3R)-2,3-dihydroxybutanedioic acid Chemical compound O[C@H]([C@@H](O)C(O)=O)C(O)=O.CC(C)(C)OC[C@H]1N(CCNC1=O)C(=O)C[C@H](N)Cc1cc(F)c(F)cc1F RBBXDAJRSNHIJZ-DLDKMZOSSA-N 0.000 description 8
- 229920000881 Modified starch Polymers 0.000 description 7
- 230000008901 benefit Effects 0.000 description 7
- 238000002156 mixing Methods 0.000 description 7
- 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 6
- 229930195725 Mannitol Natural products 0.000 description 6
- 239000000594 mannitol Substances 0.000 description 6
- 235000010355 mannitol Nutrition 0.000 description 6
- 230000008569 process Effects 0.000 description 6
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 6
- ZWPRRQZNBDYKLH-VIFPVBQESA-N Gemigliptin Chemical compound C([C@@H](N)CC(=O)N1CC2=C(C(=NC(=N2)C(F)(F)F)C(F)(F)F)CC1)N1CC(F)(F)CCC1=O ZWPRRQZNBDYKLH-VIFPVBQESA-N 0.000 description 5
- 229940000425 combination drug Drugs 0.000 description 5
- 229940079593 drug Drugs 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 229960002458 gemigliptin Drugs 0.000 description 5
- 239000004615 ingredient Substances 0.000 description 5
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 5
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 4
- 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 4
- 230000007246 mechanism Effects 0.000 description 4
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 4
- 239000002994 raw material Substances 0.000 description 4
- 229910052814 silicon oxide Inorganic materials 0.000 description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- 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 3
- LTXREWYXXSTFRX-QGZVFWFLSA-N Linagliptin Chemical compound N=1C=2N(C)C(=O)N(CC=3N=C4C=CC=CC4=C(C)N=3)C(=O)C=2N(CC#CC)C=1N1CCC[C@@H](N)C1 LTXREWYXXSTFRX-QGZVFWFLSA-N 0.000 description 3
- 239000002202 Polyethylene glycol Substances 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 3
- 239000008280 blood Substances 0.000 description 3
- 210000004369 blood Anatomy 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 238000005469 granulation Methods 0.000 description 3
- 230000003179 granulation Effects 0.000 description 3
- 229920001223 polyethylene glycol Polymers 0.000 description 3
- 229960004937 saxagliptin Drugs 0.000 description 3
- QGJUIPDUBHWZPV-SGTAVMJGSA-N saxagliptin Chemical compound C1C(C2)CC(C3)CC2(O)CC13[C@H](N)C(=O)N1[C@H](C#N)C[C@@H]2C[C@@H]21 QGJUIPDUBHWZPV-SGTAVMJGSA-N 0.000 description 3
- 108010033693 saxagliptin Proteins 0.000 description 3
- LNAZSHAWQACDHT-XIYTZBAFSA-N (2r,3r,4s,5r,6s)-4,5-dimethoxy-2-(methoxymethyl)-3-[(2s,3r,4s,5r,6r)-3,4,5-trimethoxy-6-(methoxymethyl)oxan-2-yl]oxy-6-[(2r,3r,4s,5r,6r)-4,5,6-trimethoxy-2-(methoxymethyl)oxan-3-yl]oxyoxane Chemical compound CO[C@@H]1[C@@H](OC)[C@H](OC)[C@@H](COC)O[C@H]1O[C@H]1[C@H](OC)[C@@H](OC)[C@H](O[C@H]2[C@@H]([C@@H](OC)[C@H](OC)O[C@@H]2COC)OC)O[C@@H]1COC LNAZSHAWQACDHT-XIYTZBAFSA-N 0.000 description 2
- 229910002012 Aerosil® Inorganic materials 0.000 description 2
- 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 2
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 2
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 2
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 description 2
- 108010010803 Gelatin Proteins 0.000 description 2
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 2
- 102000004877 Insulin Human genes 0.000 description 2
- 108090001061 Insulin Proteins 0.000 description 2
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-L L-tartrate(2-) Chemical compound [O-]C(=O)[C@H](O)[C@@H](O)C([O-])=O FEWJPZIEWOKRBE-JCYAYHJZSA-L 0.000 description 2
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- RVGRUAULSDPKGF-UHFFFAOYSA-N Poloxamer Chemical compound C1CO1.CC1CO1 RVGRUAULSDPKGF-UHFFFAOYSA-N 0.000 description 2
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 2
- 229920002319 Poly(methyl acrylate) Polymers 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 2
- 239000002253 acid Substances 0.000 description 2
- 150000007513 acids Chemical class 0.000 description 2
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 2
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 2
- CJZGTCYPCWQAJB-UHFFFAOYSA-L calcium stearate Chemical compound [Ca+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O CJZGTCYPCWQAJB-UHFFFAOYSA-L 0.000 description 2
- 235000013539 calcium stearate Nutrition 0.000 description 2
- 239000008116 calcium stearate Substances 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 238000000576 coating method Methods 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 229920001531 copovidone Polymers 0.000 description 2
- 239000003405 delayed action preparation Substances 0.000 description 2
- 230000001419 dependent effect Effects 0.000 description 2
- 235000019700 dicalcium phosphate Nutrition 0.000 description 2
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 2
- 229910021485 fumed silica Inorganic materials 0.000 description 2
- 229920000159 gelatin Polymers 0.000 description 2
- 239000008273 gelatin Substances 0.000 description 2
- 235000019322 gelatine Nutrition 0.000 description 2
- 235000011852 gelatine desserts Nutrition 0.000 description 2
- 229940095884 glucophage Drugs 0.000 description 2
- 239000008103 glucose Substances 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 229940075507 glyceryl monostearate Drugs 0.000 description 2
- FETSQPAGYOVAQU-UHFFFAOYSA-N glyceryl palmitostearate Chemical compound OCC(O)CO.CCCCCCCCCCCCCCCC(O)=O.CCCCCCCCCCCCCCCCCC(O)=O FETSQPAGYOVAQU-UHFFFAOYSA-N 0.000 description 2
- 229940046813 glyceryl palmitostearate Drugs 0.000 description 2
- 229920000591 gum Polymers 0.000 description 2
- 239000008172 hydrogenated vegetable oil Substances 0.000 description 2
- 239000003112 inhibitor Substances 0.000 description 2
- 229940125396 insulin Drugs 0.000 description 2
- 230000003914 insulin secretion Effects 0.000 description 2
- 239000008101 lactose Substances 0.000 description 2
- 229960002397 linagliptin Drugs 0.000 description 2
- 229940057948 magnesium stearate Drugs 0.000 description 2
- 230000010534 mechanism of action Effects 0.000 description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 235000010981 methylcellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 2
- 229920001206 natural gum Polymers 0.000 description 2
- 230000004526 pharmaceutical effect Effects 0.000 description 2
- 230000000144 pharmacologic effect Effects 0.000 description 2
- 229960000502 poloxamer Drugs 0.000 description 2
- 229920001983 poloxamer Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 229960004034 sitagliptin Drugs 0.000 description 2
- MFFMDFFZMYYVKS-SECBINFHSA-N sitagliptin Chemical compound C([C@H](CC(=O)N1CC=2N(C(=NN=2)C(F)(F)F)CC1)N)C1=CC(F)=C(F)C=C1F MFFMDFFZMYYVKS-SECBINFHSA-N 0.000 description 2
- WXMKPNITSTVMEF-UHFFFAOYSA-M sodium benzoate Chemical compound [Na+].[O-]C(=O)C1=CC=CC=C1 WXMKPNITSTVMEF-UHFFFAOYSA-M 0.000 description 2
- 235000010234 sodium benzoate Nutrition 0.000 description 2
- 239000004299 sodium benzoate Substances 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 2
- 239000000600 sorbitol Substances 0.000 description 2
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 230000002459 sustained effect Effects 0.000 description 2
- 239000007939 sustained release tablet Substances 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- WGRQANOPCQRCME-PMACEKPBSA-N teneligliptin Chemical compound O=C([C@H]1NC[C@H](C1)N1CCN(CC1)C1=CC(=NN1C=1C=CC=CC=1)C)N1CCSC1 WGRQANOPCQRCME-PMACEKPBSA-N 0.000 description 2
- 229950000034 teneligliptin Drugs 0.000 description 2
- 239000000811 xylitol Substances 0.000 description 2
- 235000010447 xylitol Nutrition 0.000 description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 2
- 229960002675 xylitol Drugs 0.000 description 2
- XOOUIPVCVHRTMJ-UHFFFAOYSA-L zinc stearate Chemical compound [Zn+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O XOOUIPVCVHRTMJ-UHFFFAOYSA-L 0.000 description 2
- 229940057977 zinc stearate Drugs 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- 206010000060 Abdominal distension Diseases 0.000 description 1
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- 239000005995 Aluminium silicate Substances 0.000 description 1
- 210000002237 B-cell of pancreatic islet Anatomy 0.000 description 1
- XNCOSPRUTUOJCJ-UHFFFAOYSA-N Biguanide Chemical compound NC(N)=NC(N)=N XNCOSPRUTUOJCJ-UHFFFAOYSA-N 0.000 description 1
- KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 description 1
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 description 1
- 206010012735 Diarrhoea Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 description 1
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 description 1
- 101710198884 GATA-type zinc finger protein 1 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
- 229920000084 Gum arabic Polymers 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- 208000013016 Hypoglycemia Diseases 0.000 description 1
- 206010022489 Insulin Resistance Diseases 0.000 description 1
- 206010028813 Nausea Diseases 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 241000978776 Senegalia senegal Species 0.000 description 1
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 description 1
- 235000021355 Stearic acid Nutrition 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 235000012211 aluminium silicate Nutrition 0.000 description 1
- 229940125708 antidiabetic agent Drugs 0.000 description 1
- 239000003472 antidiabetic agent Substances 0.000 description 1
- 230000004596 appetite loss Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000000440 bentonite Substances 0.000 description 1
- 229910000278 bentonite Inorganic materials 0.000 description 1
- 235000012216 bentonite Nutrition 0.000 description 1
- SVPXDRXYRYOSEX-UHFFFAOYSA-N bentoquatam Chemical compound O.O=[Si]=O.O=[Al]O[Al]=O SVPXDRXYRYOSEX-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000036765 blood level Effects 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 230000003915 cell function Effects 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 238000012790 confirmation Methods 0.000 description 1
- 230000003247 decreasing effect Effects 0.000 description 1
- 229940008099 dimethicone Drugs 0.000 description 1
- 239000004205 dimethyl polysiloxane Substances 0.000 description 1
- 235000013870 dimethyl polysiloxane Nutrition 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 230000014101 glucose homeostasis Effects 0.000 description 1
- 229940071676 hydroxypropylcellulose Drugs 0.000 description 1
- 230000002218 hypoglycaemic effect Effects 0.000 description 1
- 238000011221 initial treatment Methods 0.000 description 1
- 210000000936 intestine Anatomy 0.000 description 1
- 229940103445 janumet Drugs 0.000 description 1
- NLYAJNPCOHFWQQ-UHFFFAOYSA-N kaolin Chemical compound O.O.O=[Al]O[Si](=O)O[Si](=O)O[Al]=O NLYAJNPCOHFWQQ-UHFFFAOYSA-N 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 235000021266 loss of appetite Nutrition 0.000 description 1
- 208000019017 loss of appetite Diseases 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- BJEPYKJPYRNKOW-UHFFFAOYSA-N malic acid Chemical compound OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 description 1
- 239000011159 matrix material Substances 0.000 description 1
- 208000030159 metabolic disease Diseases 0.000 description 1
- 230000008693 nausea Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-N octadecanoic acid Chemical compound CCCCCCCCCCCCCCCCCC(O)=O QIQXTHQIDYTFRH-UHFFFAOYSA-N 0.000 description 1
- OQCDKBAXFALNLD-UHFFFAOYSA-N octadecanoic acid Natural products CCCCCCCC(C)CCCCCCCCC(O)=O OQCDKBAXFALNLD-UHFFFAOYSA-N 0.000 description 1
- 229940126701 oral medication Drugs 0.000 description 1
- TWNQGVIAIRXVLR-UHFFFAOYSA-N oxo(oxoalumanyloxy)alumane Chemical compound O=[Al]O[Al]=O TWNQGVIAIRXVLR-UHFFFAOYSA-N 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000008194 pharmaceutical composition Substances 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 229920000435 poly(dimethylsiloxane) Polymers 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229920002050 silicone resin Polymers 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000008117 stearic acid Substances 0.000 description 1
- 230000009747 swallowing Effects 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 239000007916 tablet composition Substances 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 229940127279 trajenta Drugs 0.000 description 1
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 description 1
- 238000011077 uniformity evaluation Methods 0.000 description 1
- 229960001254 vildagliptin Drugs 0.000 description 1
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 1
- 230000004584 weight gain Effects 0.000 description 1
- 235000019786 weight gain Nutrition 0.000 description 1
Images
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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
-
- 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
- A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
- A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
- A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- the present invention relates to a combination preparation containing evogliptin and metformin and a method for producing the same. More specifically, it is a combination preparation consisting of immediate-release granules containing evogliptin and sustained-release granules containing metformin. Due to its bilayer tablet structure, there are problems in manufacturing the combination preparation containing both evogliptin and metformin. It relates to a composite preparation and a manufacturing method thereof that solve the problems of improving content uniformity, size of the preparation, and dissolution rate.
- Diabetes is largely divided into insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes, which accounts for the majority of diabetes patients.
- Metformin a biguanide diabetes treatment, is an oral drug mainly used to treat type 2 diabetes.
- Metformin acts independently of insulin secretion and acts by a mechanism to reduce sugar synthesis in the liver, reduce sugar absorption in the intestines, and increase insulin sensitivity in peripheral tissues.
- metformin hydrochloride tablets are sold under the brand name Glucophage. Glucophage tablets contain 250 mg, 500 mg, or 1000 mg of metformin hydrochloride and are administered within a maximum dosage of 2500 mg per day. Side effects related to metformin include loss of appetite, abdominal bloating, nausea, and diarrhea, and these side effects can be partially avoided by using sustained-release preparations.
- DPP-4 dipeptidyl-peptidase-4
- Evogliptin is (R)-4- ⁇ (R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl ⁇ -3-(t-butoxymethyl)piperazine- 2-membered L-tartrate ((R)-4- ⁇ (R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl ⁇ -3-(t-butoxymethyl)piperazin-2-one It is the common name for L-tartrate and has the following molecular formula.
- Evogliptin tartrate is sold by Dong-A ST under the brand name Suganon.
- Evogliptin acts as an inhibitor of the DPP-4 enzyme and is a diabetes treatment disclosed in Korean Patent No. 10-1054911.
- Evogliptin has a mechanism of action that maintains blood sugar by maintaining high blood levels of GLP-1, which plays an important role in maintaining glucose homeostasis. This mechanism promotes insulin secretion, improves pancreatic beta cell function, and increases weight gain. It has the advantage of controlling blood sugar levels without the side effects of hypoglycemia.
- DPP-4 inhibitors currently on the market include sitagliptin (Korean Patent 10-0606871), vildagliptin (Korean Patent 10-0509311), saxagliptin (Korean Patent 10-0758407), and linagliptin (Korean Patent 10-0758407). 1150449), Gemigliptin (Korean Patent 10-0776623), etc.
- metformin hydrochloride is used as a first-line treatment, and other drugs are administered in combination when blood sugar control cannot be achieved with metformin.
- DPP-4 inhibitors which have a different therapeutic mechanism from metformin, are frequently administered in combination with metformin hydrochloride, and for patients suffering from chronic metabolic diseases, the prescription of combination drugs is increasing to improve the convenience of taking due to the combination of multiple drugs.
- Combination drugs of these DPP-4 inhibitors and metformin hydrochloride include Janumet (MSD), Gavsmet (Novartis), Combiglyze (BMS), Trajenta Duo (Boehringer Ingelheim), Zemimet (LG Life Sciences), and Guardmet. (JW Pharmaceutical) and Tenelia M (Handok) are on the market.
- DPP-4 inhibitors including evogliptin
- metformin is used in both immediate-release and sustained-release formulations.
- the formulation should be designed considering the release characteristics of the two drugs.
- Korean Patent 10-1290925 “Coated Tablet Formulation and Method,” describes a method of coating a tablet core with saxagliptin, a DPP-4 inhibitor.
- Korean Patent Publication KR10-2014-0131950 is a “pharmaceutical composition containing metformin and a DPP-4 inhibitor or SGLT-2 inhibitor” and describes a method of coating linagliptin, a DPP-4 inhibitor, on metformin sustained-release core. I'm doing it.
- Korean Patent Publication No. KR10-2014-0045271 is a “combined preparation containing gemigliptin and metformin and a manufacturing method thereof,” which describes a method for manufacturing a bilayer tablet of Gemigliptin, a DPP-4 inhibitor, and metformin, or Gemiglip on a metformin tablet core. It describes how to coat liptin.
- the above document contains information on a method for manufacturing a bilayer tablet, but unlike the present invention, pregelatinized starch is used to construct a sustained-release matrix of metformin, and the weight percent of pregelatinized starch is most preferably 55% compared to metformin hydrochloride.
- DPP-4 inhibitors consist of 100 mg of sitagliptin, 5 mg of saxagliptin, 50 mg of gemigliptin, and 20 mg of teneligliptin.
- Gemigliptin which consists of a DPP-4 inhibitor and a metformin sustained-release combination preparation and is the only product other than the present invention to contain information on the bilayer tablet manufacturing method, also contains 50 mg of active ingredient, 10 times more than Evogliptin.
- all DPP-4 inhibitors are manufactured as a composite preparation coated on the metformin extended-release core, it can be seen that manufacturing a bilayer tablet of two components with large differences in content is very difficult.
- metformin sustained-release granules were prepared using metformin hydrochloride and a sustained-release agent, and evogliptin immediate-release granules were prepared using evogliptin tartrate and a disintegrant.
- the purpose of the present invention is to develop an effective combination preparation in which evogliptin exhibits immediate release and metformin exhibits sustained release when evogliptin is used together with metformin.
- it is important to ensure content uniformity because evogliptin is contained in a very small amount compared to the total weight of the combination preparation.
- the present invention provides a combination preparation containing evogliptin and metformin, which not only exhibits immediate release of evogliptin without being affected by the sustained release of metformin, but also ensures content uniformity of evogliptin, and a method for producing the same.
- the purpose is to
- a composite preparation consisting of a sustained-release layer containing metformin hydrochloride and a sustained-release agent and an immediate-release layer containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant may be provided.
- the combination preparation may be in the form of a double-layer tablet.
- the combination preparation is a preparation for treating diabetes, especially type 2 diabetes.
- a method for producing a composite formulation consisting of a sustained-release layer containing metformin hydrochloride and a sustained-release agent and an immediate-release layer containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant may be provided.
- a sustained-release layer containing metformin hydrochloride and a sustained-release agent and an immediate-release layer containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant
- the oral combination preparation according to the present invention simultaneously contains metformin and evogliptin, and can reduce the side effects of metformin by delaying the release rate of metformin. Additionally, it can reduce the side effects of evogliptin without reducing the dissolution of the immediate-release layer by the sustained-release layer.
- a double-layer tablet combination preparation containing antidiabetic agents of different mechanisms that can exhibit rapid dissolution it can be usefully used in the effective treatment of diabetes.
- Figure 1 is a graph showing the results of analyzing the dissolution rate of evogliptin in the dissolution test of Examples 5 to 7 and Comparative Example 3.
- Figure 2 is a photograph confirming the thickness of the immediate-release layer of evogliptin through a cross section of the combination preparation prepared according to Example 6 and Comparative Example 7.
- the oral composite preparation of the present invention includes metformin-containing sustained-release granules containing metformin hydrochloride and a sustained-release agent as active ingredients, and Evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant. It may contain liptin-containing granules.
- the combination preparation of the present invention may be administered orally.
- the combination preparation according to the present invention may include metformin-containing sustained-release granules containing metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent.
- the granules include dry granules or wet granules.
- the metformin-containing sustained-release granules contain metformin or a pharmaceutically acceptable salt thereof as an active ingredient.
- pharmaceutically acceptable salt refers to any organic or organic salt of the compound at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of metformin. It refers to an inorganic addition salt and includes, but is not limited to, metformin hydrochloride, succinate, and fumarate.
- the pharmaceutically acceptable salt of metformin may be metformin hydrochloride.
- metformin or a pharmaceutically acceptable salt thereof may be included in an amount of about 500 to 1,000 mg per combination preparation.
- the metformin-containing sustained-release granules may also include a sustained-release agent to allow sustained release of metformin.
- This sustained release agent is characterized by being selected from the group consisting of methacrylic acid copolymer, hypromellose, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose, and mixtures thereof.
- the amount of the sustained-release agent is 11 to 30% by weight, 11 to 28% by weight, 11 to 25% by weight, 12 to 30% by weight, 12 to 28% by weight, 12 to 25% by weight, and 13 to 30% by weight of the total weight of the sustained-release granules.
- Weight % 13 to 28% by weight, 13 to 25% by weight, 14 to 30% by weight, 14 to 28% by weight, 14 to 25% by weight, 15 to 30% by weight, 15 to 28% by weight, 15 to 25% by weight , 16 to 30% by weight, 16 to 28% by weight, 16 to 25% by weight, 17 to 30% by weight, 17 to 28% by weight, 17 to 25% by weight, 18 to 30% by weight, 18 to 28% by weight, 18 It may be included in an amount of from 25% by weight, 19 to 30% by weight, 19 to 28% by weight, 19 to 25% by weight, 20 to 30% by weight, 20 to 28% by weight, or 20 to 25% by weight.
- metformin-containing sustained-release granules may further include pharmaceutically acceptable additives such as lubricants, binders, diluents, etc.
- the lubricant includes calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, and stear. It may be selected from the group consisting of acids, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and combinations thereof, but is not limited thereto. In one embodiment, the lubricant is magnesium stearate. The lubricant may be contained in an amount of 0.1 to 5% by weight based on the total weight of metformin-containing sustained-release granules, but is not limited thereto.
- the binder is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethyl acrylate, natural gum, synthetic gum, copovidone, gelatin and these. It may be selected from the group consisting of combinations, but is not limited thereto. In one embodiment, the binder is hydroxypropyl cellulose. The binder may be contained in an amount of 1 to 10% by weight based on the total weight of metformin-containing sustained-release granules, but is not limited thereto.
- the diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and combinations thereof, but is not limited thereto.
- the diluent may be contained in an amount of 50 to 80% by weight based on the total weight of metformin-containing sustained-release granules.
- the combination preparation according to the present invention may include immediate-release granules containing epogliptin or a pharmaceutically acceptable salt thereof and a disintegrant.
- the pharmaceutically acceptable salt of evogliptin may include tartrate, hydrochloride, citrate, phosphate, acetate, malate, succinate, etc., preferably evogliptin tartrate. It's salt.
- Such evogliptin or a pharmaceutically acceptable salt thereof includes about 2.5 to 10 mg of evogliptin per combination preparation.
- the disintegrant included in the immediate-release granules containing evogliptin along with evogliptin or a pharmaceutically acceptable salt thereof is low-substituted hydroxypropylcellulose, croscarmellose sodium, and crospovidone. And it may be one or more types selected from the group consisting of combinations thereof.
- the amount of the disintegrant is more than 0% by weight, more than 0.1% by weight, more than 0.5% by weight, more than 1% by weight, more than 2% by weight, more than 3% by weight, more than 4% by weight based on the total weight of the immediate-release granules containing evogliptin.
- the upper limit of the amount of the disintegrant is 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, or 20% by weight or less, based on the total weight of the immediate-release granules containing evogliptin. It may be less than % by weight, but is not limited thereto.
- the amount of the disintegrant is 1 to 40% by weight, 1 to 35% by weight, 1 to 30% by weight, 1 to 25% by weight, 1 to 20% by weight, 5%, based on the total weight of the immediate-release granules containing evogliptin.
- the evogliptin-containing immediate-release granules may further include pharmaceutically acceptable additives such as diluents, lubricants, binders, plasticizers, dispersants, colorants, etc.
- the diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, pregelatinized starch, and combinations thereof, but is not limited thereto.
- the diluent may be contained in an amount of 50 to 80% by weight based on the total weight of the evogliptin-containing immediate-release granules.
- the lubricant includes calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, and stear. It may be selected from the group consisting of acids, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and combinations thereof, but is not limited thereto. In one embodiment, the lubricant is magnesium stearate or colloidal silicon dioxide. The lubricant may be contained in an amount of 0.1 to 5% by weight based on the total weight of evogliptin-containing immediate-release granules.
- the binder is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethyl acrylate, natural gum, synthetic gum, copovidone, gelatin and these. It may be selected from the group consisting of combinations, but is not limited thereto. In one embodiment, the binder is hydroxypropyl cellulose. The binder may be contained in an amount of 1 to 10% by weight based on the total weight of the evogliptin-containing immediate-release granules, but is not limited thereto.
- the plasticizer may be selected from the group consisting of polyethylene glycol, glycerin, stearic acid, silica, dimethicone, concentrated glycerin, propylene glycol, and combinations thereof, but is not limited thereto.
- the dispersant may be selected from the group consisting of kaolin, aluminum oxide, titanium oxide, sorbitane sesquiol, silicone resin, gum arabic, ethyl cellulose, calcium carbonate, bentonite, carbomer, and combinations thereof, but is not limited thereto.
- the colorant includes titanium dioxide, red iron oxide, etc., but is not limited thereto.
- the combination preparation contains 5 to 30 parts by weight, 5 to 25 parts by weight, 5 to 20 parts by weight, and 7 to 30 parts by weight of evogliptin-containing granules based on 100 parts by weight of metformin-containing sustained-release granules. parts, 7 to 25 parts by weight, 7 to 20 parts by weight, 10 to 30 parts by weight, 10 to 25 parts by weight, or 10 to 20 parts by weight.
- the thickness of the layer containing the evogliptin-containing granules is not excessively thin, thereby improving not only the content uniformity of the bilayer tablet but also the pharmaceutical effect of evogliptin or its pharmaceutical content. It has the advantage of rapid release of acceptable salts.
- the combination preparation according to the present invention is characterized in that it is in the form of a double-layer tablet.
- the combination preparation according to the present invention contains evogliptin and metformin as active ingredients, which are difficult to formulate as a conventional combination preparation, and is formulated into a bilayer tablet among various combination preparations.
- the content that may be problematic even when formulating a bilayer tablet is included. It is characterized as a preparation that ensures uniformity, etc.
- the combination preparation according to the present invention includes a first layer and a second layer.
- the descriptions of the first layer and the second layer refer to each other to distinguish between different layers (i.e., the first layer refers to any one layer of the two-layer tablet, and the second layer refers to a layer other than the above layer) ), the first layer may be located at the top, but may be located below, and the second layer may be located at the bottom, but may also be located on the upper floor.
- Such a two-layer tablet may contain the metformin-containing sustained-release granules and Evogliptin-containing granules in different layers (for example, the first layer is a sustained-release layer consisting only of metformin-containing sustained-release granules, and the second layer is Evogliptin-containing granules).
- Double-layer tablet form with an immediate-release layer consisting only of liptin-containing granules).
- the two-layer tablet may include a first layer consisting only of metformin-containing sustained-release granules and a second layer containing a mixture of immediate-release granules containing evogliptin and metformin granules.
- the metformin-containing sustained-release granules relative to the total weight of the evogliptin-containing immediate-release granules and metformin-containing sustained-release granules
- the weight ratio of the granules may be less than 20% by weight, less than 15% by weight, for example, 1 to 15% by weight.
- one layer contains immediate-release granules containing evogliptin and sustained-release granules containing metformin in the above ratio, despite mixing the granules, which has the advantage of effectively reducing the size of the tablet, evogliptin or its pharmaceutical It has the advantage that an acceptable salt can exhibit a desired immediate-release dissolution pattern and thus exhibit appropriate pharmacological effects.
- the combination preparation according to the present invention is characterized in that the dissolution rate of evogliptin is more than 80% within 30 minutes during a dissolution test (pH 1.2 solution, 37°C, 900mL, 50rpm).
- the combination preparation according to the present invention has a dissolution rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% in 10 hours during a dissolution test (pH 1.2 solution, 37°C, 900mL, 100rpm). It is characterized by being more than %.
- the combination preparation according to the present invention includes metformin-containing sustained-release granules containing metformin hydrochloride and a sustained-release agent; and evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant, and thus have a bilayer tablet form containing granules containing evogliptin or a pharmaceutically acceptable salt thereof, so that evogliptin or a pharmaceutically acceptable salt thereof has immediate release properties.
- Metformin has the advantage of being able to achieve rapid and sufficient pharmacological effects within the administration period by exhibiting sustained release properties.
- the combination preparation according to the present invention can provide an effective preparation in that content uniformity is ensured even though it contains a very small amount compared to the total weight of the preparation, and the possibility of damage that may occur during the manufacturing and distribution of the preparation is low. It has the advantage of
- the present invention relates to a method for manufacturing an oral combination preparation containing evogliptin and metformin. More specifically, the manufacturing method according to the present invention may be provided as a granule manufacturing and tableting process. In one aspect, the manufacturing method according to the present invention may include the following steps.
- step (c) compressing the metformin-containing sustained-release granules and evogliptin-containing granules prepared in steps (a) and (b), respectively, into double-layer tablets.
- the step (a) is a step of manufacturing metformin-containing sustained-release granules included in the combination preparation of the present invention, and is performed by granulating using metformin or a pharmaceutically acceptable salt thereof as an active ingredient and a sustained-release agent. You can.
- This granulation process can be performed by a wet granulation method or a dry granulation method, and the wet or dry granulation method can be performed by a conventional method well known in the art.
- the individual components included in the granules can be blended to prepare a mixture, and then, if necessary, a granulation solvent such as purified water, ethanol, isopropanol, or a combination thereof can be added and kneaded, and then granulated.
- a granulation solvent such as purified water, ethanol, isopropanol, or a combination thereof can be added and kneaded, and then granulated.
- step (a) granules may be prepared by adding and mixing metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent along with pharmaceutically acceptable additives such as lubricants, binders, and diluents well known in the art. there is.
- Step (b) is a step of manufacturing immediate-release granules containing evogliptin included in the combination preparation of the present invention, which involves granulating using evogliptin or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrant. It can be performed by .
- This granulation process can be performed by a wet granulation method or a dry granulation method, and the wet or dry granulation method can be performed by a conventional method well known in the art.
- step (b) pharmaceutically acceptable additives such as lubricants, binders, diluents, plasticizers, dispersants, colorants, etc. well known in the art are added along with evogliptin or its pharmaceutically acceptable salt and disintegrant. Granules can also be produced by mixing them together.
- pharmaceutically acceptable additives such as lubricants, binders, diluents, plasticizers, dispersants, colorants, etc. well known in the art are added along with evogliptin or its pharmaceutically acceptable salt and disintegrant.
- Granules can also be produced by mixing them together.
- a bilayer tablet is manufactured using metformin-containing sustained-release granules and evogliptin-containing immediate-release granules prepared in steps (a) and (b), respectively. These two-layer tablets can be manufactured by tableting using a commonly known double-layer tablet tablet press.
- the first layer is compressed into tablets using only the metformin-containing sustained-release granules prepared in step (a), and then only the evogliptin-containing granules prepared in step (b) are used on the compressed first layer.
- the composite preparation according to the present invention can be manufactured.
- the first layer is compressed into tablets using only the metformin-containing sustained-release granules prepared in step (a), and then the metformin-containing sustained-release granules prepared in step (a) are placed on the compressed first layer.
- the composite preparation according to the present invention can be prepared by compressing the second layer into tablets using the mixture of evogliptin-containing granules prepared in step (b). At this time, the weight ratio of the metformin-containing sustained-release granules to the total weight of the evogliptin-containing immediate-release granules and the metformin-containing sustained-release granules may be 15% by weight or less, preferably 1 to 15% by weight.
- the evogliptin-containing granules used in the above production method may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the metformin-containing sustained-release granules.
- the metformin-containing sustained-release granules and the evogliptin-containing granules have the above weight ratio, the thickness of the layer containing the evogliptin-containing granules is not excessively thin, thereby improving not only the content uniformity of the bilayer tablet but also the pharmaceutical effect of evogliptin or its pharmaceutical content. It has the advantage of rapid release of acceptable salts.
- Step 1 This is the step of making sustained-release granules containing metformin hydrochloride and can be performed through various processes such as wet granulation and dry granulation.
- Step 2 This is a step of making immediate-release granules containing evogliptin or a pharmaceutically acceptable salt thereof and can be performed through various processes such as wet granulation, dry granulation, and mixing.
- Step 3 It may include manufacturing a double-layer tablet by compressing the sustained-release granules and the immediate-release granules.
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2, respectively, with the composition and weight shown in Table 1 below, and then compressed into double-layer tablets according to step 3 to obtain the preparations of Examples 1 to 4. was manufactured.
- Table 1 the unit of content is all mg.
- Metformin sustained-release granules and Evogliptin immediate-release granules were prepared using the composition and weight of Comparative Examples 1 to 2 in [Table 1] according to Steps 1 and 2, respectively, and then compressed into double-layer tablets according to Step 3 for comparison.
- the formulations of Examples 1 and 2 were prepared.
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2, respectively, with the composition and weight shown in Table 2 below, and then compressed into double-layer tablets according to step 3 to obtain the preparations of Examples 5 to 7. was manufactured.
- Table 2 the unit of content is all mg.
- Example 5 Example 6
- Example 7 Comparative Example 3 metformin sustained release granule metformin hydrochloride 1000 1000 1000 1000 Methacrylic acid copolymer 80 80 80 80 Hydroxypropylcellulose 40 40 40 40 Hypromellose 200 200 200 200 carbomer 55 55 55 55 55
- Evogliptin immediate release granule Evogliptin Tartrate 6.87 6.87 6.87 6.87
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared using the composition and weight of Comparative Example 3 in [Table 2] according to Steps 1 and 2, respectively, and then compressed into double-layer tablets according to Step 3, giving Comparative Example 3. A preparation was prepared.
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in [Table 3] below, and 1-layer and 2-layer granules were prepared according to the ratios in [Table 4], followed by step 3.
- the formulations of Examples 8 to 10 were prepared by tableting into double-layer tablets according to the above. In Table 3, the unit of content is all mg.
- Example 8 Example 9
- Example 10 Comparative Example 4 Comparative Example 5 1st floor Metformin extended-release granules 95% 85% 85% 85% 75% 2nd floor Metformin extended-release granules 5% 15% 15% 15% 25% Evogliptin immediate-release granules 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100% 100%
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in [Table 3], and the first and second layer granules were formed according to the ratios in [Table 4],
- the formulations of Comparative Examples 4 and 5 were prepared by tableting into double-layer tablets according to Step 3.
- Comparative Example 6 was prepared by mixing sustained-release granules and immediate-release granules and compressing them into single tablets.
- Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in Table 5 below, and then compressed into double-layer tablets according to step 3 to prepare the formulations of Examples 11 and 12.
- Table 5 the unit of content is all mg.
- Example 11 Comparative Example 7 metformin sustained release granule metformin hydrochloride 1000 1000 1000 Methacrylic acid copolymer 80 80 80 Hydroxypropylcellulose 40 40 40 Hypromellose 200 200 200 carbomer 55 55 55 55 Magnesium stearate 5 5 5 Evogliptin immediate release granule Evogliptin Tartrate 6.87 6.87 6.87 mannitol 88.2 174.43 55.08 Pregelatinized starch 10.2 20.1 6.4 Low-substituted hydroxypropyl cellulose 10.2 20.1 6.4 Croscarmellose Sodium 17 33.5 10.6 Hydroxypropylcellulose 3.4 6.7 2.1 Colloidal silicon oxide 1.33 2.7 0.8 Magnesium stearate 2.7 5.4 1.7 red iron oxide 0.1 0.2 0.05
- Metformin sustained-release granules and Evogliptin immediate-release granules were prepared according to Steps 1 and 2 using the composition and weight of Comparative Example 7 in [Table 5], and then compressed into double-layer tablets according to Step 3 to prepare the formulation of Comparative Example 7. did.
- Dissolution evaluation of metformin was conducted for Examples 1 to 4 and Comparative Examples 1 and 2. Dissolution evaluation was conducted at pH 1.2, 37°C, 900mL, and 100rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours. The metformin dissolution results of Examples 1 to 4 and Comparative Examples 1 and 2 are shown in Table 6 below.
- Example 1 Example 2
- Example 3 Example 4 Comparative Example 1 Comparative Example 2 1 hours 27.6% 29.1% 28.3% 31.9% 46.7% 49.4% 3 hours 49.9% 50.3% 50.7% 53.8% 70.3% 75.1% 10 hours 89.1% 91.0% 92.5% 93.1% 101.2% 99.7%
- evogliptin The dissolution evaluation of evogliptin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 50 rpm. Evogliptin must exhibit immediate release, so the dissolution rate must be at least 80% within 30 minutes.
- metformin The dissolution evaluation of metformin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 100 rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours.
- Example 5 Example 6
- Example 7 Comparative Example 3 30 minutes dissolution rate (%) 89.4% 92.6% 93.8% 27.5%
- Example 5 Example 6
- Example 7 Comparative Example 3 1 hours 29.1% 28.4% 28.7% 27.9% 3 hours 50.4% 50.1% 51.0% 50.6% 10 hours 91.8% 93.3% 92.9% 92.8%
- the dissolution evaluation of evogliptin was conducted by sampling for 30 minutes in a pH 1.2 solution, 37°C, 900mL, and 50rpm. Evogliptin must exhibit immediate release, so the dissolution rate must be at least 80% within 30 minutes.
- metformin The dissolution evaluation of metformin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 100 rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours.
- Example 5 Example 8.
- Example 9. Example 10. Comparative example 4. Comparative example 5. Comparative example 6. Dissolution (%) 91.3% 87.1% 89.5% 84.6% 63.7% 70.3% 18.9% Content uniformity RSD% 1.37 1.18 0.42 0.53 0.68 0.36 0.31
- Example 5 Example 8
- Example 9 Example 10. Comparative example 4. Comparative example 5. Comparative example 6. 1 hours 28.3% 29.1% 33.6% 31.1% 30.7% 37.1% 31.7% 3 hours 50.1% 51.2% 54.9% 53.8% 51.5% 59.6% 54.0% 10 hours 90.3% 90.4% 93.6% 92.5% 91.1% 95.2% 93.1%
- metformin showed sustained release, but as the ratio of sustained-release granules mixed with evogliptin immediate-release granules increased, dissolution became slightly faster.
- Example 6 Example 11
- Example 12 Comparative Example 7 content (%) 98.9% 97.3% 102.5% 101.2% Content uniformity RSD% 1.49 2.33 1.03 8.79 30 minutes dissolution rate (%) 92.6% 84.9% 94.4% 61.5%
Abstract
The present invention relates to: a composite formulation which is an oral composite composition consisting of evogliptin, that is a diabetes treatment agent and is a DPP-4 inhibitor, and metformin, that is a biguanide diabetes treatment agent, and which comprises rapid-release granules containing evogliptin exhibiting rapid release, and sustained-release granules containing metformin exhibiting sustained release; and a method for preparing same. The composite formulation, according to the present invention, was prepared in the form of a double-layer tablet by using the rapid-release granules containing evogliptin and granules containing metformin. Although the content of evogliptin used as an active ingredient in the composite formulation is only a trace amount of 0.5% by weight, the content is uniform, a high dissolution rate is exhibited, and metformin, which is the other active ingredient, is slowly released.
Description
본 발명은 에보글립틴 및 메트포르민을 포함하는 복합제제 및 그의 제조방법에 관한 것이다. 보다 상세하게는, 에보글립틴을 포함하는 속방성 과립 및 메트포르민을 포함하는 서방성 과립으로 이루어진 복합제제로서, 이층정 구조를 가짐으로 인해 에보글립틴과 메트포르민을 동시에 포함하는 복합제제의 제조시 문제될 수 있는 함량 균일성, 제제의 크기 및 용출율 개선의 문제를 해소한 복합제제 및 이의 제조방법에 관한 것이다.The present invention relates to a combination preparation containing evogliptin and metformin and a method for producing the same. More specifically, it is a combination preparation consisting of immediate-release granules containing evogliptin and sustained-release granules containing metformin. Due to its bilayer tablet structure, there are problems in manufacturing the combination preparation containing both evogliptin and metformin. It relates to a composite preparation and a manufacturing method thereof that solve the problems of improving content uniformity, size of the preparation, and dissolution rate.
당뇨병은 크게 인슐린 의존형 제 1형 당뇨병과 전체 당뇨병 환자의 대부분을 차지하는 인슐린 비의존형 제 2형 당뇨병으로 나뉜다. 비구아나이드계 당뇨병 치료제인 메트포르민은 제 2형 당뇨병 치료에 주로 사용되는 경구용 약물이다.Diabetes is largely divided into insulin-dependent type 1 diabetes and non-insulin-dependent type 2 diabetes, which accounts for the majority of diabetes patients. Metformin, a biguanide diabetes treatment, is an oral drug mainly used to treat type 2 diabetes.
메트포르민은 인슐린 분비와는 무관하게 작용하며, 간에서의 당 합성을 감소시키고, 장에서의 당 흡수를 감소시키며, 말초조직에서 인슐린 감수성을 증가시키는 기전으로 작용한다. 현재 메트포르민은 염산염의 정제 형태로 글루코파지라는 상품명 등으로 시판되고 있으며, 글루코파지 정제는 250mg, 500mg 또는 1000mg 의 메트포르민 염산염을 함유하고 있으며, 1일 최대 2500mg 의 최대 용량 범위 내에서 투여된다. 메트포르민 관련한 부작용은 식욕감퇴, 복부팽만감, 구역, 설사 등이 있으며, 이러한 부작용은 서방성 제제를 이용함으로써 부분적으로 피할 수 있다.Metformin acts independently of insulin secretion and acts by a mechanism to reduce sugar synthesis in the liver, reduce sugar absorption in the intestines, and increase insulin sensitivity in peripheral tissues. Currently, metformin hydrochloride tablets are sold under the brand name Glucophage. Glucophage tablets contain 250 mg, 500 mg, or 1000 mg of metformin hydrochloride and are administered within a maximum dosage of 2500 mg per day. Side effects related to metformin include loss of appetite, abdominal bloating, nausea, and diarrhea, and these side effects can be partially avoided by using sustained-release preparations.
한편, 디펩티딜-펩티다제-4(DPP-4) 효소의 저해제인 화합물은 당뇨병, 특히 2형 당뇨병 치료에 유용한 약제로 각광받고 있다. 예를 들어 이는 WO 제97/40832호, WO 제98/19998호, 미국 특허 5,939,560, 문헌[참고 : Bioorg. Med. Chem. Lett., 6(10), 1163 - 1166 (1996) 및 Bioorg. Med. Chem. Lett., 6(22), 2745 - 2748 (1996)]에서 확인할 수 있다.Meanwhile, compounds that are inhibitors of the dipeptidyl-peptidase-4 (DPP-4) enzyme are attracting attention as useful drugs for treating diabetes, especially type 2 diabetes. For example, this can be found in WO 97/40832, WO 98/19998, US Patent 5,939,560, Bioorg. Med. Chem. Lett., 6(10), 1163 - 1166 (1996) and Bioorg. Med. Chem. Lett., 6(22), 2745 - 2748 (1996)].
에보글립틴은 (R)-4-{(R)-3-아미노-4-(2,4,5-트리플루오로페닐)-부타노일}-3-(t-부톡시메틸)피페라진-2-원 L-타르타르산염 ((R)-4-{(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl}-3-(t-butoxymethyl)piperazin-2-one L-tartrate 의 일반명으로, 하기 분자구조식을 갖는다.Evogliptin is (R)-4-{(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl}-3-(t-butoxymethyl)piperazine- 2-membered L-tartrate ((R)-4-{(R)-3-amino-4-(2,4,5-trifluorophenyl)-butanoyl}-3-(t-butoxymethyl)piperazin-2-one It is the common name for L-tartrate and has the following molecular formula.
[화학식 1][Formula 1]
에보글립틴 타르타르산염은 동아에스티에서 슈가논이라는 상표명으로 판매되고 있다.Evogliptin tartrate is sold by Dong-A ST under the brand name Suganon.
에보글립틴은 DPP-4 효소의 저해제로 작용하며, 한국특허 10-1054911에 개시된 당뇨병 치료제이다. 에보글립틴은 당의 항상성을 유지하는 데 중요한 역할을 하는 GLP-1의 혈중농도를 높게 유지시켜 혈당을 유지하는 작용기전을 가지며, 이러한 기전은 인슐린 분비 촉진, 췌장의 베타세포 기능 개선, 그리고 체중 증가 및 저혈당의 부작용이 없으면서 혈당조절을 할 수 있는 이점을 가지고 있다. 현재 시판되고 있는 DPP-4 저해제는 시타글립틴(한국특허 10-0606871), 빌다글립틴(한국특허 10-0509311), 삭사글립틴(한국특허 10-0758407), 리나글립틴(한국특허 10-1150449), 제미글립틴(한국특허 10-0776623) 등이 있다.Evogliptin acts as an inhibitor of the DPP-4 enzyme and is a diabetes treatment disclosed in Korean Patent No. 10-1054911. Evogliptin has a mechanism of action that maintains blood sugar by maintaining high blood levels of GLP-1, which plays an important role in maintaining glucose homeostasis. This mechanism promotes insulin secretion, improves pancreatic beta cell function, and increases weight gain. It has the advantage of controlling blood sugar levels without the side effects of hypoglycemia. DPP-4 inhibitors currently on the market include sitagliptin (Korean Patent 10-0606871), vildagliptin (Korean Patent 10-0509311), saxagliptin (Korean Patent 10-0758407), and linagliptin (Korean Patent 10-0758407). 1150449), Gemigliptin (Korean Patent 10-0776623), etc.
제 2형 당뇨의 치료는, 메트포르민 염산염이 1차 치료제로 사용되고, 메트포르민에 의한 혈당조절이 안되는 경우 타 약제를 병용투여하고 있다. 메트포르민과 치료기전이 상이한 DPP-4 저해제는 메트포르민 염산염과의 병용투여가 빈번하며, 만성 대사질환을 앓고 있는 환자의 경우 다약제 병용에 따른 복용의 편의성 개선을 위해 복합제 처방이 증가하고 있는 추세이다. 이러한 DPP-4 저해제와 메트포르민 염산염의 복합제로 자누메트(MSD), 가브스메트(노바티스), 콤비글라이즈(BMS), 트라젠타듀오(베링거인겔하임), 제미메트(LG생명과학), 가드메트(JW중외), 테넬리아엠(한독) 등이 시판중이다. For the treatment of type 2 diabetes, metformin hydrochloride is used as a first-line treatment, and other drugs are administered in combination when blood sugar control cannot be achieved with metformin. DPP-4 inhibitors, which have a different therapeutic mechanism from metformin, are frequently administered in combination with metformin hydrochloride, and for patients suffering from chronic metabolic diseases, the prescription of combination drugs is increasing to improve the convenience of taking due to the combination of multiple drugs. Combination drugs of these DPP-4 inhibitors and metformin hydrochloride include Janumet (MSD), Gavsmet (Novartis), Combiglyze (BMS), Trajenta Duo (Boehringer Ingelheim), Zemimet (LG Life Sciences), and Guardmet. (JW Pharmaceutical) and Tenelia M (Handok) are on the market.
에보글립틴을 포함하여 DPP-4 저해제는 모두 속방성 제형으로 설계되어 있고, 메트포르민은 속방성과 서방성 제형의 두가지 제제가 모두 사용이 된다. 특히, 메트포르민 서방성 제형과 DPP-4 저해제를 포함하는 복합제를 제조할 경우에는 두 약물의 방출 특성을 고려하여 제형이 설계되어야 한다.All DPP-4 inhibitors, including evogliptin, are designed as immediate-release formulations, and metformin is used in both immediate-release and sustained-release formulations. In particular, when manufacturing a combination drug containing a metformin sustained-release formulation and a DPP-4 inhibitor, the formulation should be designed considering the release characteristics of the two drugs.
메트포르민의 서방성 제제과 DPP-4 저해제의 속방성 제제를 포함하는 복합제제에 대한 선행연구를 보면, 아래 특허와 같이 메트포르민 서방정 내핵에 DPP-4 저해제를 코팅하는 형태의 조성물로 개발되어 있다.Looking at previous studies on combination preparations containing a sustained-release preparation of metformin and an immediate-release preparation of a DPP-4 inhibitor, a composition was developed that coats the inner core of a metformin sustained-release tablet with a DPP-4 inhibitor, as shown in the patent below.
한국특허 10-1290925는 "코팅된 정제 제형 및 방법"으로 DPP-4 저해제인 삭사글립틴을 정제코어에 코팅하는 방법에 대해 기술되어 있다.Korean Patent 10-1290925, “Coated Tablet Formulation and Method,” describes a method of coating a tablet core with saxagliptin, a DPP-4 inhibitor.
한국특허공개공보 KR10-2014-0131950은 "메트포르민과, DPP-4 억제제 또는 SGLT-2 억제제를 포함하는 약제학적 조성물"로서 메트포르민 서방코어에 DPP-4 억제제인 리나글립틴을 코팅하는 방법에 대해 기술하고 있다.Korean Patent Publication KR10-2014-0131950 is a “pharmaceutical composition containing metformin and a DPP-4 inhibitor or SGLT-2 inhibitor” and describes a method of coating linagliptin, a DPP-4 inhibitor, on metformin sustained-release core. I'm doing it.
한국특허공개공보 KR10-2014-0045271는 "제미글립틴 및 메트포르민을 포함하는 복합제제 및 이의 제조방법"으로 DPP-4 억제제인 제미글립틴과 메트포르민의 이층정 제조방법, 또는 메트포르민 정제코어에 제미글립틴을 코팅하는 방법에 대해 기술하고 있다. 상기 문헌에는 이층정 제조방법에 대한 내용이 포함되어 있으나, 본 발명과는 달리 메트포르민의 서방형 매트릭스 구성을 위해 전호화 전분을 사용하고 있으며, 전호화 전분의 중량%는 메트포르민 염산염 대비 가장 바람직하게 55~65 중량%를 포함함으로써, 유효성분이 1,000mg 용량으로 포함되도록 제제화하기 위해 1600mg 이상의 큰 사이즈의 정제로 만들도록 기술되어 있다. 이와 같이 제조되는 최종 정제의 크기가 큰 경우 연하 곤란으로 인해 환자의 약물 순응도가 크게 낮아질 수 있다는 단점이 있다.Korean Patent Publication No. KR10-2014-0045271 is a “combined preparation containing gemigliptin and metformin and a manufacturing method thereof,” which describes a method for manufacturing a bilayer tablet of Gemigliptin, a DPP-4 inhibitor, and metformin, or Gemiglip on a metformin tablet core. It describes how to coat liptin. The above document contains information on a method for manufacturing a bilayer tablet, but unlike the present invention, pregelatinized starch is used to construct a sustained-release matrix of metformin, and the weight percent of pregelatinized starch is most preferably 55% compared to metformin hydrochloride. By containing ~65% by weight, it is described to be made into large-sized tablets of 1,600 mg or more in order to formulate the active ingredient in a dosage of 1,000 mg. If the size of the final tablet manufactured in this way is large, there is a disadvantage that the patient's drug compliance may be greatly reduced due to difficulty swallowing.
그러나, 에보글립틴과 메트포르민을 포함하는 복합제제에 대한 특허문헌은 찾아 볼 수 없었다.However, no patent literature could be found for a combination preparation containing evogliptin and metformin.
투여용량이 높은 메트포르민 염산염에 비해 에보글립틴 타르타르산염의 투여용량은 매우 작기 때문에, 함량 차이가 많이 나는 두가지 성분으로 이층정을 제조하는 것은 매우 어려운 일이다. 현재 시판되고 있는 DPP-4 저해제의 활성성분으로서 시타글립틴은 100mg, 삭사글립틴은 5mg, 제미글립틴은 50mg, 및 테네리글립틴은 20mg으로 구성되어 있다. DPP-4 저해제와 메트포르민 서방 복합제제로 구성되면서 본 발명 이외에 유일하게 이층정 제조방법에 대한 내용을 담고 있는 제미글립틴의 경우도 활성성분이 50mg 으로 에보글립틴보다 10배 많게 구성되어 있으며, 이외의 DPP-4 저해제는 모두 메트포르민 서방코어에 코팅되는 복합제제로 제조되는 것을 고려할 때, 함량 차이가 많이 나는 두 가지 성분의 이층정 제조는 매우 어려운 일임을 알 수 있다.Because the administered dose of evogliptin tartrate is very small compared to metformin hydrochloride, which has a high administered dose, it is very difficult to manufacture a double-layer tablet with two ingredients whose contents differ greatly. The active ingredients of currently commercially available DPP-4 inhibitors consist of 100 mg of sitagliptin, 5 mg of saxagliptin, 50 mg of gemigliptin, and 20 mg of teneligliptin. Gemigliptin, which consists of a DPP-4 inhibitor and a metformin sustained-release combination preparation and is the only product other than the present invention to contain information on the bilayer tablet manufacturing method, also contains 50 mg of active ingredient, 10 times more than Evogliptin. Considering that all DPP-4 inhibitors are manufactured as a composite preparation coated on the metformin extended-release core, it can be seen that manufacturing a bilayer tablet of two components with large differences in content is very difficult.
이러한 상황에서 본 발명자들은 제 2형 당뇨병의 1차 치료제로 사용되는 메트포르민 염산염의 부작용을 감소시키기 위해 서방정으로 하고, 여기에 작용 메커니즘이 상이한 DPP-4 저해제인 에보글립틴과의 복합제로 개발하기 위해 연구를 수행하였다. 그 결과, 메트포르민 염산염과 서방화제를 사용하여 메트포르민 서방성 과립을 제조하고, 에보글립틴 타르트산염과 붕해제를 사용하여 에보글립틴 속방성 과립을 제조하였다. 상기 2종 과립을 사용하여 이층정으로 타정하여 메트포르민은 서방출의 특성을 나타내고, 에보글립틴은 속방출의 특성을 나타내는 복합 제제를 제공하고, 상기 두 가지 과립의 비율과 조성을 조절하여 더욱 바람직한 복합제제를 개발하였다.In this situation, the present inventors developed a sustained-release tablet to reduce the side effects of metformin hydrochloride, which is used as a primary treatment for type 2 diabetes, and a combination drug with evogliptin, a DPP-4 inhibitor with a different mechanism of action. conducted a study. As a result, metformin sustained-release granules were prepared using metformin hydrochloride and a sustained-release agent, and evogliptin immediate-release granules were prepared using evogliptin tartrate and a disintegrant. By compressing the two types of granules into double-layer tablets, metformin exhibits sustained-release characteristics and evogliptin exhibits immediate-release characteristics, providing a composite preparation. By controlling the ratio and composition of the two granules, a more desirable composite formulation is provided. A formulation was developed.
에보글립틴은 매우 소량으로 포함되고, 서방출의 과립과 타정하기 때문에 함량균일성과 에보글립틴의 빠른 용출을 확보하기 위해서는 종래의 일반적인 제제기술로 충족시키기는 어려운 상황이다. 그 결과 이층정을 통하여 안정성이 개선된 복합제를 개발할 수 있음을 발견하여 본 발명을 완성하게 되었다. 그 중에서도 특히 메트포르민 서방성 과립의 일부와 에보글립틴 속방성 과립을 혼합하여 이층정으로 제조하였을 경우에도 에보글립틴의 속방 용출을 유지할 수 있었다.Since evogliptin is contained in a very small amount and is tableted with sustained-release granules, it is difficult to achieve content uniformity and rapid dissolution of evogliptin using conventional general formulation techniques. As a result, it was discovered that a combination drug with improved stability could be developed through a double-layer tablet, and the present invention was completed. In particular, even when a part of metformin sustained-release granules and Evogliptin immediate-release granules were mixed to form a double-layer tablet, the immediate-release dissolution of Evogliptin was maintained.
본 발명의 목적은 에보글립틴이 메트포르민과 함께 사용될 때, 에보글립틴은 속방출을 나타내고 메트포르민은 서방출을 나타내는 효과적인 복합제제를 개발하는 것이다. 특히, 에보글립틴은 복합제제의 전체중량 대비로 매우 소량이 포함되기 때문에 함량균일성을 확보하는 것도 중요하다.The purpose of the present invention is to develop an effective combination preparation in which evogliptin exhibits immediate release and metformin exhibits sustained release when evogliptin is used together with metformin. In particular, it is important to ensure content uniformity because evogliptin is contained in a very small amount compared to the total weight of the combination preparation.
본 발명은 에보글립틴과 메트포르민을 포함하고, 메트포르민의 서방출에 영향을 받지 않고 에보글립틴이 속방출을 나타낼 뿐만 아니라, 에보글립틴의 함량균일성이 확보된 복합제제 및 그의 제조방법을 제공하는 것을 목적으로 한다.The present invention provides a combination preparation containing evogliptin and metformin, which not only exhibits immediate release of evogliptin without being affected by the sustained release of metformin, but also ensures content uniformity of evogliptin, and a method for producing the same. The purpose is to
상기 목적을 위한 본 발명의 일측면에 따르면, 메트포르민 염산염 및 서방화제를 포함하는 서방층과 에보글립틴 또는 그의 약학적으로 허용가능한 염 및 붕해제를 포함하는 속방층으로 이루어진 복합제제가 제공될 수 있다. 상기 복합제제는 이층정 형태일 수 있다. 상기 복합제제는 당뇨병, 특히 제2형 당뇨병의 치료용 제제이다.According to one aspect of the present invention for the above purpose, a composite preparation consisting of a sustained-release layer containing metformin hydrochloride and a sustained-release agent and an immediate-release layer containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant may be provided. . The combination preparation may be in the form of a double-layer tablet. The combination preparation is a preparation for treating diabetes, especially type 2 diabetes.
또 다른 본 발명의 일측면에서, 메트포르민 염산염 및 서방화제를 포함하는 서방층과 에보글립틴 또는 그의 약학적으로 허용가능한 염 및 붕해제를 포함하는 속방층으로 이루어진 복합제제의 제조방법이 제공될 수 있다.In another aspect of the present invention, a method for producing a composite formulation consisting of a sustained-release layer containing metformin hydrochloride and a sustained-release agent and an immediate-release layer containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant may be provided. there is.
본 발명에 따른 경구용 복합제제는 메트포르민과 에보글립틴을 동시에 포함하면서도, 메트포르민의 방출속도를 지연하여 메트포르민의 부작용을 감소시킬 수 있으며, 또한 서방층에 의한 속방층의 용출 저하 없이 에보글립틴의 신속한 용출을 나타낼 수 있는 서로 다른 메커니즘의 당뇨병 치료제를 포함한 이층정 복합제제를 제공함으로써 당뇨병의 효과적인 치료에 유용하게 사용될 수 있다.The oral combination preparation according to the present invention simultaneously contains metformin and evogliptin, and can reduce the side effects of metformin by delaying the release rate of metformin. Additionally, it can reduce the side effects of evogliptin without reducing the dissolution of the immediate-release layer by the sustained-release layer. By providing a double-layer tablet combination preparation containing antidiabetic agents of different mechanisms that can exhibit rapid dissolution, it can be usefully used in the effective treatment of diabetes.
도 1은 실시예 5 내지 7 및 비교예 3의 용출시험에서 에보글립틴의 용출률을 분석한 결과를 나타낸 그래프이다.Figure 1 is a graph showing the results of analyzing the dissolution rate of evogliptin in the dissolution test of Examples 5 to 7 and Comparative Example 3.
도 2는 실시예 6 및 비교예 7에 따라 제조한 복합제제의 단면을 통해 에보글립틴 속방층의 두께를 확인한 사진이다.Figure 2 is a photograph confirming the thickness of the immediate-release layer of evogliptin through a cross section of the combination preparation prepared according to Example 6 and Comparative Example 7.
이하, 본 발명을 상세하게 설명한다.Hereinafter, the present invention will be described in detail.
하나의 양태로, 본 발명의 경구용 복합 제제는 유효성분으로서 메트포르민 염산염 및 서방화제를 포함하는 메트포르민 함유 서방성 과립, 및 에보글립틴 또는 이의 약학적으로 허용가능한 염 및 붕해제를 포함하는 에보글립틴 함유 과립을 포함할 수 있다.In one embodiment, the oral composite preparation of the present invention includes metformin-containing sustained-release granules containing metformin hydrochloride and a sustained-release agent as active ingredients, and Evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant. It may contain liptin-containing granules.
일 양태로서, 본 발명의 복합 제제는 경구용일 수 있다.In one embodiment, the combination preparation of the present invention may be administered orally.
본 발명에 따르는 복합제제에서는 메트포르민 또는 이의 약학적으로 허용가능한 염 및 서방화제를 포함하는 메트포르민 함유 서방 과립을 포함할 수 있다. 상기 과립은 건식과립 또는 습식과립을 포함한다.The combination preparation according to the present invention may include metformin-containing sustained-release granules containing metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent. The granules include dry granules or wet granules.
상기 메트포르민 함유 서방성 과립은 유효성분으로서 메트포르민 또는 또는 이의 약학적으로 허용가능한 염을 포함한다. 본 발명의 용어 "약학적으로 허용되는 염"은, 환자에게 비교적 비독성이고 무해한 유효작용을 갖는 농도로서 이 염에 기인한 부작용이 메트포르민의 이로운 효능을 저하시키지 않는 상기 화합물의 임의의 모든 유기 또는 무기 부가염을 의미하며, 메트포르민의 염산염, 숙신산염, 푸마르산염 등을 들 수 있으나 이에 제한되는 것은 아니다. 구체적인 일 예로, 상기 메트포르민의 약학적으로 허용가능한 염은 메트포르민 염산염일 수 있다.The metformin-containing sustained-release granules contain metformin or a pharmaceutically acceptable salt thereof as an active ingredient. The term "pharmaceutically acceptable salt" of the present invention refers to any organic or organic salt of the compound at a concentration that is relatively non-toxic and harmless to the patient and has an effective effect, and side effects due to the salt do not reduce the beneficial efficacy of metformin. It refers to an inorganic addition salt and includes, but is not limited to, metformin hydrochloride, succinate, and fumarate. As a specific example, the pharmaceutically acceptable salt of metformin may be metformin hydrochloride.
상기 메트포르민 또는 이의 약학적으로 허용가능한 염은 복합제제 당 약 500 내지 1,000mg이 포함될 수 있다.The metformin or a pharmaceutically acceptable salt thereof may be included in an amount of about 500 to 1,000 mg per combination preparation.
상기 메트포르민 함유 서방성 과립은 메트포르민이 서방출될 수 있도록 서방화제를 함께 포함할 수 있다. 이러한 서방화제로는 메타아크릴산공중합체, 히프로멜로오스, 카보머, 히드록시프로필셀룰로오스, 히드록시프로필메틸셀룰로오스 및 이의 혼합물로 이루어지는 군으로부터 선택되는 것을 특징으로 한다. 상기 서방화제의 양은 서방성 과립 총 중량의 11 내지 30중량%, 11 내지 28중량%, 11 내지 25중량%, 12 내지 30중량%, 12 내지 28중량%, 12 내지 25중량%, 13 내지 30중량%, 13 내지 28중량%, 13 내지 25중량%, 14 내지 30중량%, 14 내지 28중량%, 14 내지 25중량%, 15 내지 30 중량%, 15 내지 28중량%, 15 내지 25중량%, 16 내지 30중량%, 16 내지 28중량%, 16 내지 25중량%, 17 내지 30중량%, 17 내지 28중량%, 17 내지 25 중량%, 18 내지 30중량%, 18 내지 28중량%, 18 내지 25중량%, 19 내지 30중량%, 19 내지 28중량%, 19 내지 25중량%, 20 내지 30중량%, 20 내지 28중량%, 또는 20 내지 25중량%의 양으로 포함될 수 있다.The metformin-containing sustained-release granules may also include a sustained-release agent to allow sustained release of metformin. This sustained release agent is characterized by being selected from the group consisting of methacrylic acid copolymer, hypromellose, carbomer, hydroxypropylcellulose, hydroxypropylmethylcellulose, and mixtures thereof. The amount of the sustained-release agent is 11 to 30% by weight, 11 to 28% by weight, 11 to 25% by weight, 12 to 30% by weight, 12 to 28% by weight, 12 to 25% by weight, and 13 to 30% by weight of the total weight of the sustained-release granules. Weight %, 13 to 28% by weight, 13 to 25% by weight, 14 to 30% by weight, 14 to 28% by weight, 14 to 25% by weight, 15 to 30% by weight, 15 to 28% by weight, 15 to 25% by weight , 16 to 30% by weight, 16 to 28% by weight, 16 to 25% by weight, 17 to 30% by weight, 17 to 28% by weight, 17 to 25% by weight, 18 to 30% by weight, 18 to 28% by weight, 18 It may be included in an amount of from 25% by weight, 19 to 30% by weight, 19 to 28% by weight, 19 to 25% by weight, 20 to 30% by weight, 20 to 28% by weight, or 20 to 25% by weight.
상기 메트포르민 함유 서방성 과립은 활택제, 결합제, 희석제 등와 같은 약학적으로 허용가능한 첨가제를 더 포함할 수 있다.The metformin-containing sustained-release granules may further include pharmaceutically acceptable additives such as lubricants, binders, diluents, etc.
상기 활택제는 스테아르산칼슘, 콜로이드성 이산화규소(fumed silica, Aerosil), 글리세릴 모노스테아레이트, 글리세릴 팔미토스테아레이트, 스테아르산마그네슘, 라우릴황산나트륨, 스테아릴푸마르산나트륨, 스테아르산아 연, 스테아르산, 경화된 식물성오일, 폴리에틸렌글리콜, 벤조산나트륨, 탈크 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있으나 이에 한정되는 것은 아니다. 일 구체예에서, 상기 활택제는 스테아린산마그네슘이다. 상기 활택제는 메트포르민 함유 서방성 과립 총 중량에 대해 0.1 내지 5중량%의 양으로 함유될 수 있으나 이에 제한되는 것은 아니다.The lubricant includes calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, and stear. It may be selected from the group consisting of acids, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and combinations thereof, but is not limited thereto. In one embodiment, the lubricant is magnesium stearate. The lubricant may be contained in an amount of 0.1 to 5% by weight based on the total weight of metformin-containing sustained-release granules, but is not limited thereto.
상기 결합제는 폴리비닐피롤리돈, 히드록시프로필메틸 셀룰로오스, 히드록시프로필 셀룰로오스, 에틸 셀룰로오스, 메틸 셀룰로오스, 폴록사머, 폴리에틸렌 옥사이드, 폴리메틸아크릴레이트, 천연검, 합성검, 코포비돈, 젤라틴 및 이들의 조합으로 이루어지는 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다. 일 구체예에서 상기 결합제는 히드록시프로필 셀룰로오스이다. 상기 결합제는 메트포르민 함유 서방성 과립 총 중량에 대해 1 내지 10 중량%로 함유될 수 있으나 이에 제한되는 것은 아니다.The binder is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethyl acrylate, natural gum, synthetic gum, copovidone, gelatin and these. It may be selected from the group consisting of combinations, but is not limited thereto. In one embodiment, the binder is hydroxypropyl cellulose. The binder may be contained in an amount of 1 to 10% by weight based on the total weight of metformin-containing sustained-release granules, but is not limited thereto.
상기 희석제는 미세결정셀룰로오스, 무수인산수소칼슘, 만니톨, 수크로스, 락토스, 소르비톨, 자일리톨, 글루코오스 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다. 상기 희석제는 메트포르민 함유 서방성 과립 총 중량에 대해 50 내지 80 중량%의 양으로 함유될 수 있다.The diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, and combinations thereof, but is not limited thereto. The diluent may be contained in an amount of 50 to 80% by weight based on the total weight of metformin-containing sustained-release granules.
본 발명에 따른 복합제제에서는 에보글립틴 또는 이의 약학적으로 허용가능한 염 및 붕해제를 포함하는 에포글립틴 함유 속방성 과립을 포함할 수 있다.The combination preparation according to the present invention may include immediate-release granules containing epogliptin or a pharmaceutically acceptable salt thereof and a disintegrant.
상기 에보글립틴의 약학적으로 허용가능한 염은 에보글립틴의 염으로는 타르타르산염, 염산염, 시트르산염, 인산염, 아세트산염, 말산염, 숙신산염 등이 사용될 수 있으며, 바람직하게는 에보글립틴 타르타르산염이다. 이러한 에보글립틴 또는 이의 약학적으로 허용 가능한 염은 복합제제 당 에보글립틴으로 약 2.5 내지 10mg이 포함된다.The pharmaceutically acceptable salt of evogliptin may include tartrate, hydrochloride, citrate, phosphate, acetate, malate, succinate, etc., preferably evogliptin tartrate. It's salt. Such evogliptin or a pharmaceutically acceptable salt thereof includes about 2.5 to 10 mg of evogliptin per combination preparation.
본 발명의 일측면에 따르면, 상기 에보글립틴 또는 이의 약학적으로 허용가능한 염과 함께 에보글립틴 함유 속방성 과립에 포함되는 붕해제는 저치환도 히드록시프로필셀룰로오스, 크로스카멜로오스나트륨, 크로스포비돈 및 이의 조합으로 이루어지는 군으로부터 선택되는 1종 이상일 수 있다. 상기 붕해제의 양은 에보글립틴 함유 속방성 과립 총 중량에 대해 0중량% 초과, 0.1중량% 이상, 0.5중량% 이상, 1중량% 이상, 2중량% 이상, 3중량% 이상, 4중량% 이상, 5중량% 이상, 6중량% 이상, 7중량% 이상, 8중량% 이상, 9중량% 이상, 10중량% 이상, 11중량% 이상, 12중량% 이상, 13중량% 이상, 14중량% 이상, 또는 15중량% 이상 포함될 수 있다. 이 때, 상기 붕해제의 양의 상한값이 특정되지 않더라도, 에보글립틴 속방 용출의 저하가 일어나지 않고, 메트포르민의 서방 용출에 영향을 주지 않는 본원발명의 효과를 달성하기 위해, 통상의 기술자가 명확하게 실시할 수 있을 것이나, 예를 들어 상기 붕해제의 양의 상한값은 에보글립틴 함유 속방성 과립 총 중량에 대해 40중량% 이하, 35중량% 이하, 30중량% 이하, 25중량% 이하, 또는 20중량% 이하일 수 있으나, 이에 제한되는 것은 아니다. 일 예로, 상기 붕해제의 양은 에보글립틴 함유 속방성 과립 총 중량에 대해 1 내지 40중량%, 1 내지 35중량%, 1 내지 30중량%, 1 내지 25중량%, 1 내지 20중량%, 5 내지 40중량%, 5 내지 35중량%, 5 내지 30중량%, 5 내지 25중량%, 5 내지 20중량%, 10 내지 40중량%, 10 내지 35중량%, 10 내지 30중량%, 10 내지 25중량%, 10 내지 20중량%, 12 내지 40중량%, 12 내지 35중량%, 12 내지 30중량%, 12 내지 25중량%, 12 내지 20중량%, 14 내지 40중량%, 14 내지 35중량%, 14 내지 30중량%, 14 내지 25중량%, 14 내지 20중량%, 15 내지 40중량%, 15 내지 35중량%, 15 내지 30중량%, 15 내지 25중량%, 또는 15 내지 20중량% 의 양으로 포함될 수 있다.According to one aspect of the present invention, the disintegrant included in the immediate-release granules containing evogliptin along with evogliptin or a pharmaceutically acceptable salt thereof is low-substituted hydroxypropylcellulose, croscarmellose sodium, and crospovidone. And it may be one or more types selected from the group consisting of combinations thereof. The amount of the disintegrant is more than 0% by weight, more than 0.1% by weight, more than 0.5% by weight, more than 1% by weight, more than 2% by weight, more than 3% by weight, more than 4% by weight based on the total weight of the immediate-release granules containing evogliptin. , 5% by weight or more, 6% by weight or more, 7% by weight or more, 8% by weight or more, 9% by weight or more, 10% by weight or more, 11% by weight or more, 12% by weight or more, 13% by weight or more, 14% by weight or more. , or may contain more than 15% by weight. At this time, even if the upper limit of the amount of the disintegrant is not specified, in order to achieve the effect of the present invention in which the immediate release of evogliptin does not decrease and the sustained release of metformin is not affected, a person skilled in the art should clearly use It may be implemented, but for example, the upper limit of the amount of the disintegrant is 40% by weight or less, 35% by weight or less, 30% by weight or less, 25% by weight or less, or 20% by weight or less, based on the total weight of the immediate-release granules containing evogliptin. It may be less than % by weight, but is not limited thereto. For example, the amount of the disintegrant is 1 to 40% by weight, 1 to 35% by weight, 1 to 30% by weight, 1 to 25% by weight, 1 to 20% by weight, 5%, based on the total weight of the immediate-release granules containing evogliptin. to 40% by weight, 5 to 35% by weight, 5 to 30% by weight, 5 to 25% by weight, 5 to 20% by weight, 10 to 40% by weight, 10 to 35% by weight, 10 to 30% by weight, 10 to 25% by weight Weight %, 10 to 20% by weight, 12 to 40% by weight, 12 to 35% by weight, 12 to 30% by weight, 12 to 25% by weight, 12 to 20% by weight, 14 to 40% by weight, 14 to 35% by weight , 14 to 30% by weight, 14 to 25% by weight, 14 to 20% by weight, 15 to 40% by weight, 15 to 35% by weight, 15 to 30% by weight, 15 to 25% by weight, or 15 to 20% by weight. Can be included in quantity.
상기 에보글립틴 함유 속방성 과립은 희석제, 활택제, 결합제, 가소제, 분산제, 착색제 등과 같은 약학적으로 허용가능한 첨가제를 더 포함할 수 있다.The evogliptin-containing immediate-release granules may further include pharmaceutically acceptable additives such as diluents, lubricants, binders, plasticizers, dispersants, colorants, etc.
상기 희석제는 미세결정셀룰로스, 무수인산수소칼슘, 만니톨, 수크로오스, 락토오스, 소르비톨, 자일리톨, 글루코오스, 전호화 전분 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다. 상기 희석제는 에보글립틴 함유 속방성 과립 총 중량에 대해 50 내지 80 중량%의 양으로 함유될 수 있다. The diluent may be selected from the group consisting of microcrystalline cellulose, anhydrous calcium hydrogen phosphate, mannitol, sucrose, lactose, sorbitol, xylitol, glucose, pregelatinized starch, and combinations thereof, but is not limited thereto. The diluent may be contained in an amount of 50 to 80% by weight based on the total weight of the evogliptin-containing immediate-release granules.
상기 활택제는 스테아르산칼슘, 콜로이드성 이산화규소(fumed silica, Aerosil), 글리세릴 모노스테아레이트, 글리세릴 팔미토스테아레이트, 스테아르산마그네슘, 라우릴황산나트륨, 스테아릴푸마르산나트륨, 스테아르산아연, 스테아르산, 경화된 식물성오일, 폴리에틸렌글리콜, 벤조산나트륨, 탈크 및 이들의 조합으로 이루어진 군에서 선택될 수 있으나 이에 한정되는 것은 아니다. 일 구체예에서, 상기 활택제는 스테아린산마그네슘, 콜로이드성 이산화규소이다. 상기 활택제는 에보글립틴 함유 속방성 과립 총 중량에 대해 0.1 내지 5 중량%의 양으로 함유될 수 있다.The lubricant includes calcium stearate, colloidal silicon dioxide (fumed silica, Aerosil), glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, and stear. It may be selected from the group consisting of acids, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, talc, and combinations thereof, but is not limited thereto. In one embodiment, the lubricant is magnesium stearate or colloidal silicon dioxide. The lubricant may be contained in an amount of 0.1 to 5% by weight based on the total weight of evogliptin-containing immediate-release granules.
상기 결합제는 폴리비닐피롤리돈, 히드록시프로필메틸 셀룰로오스, 히드록시프로필 셀룰로오스, 에틸 셀룰로오스, 메틸 셀룰로오스, 폴록사머, 폴리에틸렌 옥사이드, 폴리메틸아크릴레이트, 천연검, 합성검, 코포비돈, 젤라틴 및 이들의 조합으로 이루어지는 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다. 일 구체예에서 상기 결합제는 히드록시프로필 셀룰로오스이다. 상기 결합제는 에보글립틴 함유 속방성 과립 총 중량에 대해 1 내지 10 중량%로 함유될 수 있으나 이에 제한되는 것은 아니다.The binder is polyvinylpyrrolidone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, ethyl cellulose, methyl cellulose, poloxamer, polyethylene oxide, polymethyl acrylate, natural gum, synthetic gum, copovidone, gelatin and these. It may be selected from the group consisting of combinations, but is not limited thereto. In one embodiment, the binder is hydroxypropyl cellulose. The binder may be contained in an amount of 1 to 10% by weight based on the total weight of the evogliptin-containing immediate-release granules, but is not limited thereto.
상기 가소제는 폴리에틸렌글리콜, 글리세린, 스테아르산, 실리카, 디메티콘, 농글리세린, 프로필렌글리콜 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있으나, 이에 한정되는 것은 아니다. 상기 분산제는 카올린, 산화알루미늄, 산화티탄, 소르비탄세스퀴올, 실리콘수지, 아라비아고무, 에틸셀룰로오스, 탄산칼슘, 벤토나이트, 카보머 및 이들의 조합으로 이루어진 군으로부터 선택될 수 있으나 이에 한정되는 것은 아니다.The plasticizer may be selected from the group consisting of polyethylene glycol, glycerin, stearic acid, silica, dimethicone, concentrated glycerin, propylene glycol, and combinations thereof, but is not limited thereto. The dispersant may be selected from the group consisting of kaolin, aluminum oxide, titanium oxide, sorbitane sesquiol, silicone resin, gum arabic, ethyl cellulose, calcium carbonate, bentonite, carbomer, and combinations thereof, but is not limited thereto.
상기 착색제로는 이산화티타늄, 적색산화철 등이 있으며, 이에 한정되는 것은 아니다.The colorant includes titanium dioxide, red iron oxide, etc., but is not limited thereto.
본 발명의 일측면에 따르면, 상기 복합제제는 메트포르민 함유 서방성 과립 100 중량부를 기준으로 에보글립틴 함유 과립을 5 내지 30 중량부, 5 내지 25 중량부, 5 내지 20 중량부, 7 내지 30 중량부, 7 내지 25 중량부, 7 내지 20 중량부, 10 내지 30 중량부, 10 내지 25 중량부, 또는 10 내지 20 중량부로 포함할 수 있다. 상기 메트포르민 함유 서방성 과립과 에보글립틴 함유 과립이 상기 중량비를 갖는 경우, 에보글립틴 함유 과립을 포함하는 층의 두께가 지나치게 얇아지지 않아 이층정의 함량균일성뿐 아니라 에보글립틴 또는 이의 약학적으로 허용가능한 염의 신속한 방출이 이루어진다는 장점을 갖는다.According to one aspect of the present invention, the combination preparation contains 5 to 30 parts by weight, 5 to 25 parts by weight, 5 to 20 parts by weight, and 7 to 30 parts by weight of evogliptin-containing granules based on 100 parts by weight of metformin-containing sustained-release granules. parts, 7 to 25 parts by weight, 7 to 20 parts by weight, 10 to 30 parts by weight, 10 to 25 parts by weight, or 10 to 20 parts by weight. When the metformin-containing sustained-release granules and the evogliptin-containing granules have the above weight ratio, the thickness of the layer containing the evogliptin-containing granules is not excessively thin, thereby improving not only the content uniformity of the bilayer tablet but also the pharmaceutical effect of evogliptin or its pharmaceutical content. It has the advantage of rapid release of acceptable salts.
일 양태에서, 본 발명에 따른 복합제제는 이층정 형태인 것을 특징으로 한다. 즉, 본 발명에 따른 복합제제는 종래 복합제제로 제제화하기 어려운 에보글립틴과 메트포르민을 유효성분으로 포함하는 제제를 여러 가지 복합제제 중에서도 특히 이층정으로 제제화하되, 이층정의 제제화시에도 문제될 수 있는 함량균일성 등이 확보된 제제인 것을 특징으로 한다.In one embodiment, the combination preparation according to the present invention is characterized in that it is in the form of a double-layer tablet. In other words, the combination preparation according to the present invention contains evogliptin and metformin as active ingredients, which are difficult to formulate as a conventional combination preparation, and is formulated into a bilayer tablet among various combination preparations. However, the content that may be problematic even when formulating a bilayer tablet is included. It is characterized as a preparation that ensures uniformity, etc.
일 양태에서, 본 발명에 따른 복합제제는 제1층 및 제2층을 포함한다. 상기 제1층 및 제2층이라는 기재는 서로 다른 층을 각각 구분하기 위하여 지칭(즉, 제1층은 이층정 중 임의의 어느 한 층이고, 제2층은 상기 층이 아닌 다른 층을 의미함)하는 것이며, 제1층이 위쪽에 위치할 수 있으나 아래쪽에 위치할 수도 있으며, 제2층이 아래쪽에 위치할 수도 있으나 위층에 위치할 수도 있다. 이러한 이층정은 상기 메트포르민 함유 서방성 과립과 에보글립틴 함유 과립이 각각 다른 층에 포함되는 것일 수 있다(예를 들어 제1층은 메트포르민 함유 서방성 과립으로만 이루어지는 서방층, 제2층은 에보글립틴 함유 과립으로만 이루어지는 속방층으로 이루어진 이층정 형태). 한편, 상기 이층정은 메트포르민 함유 서방성 과립만으로 이루어진 제1층 및 에보글립틴 함유 속방성 과립 및 메트포르민 과립의 혼합물을 포함하는 제2층을 포함하는 것일 수 있다. 바람직하게, 상기 제1층이 에보글립틴 함유 속방성 과립및 메트포르민 함유 서방성 과립의 혼합물을 포함하는 경우, 에보글립틴 함유 속방성 과립및 메트포르민 함유 서방성 과립의 전체 중량에 대한 메트포르민 함유 서방성 과립의 중량비는 20중량% 미만, 15중량% 이하, 일 예로 1 내지 15 중량%일 수 있다. In one aspect, the combination preparation according to the present invention includes a first layer and a second layer. The descriptions of the first layer and the second layer refer to each other to distinguish between different layers (i.e., the first layer refers to any one layer of the two-layer tablet, and the second layer refers to a layer other than the above layer) ), the first layer may be located at the top, but may be located below, and the second layer may be located at the bottom, but may also be located on the upper floor. Such a two-layer tablet may contain the metformin-containing sustained-release granules and Evogliptin-containing granules in different layers (for example, the first layer is a sustained-release layer consisting only of metformin-containing sustained-release granules, and the second layer is Evogliptin-containing granules). Double-layer tablet form with an immediate-release layer consisting only of liptin-containing granules). Meanwhile, the two-layer tablet may include a first layer consisting only of metformin-containing sustained-release granules and a second layer containing a mixture of immediate-release granules containing evogliptin and metformin granules. Preferably, when the first layer includes a mixture of evogliptin-containing immediate-release granules and metformin-containing sustained-release granules, the metformin-containing sustained-release granules relative to the total weight of the evogliptin-containing immediate-release granules and metformin-containing sustained-release granules The weight ratio of the granules may be less than 20% by weight, less than 15% by weight, for example, 1 to 15% by weight.
한 층에 에보글립틴 함유 속방성 과립및 메트포르민 함유 서방성 과립이 위와 같은 비율로 포함되는 경우, 정제의 크기를 효과적으로 감소시킬 수 있다는 장점을 가지는 상기 과립을 혼합함에도 불구하고 에보글립틴 또는 이의 약학적으로 허용가능한 염이 원하는 속방형태의 용출 패턴을 나타낼 수 있어, 적절한 약리효과를 나타낼 수 있다는 장점을 갖는다.When one layer contains immediate-release granules containing evogliptin and sustained-release granules containing metformin in the above ratio, despite mixing the granules, which has the advantage of effectively reducing the size of the tablet, evogliptin or its pharmaceutical It has the advantage that an acceptable salt can exhibit a desired immediate-release dissolution pattern and thus exhibit appropriate pharmacological effects.
일 양태로서, 본 발명에 따른 복합제제는 용출시험(pH 1.2액, 37℃, 900mL, 50rpm)시 에보글립틴의 용출률이 30분이내에 80% 이상을 나타내는 것을 특징으로 한다.In one embodiment, the combination preparation according to the present invention is characterized in that the dissolution rate of evogliptin is more than 80% within 30 minutes during a dissolution test (pH 1.2 solution, 37°C, 900mL, 50rpm).
일 양태로서, 본 발명에 따른 복합제제는 용출시험(pH 1.2액, 37℃, 900mL, 100rpm)시 메트포르민의 용출률이 1시간에 15~45%, 3시간에 35~65% 및 10시간에 80% 이상인 것을 특징으로 한다. In one embodiment, the combination preparation according to the present invention has a dissolution rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% in 10 hours during a dissolution test (pH 1.2 solution, 37°C, 900mL, 100rpm). It is characterized by being more than %.
이상과 같은, 본 발명에 따른 복합제제는 메트포르민 염산염과 서방화제를 포함하는 메트포르민 함유 서방성 과립; 및 에보글립틴 또는 약제학적으로 허용가능한 그의 염과 붕해제를 포함하는 에보글립틴 함유 과립을 포함하는 이층정 형태를 가짐으로 인해, 에보글립틴 또는 이의 약학적으로 허용가능한 염은 속방출성을 나타내고 메트포르민은 서방출성을 나타내어 투여기간 내에 신속하고 충분한 각각의 약리효과를 확보할 수 있다는 장점을 갖는다. 나아가, 본 발명에 따른 복합제제는 제제 전체 중량 대비 매우 소량이 포함됨에도 불구하고 함량균일성이 확보되고, 제제의 제조, 유통 과정에서 발생할 수 있는 파손 가능성도 낮다는 점에서 효과적인 제제의 제공이 가능하다는 장점을 갖는다. As described above, the combination preparation according to the present invention includes metformin-containing sustained-release granules containing metformin hydrochloride and a sustained-release agent; and evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant, and thus have a bilayer tablet form containing granules containing evogliptin or a pharmaceutically acceptable salt thereof, so that evogliptin or a pharmaceutically acceptable salt thereof has immediate release properties. Metformin has the advantage of being able to achieve rapid and sufficient pharmacological effects within the administration period by exhibiting sustained release properties. Furthermore, the combination preparation according to the present invention can provide an effective preparation in that content uniformity is ensured even though it contains a very small amount compared to the total weight of the preparation, and the possibility of damage that may occur during the manufacturing and distribution of the preparation is low. It has the advantage of
또 다른 양태로서, 본 발명은 에보글립틴 및 메트포르민을 포함하는 경구용 복합제제의 제조방법에 관한 것으로, 보다 상세하게 본 발명에 따른 제조방법은 과립의 제조, 타정 공정으로 제공될 수 있다. 일 양태로, 본 발명에 따른 제조방법은 다음의 단계를 포함할 수 있다. In another aspect, the present invention relates to a method for manufacturing an oral combination preparation containing evogliptin and metformin. More specifically, the manufacturing method according to the present invention may be provided as a granule manufacturing and tableting process. In one aspect, the manufacturing method according to the present invention may include the following steps.
(a) 메트포르민 또는 이의 약학적으로 허용가능한 염과 서방화제를 포함하는 메트포르민 함유 서방성 과립을 제조하는 단계; (a) preparing metformin-containing sustained-release granules comprising metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent;
(b) 에보글립틴 또는 이의 약학적으로 허용가능한 염과 붕해제를 포함하는 에보글립틴 함유 과립을 제조하는 단계; 및(b) preparing evogliptin-containing granules containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant; and
(c) 상기 단계 (a) 및 (b)에서 각각 제조된 메트포르민 함유 서방성 과립 및 에보글립틴 함유 과립을 타정하여 이층정으로 제조하는 단계.(c) compressing the metformin-containing sustained-release granules and evogliptin-containing granules prepared in steps (a) and (b), respectively, into double-layer tablets.
이하 각 단계를 좀 더 상세하게 설명한다. 달리 언급되지 않는 한, 본 제조방법에서 사용되는 각 성분 및 이들의 함량을 비롯한 사항은 모두 상기 복합제제에 관하여 개시된 사항을 그대로 적용할 수 있다. Below, each step is described in more detail. Unless otherwise stated, all matters including each ingredient used in this manufacturing method and their content can be applied as is as disclosed in relation to the above combination preparation.
상기 단계 (a)는 본 발명의 복합제제에 포함되는 메트포르민 함유 서방성 과립을 제조하는 단계로서, 유효성분으로서 메트포르민 또는 이의 약학적으로 허용가능한 염과 서방화제를 이용하여 과립화시키는 공정에 의해 수행될 수 있다. 이러한 과립화 공정으로는 습식 과립법 또는 건식 과립법을 이용할 수 있으며, 이러한 습식 또는 건식 과립법은 당업계에서 잘 알려진 통상의 방법에 의해 수행될 수 있다. 예를 들어, 과립에 포함되는 각각의 성분들을 블렌딩하여 혼합물을 제조하고, 이어 필요에 따라 정제수, 에탄올, 이소프로판올 또는 이의 배합물과 같은 과립화 용매를 첨가하여 연합한 후 이를 과립화 할 수 있다.The step (a) is a step of manufacturing metformin-containing sustained-release granules included in the combination preparation of the present invention, and is performed by granulating using metformin or a pharmaceutically acceptable salt thereof as an active ingredient and a sustained-release agent. You can. This granulation process can be performed by a wet granulation method or a dry granulation method, and the wet or dry granulation method can be performed by a conventional method well known in the art. For example, the individual components included in the granules can be blended to prepare a mixture, and then, if necessary, a granulation solvent such as purified water, ethanol, isopropanol, or a combination thereof can be added and kneaded, and then granulated.
상기 단계 (a)에서는 메트포르민 또는 이의 약학적으로 허용가능한 염 및 서방화제와 함께 당업계에서 잘 알려진 활택제, 결합제, 희석제 등과 같은 약학적으로 허용가능한 첨가제를 추가하여 함께 혼합하여 과립을 제조할 수도 있다.In step (a), granules may be prepared by adding and mixing metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent along with pharmaceutically acceptable additives such as lubricants, binders, and diluents well known in the art. there is.
상기 단계 (b)는 본 발명의 복합제제에 포함되는 에보글립틴 함유 속방성 과립을 제조하는 단계로서, 유효성분으로서 에보글립틴 또는 이의 약학적으로 허용가능한 염과 붕해제를 이용하여 과립화시키는 공정에 의해 수행될 수 있다. 이러한 과립화 공정으로는 습식 과립법 또는 건식 과립법을 이용할 수 있으며, 이러한 습식 또는 건식 과립법은 당업계에서 잘 알려진 통상의 방법에 의해 수행될 수 있다.Step (b) is a step of manufacturing immediate-release granules containing evogliptin included in the combination preparation of the present invention, which involves granulating using evogliptin or a pharmaceutically acceptable salt thereof as an active ingredient and a disintegrant. It can be performed by . This granulation process can be performed by a wet granulation method or a dry granulation method, and the wet or dry granulation method can be performed by a conventional method well known in the art.
상기 단계 (b)에서는 에보글립틴 또는 이의 약학적으로 허용가능한 염 및 붕해제와 함께 당업계에서 잘 알려진 활택제, 결합제, 희석제, 가소제, 분산제, 착색제 등과 같은 약학적으로 허용가능한 첨가제를 추가하여 함께 혼합하여 과립을 제조할 수도 있다.In step (b), pharmaceutically acceptable additives such as lubricants, binders, diluents, plasticizers, dispersants, colorants, etc. well known in the art are added along with evogliptin or its pharmaceutically acceptable salt and disintegrant. Granules can also be produced by mixing them together.
상기 단계 (c)에서는 상기 단계 (a) 및 (b)에서 각각 제조된 메트포르민 함유 서방성 과립 및 에보글립틴 함유 속방성 과립을 사용하여 이층정을 제조하는 단계이다. 이러한 이층정은 통상 알려진 이층정 타정기를 사용하여 타정함으로써 제조될 수 있다.In step (c), a bilayer tablet is manufactured using metformin-containing sustained-release granules and evogliptin-containing immediate-release granules prepared in steps (a) and (b), respectively. These two-layer tablets can be manufactured by tableting using a commonly known double-layer tablet tablet press.
일 양태로서, 상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립만을 사용하여 제1층을 타정한 후, 타정된 제1층 상에 상기 단계 (b)에서 제조된 에보글립틴 함유 과립만을 사용하여 제2층을 타정하여 본 발명에 따른 복합제제를 제조할 수 있다.In one embodiment, the first layer is compressed into tablets using only the metformin-containing sustained-release granules prepared in step (a), and then only the evogliptin-containing granules prepared in step (b) are used on the compressed first layer. By compressing the second layer into tablets, the composite preparation according to the present invention can be manufactured.
또 다른 양태로서, 상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립만을 사용하여 제1층을 타정한 후, 타정된 제1층 상에 상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립 및 단계 (b)에서 제조된 에보글립틴 함유 과립의 혼합물을 사용하여 제2층을 타정하여 본 발명에 따른 복합제제를 제조할 수 있다. 이때 에보글립틴 함유 속방성 과립및 메트포르민 함유 서방성 과립의 전체 중량에 대한 메트포르민 함유 서방성 과립의 중량비는 15중량% 이하, 바람직하게는 1 내지 15중량% 일 수 있다.In another embodiment, the first layer is compressed into tablets using only the metformin-containing sustained-release granules prepared in step (a), and then the metformin-containing sustained-release granules prepared in step (a) are placed on the compressed first layer. The composite preparation according to the present invention can be prepared by compressing the second layer into tablets using the mixture of evogliptin-containing granules prepared in step (b). At this time, the weight ratio of the metformin-containing sustained-release granules to the total weight of the evogliptin-containing immediate-release granules and the metformin-containing sustained-release granules may be 15% by weight or less, preferably 1 to 15% by weight.
본 발명의 일측면에 따르면, 상기 제조방법에서 사용되는 에보글립틴 함유 과립은 메트포르민 함유 서방성 과립 100 중량부를 기준으로 10 내지 20 중량부로 포함될 수 있다. 상기 메트포르민 함유 서방성 과립과 에보글립틴 함유 과립이 상기 중량비를 갖는 경우, 에보글립틴 함유 과립을 포함하는 층의 두께가 지나치게 얇아지지 않아 이층정의 함량균일성뿐 아니라 에보글립틴 또는 이의 약학적으로 허용가능한 염의 신속한 방출이 이루어진다는 장점을 갖는다.According to one aspect of the present invention, the evogliptin-containing granules used in the above production method may be included in an amount of 10 to 20 parts by weight based on 100 parts by weight of the metformin-containing sustained-release granules. When the metformin-containing sustained-release granules and the evogliptin-containing granules have the above weight ratio, the thickness of the layer containing the evogliptin-containing granules is not excessively thin, thereby improving not only the content uniformity of the bilayer tablet but also the pharmaceutical effect of evogliptin or its pharmaceutical content. It has the advantage of rapid release of acceptable salts.
[실시예][Example]
이하, 본 발명의 이해를 돕기 위하여 실시예를 제시한다. 하기의 실시예는 본 발명을 보다 쉽게 이해하기 위하여 제공되는 것일 뿐, 실시예에 의해 본 발명의 내용이 한정되는 것은 아니다.Below, examples are presented to aid understanding of the present invention. The following examples are provided to make the present invention easier to understand, and the content of the present invention is not limited by the examples.
실시예 및 비교예의 제제들은 다음의 단계에 따라 과립을 제조한 후, 타정하는 공정을 수행하여 제조되었다.The preparations of Examples and Comparative Examples were manufactured by manufacturing granules according to the following steps and then performing a tableting process.
단계 1 : 메트포르민 염산염을 포함하는 서방성 과립을 만드는 단계로 습식과립, 건식과립 등의 다양한 공정으로 수행될 수 있다.Step 1: This is the step of making sustained-release granules containing metformin hydrochloride and can be performed through various processes such as wet granulation and dry granulation.
단계 2 : 에보글립틴 또는 그의 약제학적으로 허용가능한 염을 포함하는 속방성 과립을 만드는 단계로 습식과립, 건식과립, 혼합 등의 다양한 공정으로 수행될 수 있다.Step 2: This is a step of making immediate-release granules containing evogliptin or a pharmaceutically acceptable salt thereof and can be performed through various processes such as wet granulation, dry granulation, and mixing.
단계 3 : 서방성 과립과 속방성 과립을 이용하여 타정하여 이층정을 제조하는 단계를 포함할 수 있다. Step 3: It may include manufacturing a double-layer tablet by compressing the sustained-release granules and the immediate-release granules.
실시예 1 내지 4. 에보글립틴-메트포르민 복합제의 제조Examples 1 to 4. Preparation of evogliptin-metformin complex preparation
하기 [표 1]의 조성 및 중량으로 상기 단계 1 및 2에 따라 각각 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조한 후, 단계 3에 따라 이층정으로 타정하여 실시예 1 내지 4의 제제를 제조하였다. 표 1에서 함량의 단위는 모두 mg이다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2, respectively, with the composition and weight shown in Table 1 below, and then compressed into double-layer tablets according to step 3 to obtain the preparations of Examples 1 to 4. was manufactured. In Table 1, the unit of content is all mg.
|
항목 item |
원료명Raw material name | 실시예 1Example 1 | 실시예 2Example 2 | 실시예 3Example 3 | 실시예 4Example 4 | 비교예 1Comparative Example 1 | 비교예 2Comparative Example 2 |
|
메트포르민 서방성 과립metformin sustained release granule |
메트포르민 염산염metformin hydrochloride | 10001000 | 10001000 | 10001000 | 10001000 | 10001000 | 10001000 |
| 메타아크릴산공중합체Methacrylic acid copolymer | 9090 | -- | 8080 | 6060 | 2020 | 2020 | |
| 히드록시프로필셀룰로오스Hydroxypropylcellulose | 4545 | 5555 | 4040 | 4040 | 6060 | 6060 | |
| 히프로멜로오스Hypromellose | 230230 | 210210 | 200200 | 120120 | 9090 | 110110 | |
| 카보머carbomer | -- | 7070 | 5555 | 4040 | 2020 | -- | |
| 스테아르산마그네슘Magnesium stearate | 55 | 55 | 55 | 55 | 55 | 55 | |
|
에보글립틴 속방성 과립Evogliptin immediate release granule |
에보글립틴 타르타르산염Evogliptin Tartrate | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 |
| 만니톨Mannitol | 130130 | 130130 | 130130 | 130130 | 130130 | 130130 | |
| 전호화전분Pregelatinized starch | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | |
| 크로스카르멜로스 나트륨Croscarmellose Sodium | 2727 | 2727 | 2727 | 2727 | 2727 | 2727 | |
| 히드록시프로필셀룰로오스Hydroxypropylcellulose | 55 | 55 | 55 | 55 | 55 | 55 | |
| 콜로이드성이산화규소Colloidal silicon oxide | 22 | 22 | 22 | 22 | 22 | 22 | |
| 스테아르산마그네슘Magnesium stearate | 44 | 44 | 44 | 44 | 44 | 44 | |
| 적색산화철red iron oxide | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 |
비교예 1 및 2. 에보글립틴-메트포르민 복합제의 제조Comparative Examples 1 and 2. Preparation of evogliptin-metformin complex preparation
상기 [표 1]의 비교예 1 내지 2의 조성 및 중량으로 상기 단계 1 및 2에 따라 각각 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조한 후, 단계 3에 따라 이층정으로 타정하여 비교예 1 및 2의 제제를 제조하였다.Metformin sustained-release granules and Evogliptin immediate-release granules were prepared using the composition and weight of Comparative Examples 1 to 2 in [Table 1] according to Steps 1 and 2, respectively, and then compressed into double-layer tablets according to Step 3 for comparison. The formulations of Examples 1 and 2 were prepared.
실시예 5 내지 7. 에보글립틴-메트포르민 복합제의 제조Examples 5 to 7. Preparation of evogliptin-metformin complex preparation
하기 [표 2]의 조성 및 중량으로 상기 단계 1 및 2에 따라 각각 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조한 후, 단계 3에 따라 이층정으로 타정하여 실시예 5 내지 7의 제제를 제조하였다. 표 2에서 함량의 단위는 모두 mg이다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2, respectively, with the composition and weight shown in Table 2 below, and then compressed into double-layer tablets according to step 3 to obtain the preparations of Examples 5 to 7. was manufactured. In Table 2, the unit of content is all mg.
| 항목item | 원료명Raw material name | 실시예 5Example 5 | 실시예 6Example 6 | 실시예 7Example 7 | 비교예 3Comparative Example 3 |
|
메트포르민 서방성 과립metformin sustained release granule |
메트포르민 염산염metformin hydrochloride | 10001000 | 10001000 | 10001000 | 10001000 |
|
메타아크릴산공중합체 |
8080 | 8080 | 8080 | 8080 | |
|
히드록시프로필셀룰로오스 |
4040 | 4040 | 4040 | 4040 | |
| 히프로멜로오스Hypromellose | 200200 | 200200 | 200200 | 200200 | |
| 카보머carbomer | 5555 | 5555 | 5555 | 5555 | |
| 스테아르산마그네슘Magnesium stearate | 55 | 55 | 55 | 55 | |
|
에보글립틴 속방성 과립Evogliptin immediate release granule |
에보글립틴 타르타르산염Evogliptin Tartrate | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 |
| 만니톨Mannitol | 130130 | 130130 | 130130 | 130130 | |
| 전호화전분Pregelatinized starch | 1515 | 1515 | 1515 | 1515 | |
| 저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | -- | 1515 | 1515 | -- | |
| 크로스카르멜로스 나트륨Croscarmellose Sodium | 2727 | 2525 | -- | -- | |
| 크로스포비돈Crospovidone | -- | -- | 2525 | -- | |
| 히드록시프로필셀룰로오스Hydroxypropylcellulose | 55 | 55 | 55 | 55 | |
| 콜로이드성이산화규소Colloidal silicon oxide | 22 | 22 | 22 | 22 | |
| 스테아르산마그네슘Magnesium stearate | 44 | 44 | 44 | 44 | |
| 적색산화철red iron oxide | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 |
비교예 3. 에보글립틴-메트포르민 복합제의 제조Comparative Example 3. Preparation of evogliptin-metformin combination agent
상기 [표 2]의 비교예 3의 조성 및 중량으로 상기 단계 1 및 2에 따라 각각 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조한 후, 단계 3에 따라 이층정으로 타정하여 비교예 3의 제제를 제조하였다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared using the composition and weight of Comparative Example 3 in [Table 2] according to Steps 1 and 2, respectively, and then compressed into double-layer tablets according to Step 3, giving Comparative Example 3. A preparation was prepared.
실시예 8 내지 10. 에보글립틴-메트포르민 복합제의 제조Examples 8 to 10. Preparation of evogliptin-metformin combination preparation
하기 [표 3]의 조성 및 중량으로 단계 1, 2에 따라 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조하고 [표 4]의 비율에 따라 1층부와 2층부의 과립을 구성한 뒤 단계 3에 따라 이층정으로 타정하여 실시예 8 내지 10의 제제를 제조하였다. 표 3에서 함량의 단위는 모두 mg이다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in [Table 3] below, and 1-layer and 2-layer granules were prepared according to the ratios in [Table 4], followed by step 3. The formulations of Examples 8 to 10 were prepared by tableting into double-layer tablets according to the above. In Table 3, the unit of content is all mg.
| 항목item | 원료명Raw material name | 실시예 8Example 8 | 실시예 9Example 9 | 실시예 10Example 10 | 비교예 4Comparative Example 4 | 비교예 5Comparative Example 5 | 비교예 6Comparative Example 6 |
|
메트포르민 서방성 과립metformin sustained release granule |
메트포르민 염산염metformin hydrochloride | 10001000 | 10001000 | 10001000 | 10001000 | 10001000 | 10001000 |
|
메타아크릴산공중합체 |
8080 | 8080 | 8080 | 8080 | 8080 | 8080 | |
|
히드록시프로필셀룰로오스 |
4040 | 4040 | 4040 | 4040 | 4040 | 4040 | |
| 히프로멜로오스Hypromellose | 200200 | 200200 | 200200 | 200200 | 200200 | 200200 | |
| 카보머carbomer | 5555 | 5555 | 5555 | 5555 | 5555 | 5555 | |
| 스테아르산마그네슘Magnesium stearate | 55 | 55 | 55 | 55 | 55 | 55 | |
|
에보글립틴 속방성 과립Evogliptin immediate release granule |
에보글립틴 타르타르산염Evogliptin Tartrate | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 | 6.876.87 |
| 만니톨mannitol | 130130 | 130130 | 130130 | 130130 | 130130 | 130130 | |
| 전호화전분Pregelatinized starch | 1515 | 1515 | 1515 | 1515 | 1515 | 1515 | |
| 저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | -- | 1515 | -- | -- | 1515 | 1515 | |
| 크로스카르멜로스 나트륨Croscarmellose Sodium | 2727 | 2525 | 2727 | -- | 2525 | 2525 | |
| 크로스포비돈Crospovidone | -- | -- | -- | -- | -- | -- | |
| 히드록시프로필셀룰로오스Hydroxypropylcellulose | 55 | 55 | 55 | 55 | 55 | 55 | |
| 콜로이드성이산화규소Colloidal silicon oxide | 22 | 22 | 22 | 22 | 22 | 22 | |
| 스테아르산마그네슘Magnesium stearate | 44 | 44 | 44 | 44 | 44 | 44 | |
| 적색산화철red iron oxide | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 | 0.130.13 |
| 항목item | 과립granule | 실시예 8Example 8 | 실시예 9Example 9 | 실시예 10Example 10 | 비교예 4Comparative Example 4 | 비교예 5Comparative Example 5 |
| 1층부1st floor | 메트포르민 서방성 과립Metformin extended-release granules | 95%95% | 85%85% | 85%85% | 85%85% | 75%75% |
| 2층부2nd floor | 메트포르민 서방성 과립Metformin extended-release granules | 5%5% | 15%15% | 15%15% | 15%15% | 25%25% |
|
에보글립틴 속방성 과립Evogliptin immediate- |
100%100% | 100%100% | 100%100% | 100%100% | 100%100% |
비교예 4 내지 6. 에보글립틴-메트포르민 복합제의 제조Comparative Examples 4 to 6. Preparation of evogliptin-metformin complex preparation
상기 [표 3]의 조성 및 중량으로 단계 1, 2에 따라 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조하고, [표 4]의 비율에 따라 1층부와 2층부의 과립을 구성한 뒤, 단계 3에 따라 이층정으로 타정하여 비교예 4 및 5의 제제를 제조하였다. 또한 비교예 6은 서방과립과 속방과립을 혼합하여 단일정으로 타정하여 제조하였다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in [Table 3], and the first and second layer granules were formed according to the ratios in [Table 4], The formulations of Comparative Examples 4 and 5 were prepared by tableting into double-layer tablets according to Step 3. In addition, Comparative Example 6 was prepared by mixing sustained-release granules and immediate-release granules and compressing them into single tablets.
실시예 11 및 12. 에보글립틴-메트포르민 복합제의 제조Examples 11 and 12. Preparation of evogliptin-metformin complex
하기 [표 5]의 조성 및 중량으로 단계 1, 2에 따라 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조 후 단계 3에 따라 이층정으로 타정하여 실시예 11 및 12의 제제를 제조하였다. 표 5에서 함량의 단위는 모두 mg이다.Metformin sustained-release granules and evogliptin immediate-release granules were prepared according to steps 1 and 2 with the composition and weight shown in Table 5 below, and then compressed into double-layer tablets according to step 3 to prepare the formulations of Examples 11 and 12. In Table 5, the unit of content is all mg.
| 항목item | 원료명Raw material name | 실시예 11Example 11 | 실시예 12Example 12 | 비교예 7Comparative Example 7 |
|
메트포르민 서방성 과립metformin sustained release granule |
메트포르민 염산염metformin hydrochloride | 10001000 | 10001000 | 10001000 |
|
메타아크릴산공중합체 |
8080 | 8080 | 8080 | |
|
히드록시프로필셀룰로오스 |
4040 | 4040 | 4040 | |
| 히프로멜로오스Hypromellose | 200200 | 200200 | 200200 | |
| 카보머carbomer | 5555 | 5555 | 5555 | |
| 스테아르산마그네슘Magnesium stearate | 55 | 55 | 55 | |
|
에보글립틴 속방성 과립Evogliptin immediate release granule |
에보글립틴 타르타르산염Evogliptin Tartrate | 6.876.87 | 6.876.87 | 6.876.87 |
| 만니톨mannitol | 88.288.2 | 174.43174.43 | 55.0855.08 | |
| 전호화전분Pregelatinized starch | 10.210.2 | 20.120.1 | 6.46.4 | |
| 저치환도히드록시프로필셀룰로오스Low-substituted hydroxypropyl cellulose | 10.210.2 | 20.120.1 | 6.46.4 | |
| 크로스카르멜로스 나트륨Croscarmellose Sodium | 1717 | 33.533.5 | 10.610.6 | |
| 히드록시프로필셀룰로오스Hydroxypropylcellulose | 3.43.4 | 6.76.7 | 2.12.1 | |
| 콜로이드성이산화규소Colloidal silicon oxide | 1.331.33 | 2.72.7 | 0.80.8 | |
| 스테아르산마그네슘Magnesium stearate | 2.72.7 | 5.45.4 | 1.71.7 | |
| 적색산화철red iron oxide | 0.10.1 | 0.20.2 | 0.050.05 |
비교예 7. 에보글립틴-메트포르민 복합제의 제조Comparative Example 7. Preparation of evogliptin-metformin combination agent
상기 [표 5]의 비교예 7의 조성 및 중량으로 단계 1, 2에 따라 메트포르민 서방성 과립과 에보글립틴 속방성 과립을 제조 후 단계 3에 따라 이층정으로 타정하여 비교예 7의 제제를 제조하였다.Metformin sustained-release granules and Evogliptin immediate-release granules were prepared according to Steps 1 and 2 using the composition and weight of Comparative Example 7 in [Table 5], and then compressed into double-layer tablets according to Step 3 to prepare the formulation of Comparative Example 7. did.
실험예 1. 메트포르민의 용출 평가Experimental Example 1. Dissolution evaluation of metformin
실시예 1 내지 4 및 비교예 1, 2에 대하여 메트포르민의 용출 평가를 진행하였다. 용출평가는 pH 1.2액, 37℃, 900mL, 100rpm에서 진행하였다. 메트포르민 성분은 서방 용출을 나타내기 때문에 1시간에 15~45%, 3시간에 35~65%, 10시간에 80% 이상의 용출을 나타내어야 한다. 실시예 1 내지 4 및 비교예 1, 2의 메트포르민 용출 결과는 아래 [표 6]에 나타내었다.Dissolution evaluation of metformin was conducted for Examples 1 to 4 and Comparative Examples 1 and 2. Dissolution evaluation was conducted at pH 1.2, 37°C, 900mL, and 100rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours. The metformin dissolution results of Examples 1 to 4 and Comparative Examples 1 and 2 are shown in Table 6 below.
| 시간hour | 실시예 1Example 1 | 실시예 2Example 2 | 실시예 3Example 3 | 실시예 4Example 4 | 비교예 1Comparative Example 1 | 비교예 2Comparative Example 2 |
| 1시간1 hours | 27.6 %27.6% | 29.1 %29.1% | 28.3 %28.3% | 31.9 %31.9% | 46.7 %46.7% | 49.4 %49.4% |
| 3시간3 hours | 49.9 %49.9% | 50.3 %50.3% | 50.7 %50.7% | 53.8 %53.8% | 70.3 %70.3% | 75.1 %75.1% |
| 10시간10 hours | 89.1 %89.1% | 91.0 %91.0% | 92.5 %92.5% | 93.1 %93.1% | 101.2 %101.2% | 99.7 %99.7% |
상기 [표 6]에 나타난 바와 같이 실시예 1 내지 4의 제제는 메트포르민의 용출률이 양호한 서방 용출을 나타내었으나, 비교예 1, 2의 경우는 이층정 중 서방성 과립을 구성하는 서방화제의 함량이 적어 서방 용출을 나타내지 못하고 빠른 용출을 나타내었다.As shown in [Table 6], the formulations of Examples 1 to 4 showed sustained-release dissolution with a good dissolution rate of metformin, but in the case of Comparative Examples 1 and 2, the content of the sustained-release agent constituting the sustained-release granules in the bilayer tablet was low. It did not show sustained dissolution and showed rapid dissolution.
실험예 2. 복합제제의 용출평가Experimental Example 2. Dissolution evaluation of combination preparation
실시예 5 내지 7 및 비교예 3에 대하여 에보글립틴 성분과 메트포르민 성분의 용출 평가를 진행하였다.For Examples 5 to 7 and Comparative Example 3, dissolution evaluation of the evogliptin component and the metformin component was performed.
에보글립틴의 용출평가는 pH 1.2액, 37℃, 900mL, 50rpm에서 진행하였다. 에보글립틴은 속방용출을 나타내어야 하므로 30분이내에 용출률이 80% 이상을 나타내어야 한다. The dissolution evaluation of evogliptin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 50 rpm. Evogliptin must exhibit immediate release, so the dissolution rate must be at least 80% within 30 minutes.
메트포르민의 용출평가는 pH 1.2액, 37℃, 900mL, 100rpm에서 진행하였다. 메트포르민 성분은 서방 용출을 나타내기 때문에 1시간에 15~45%, 3시간에 35~65%, 10시간에 80% 이상의 용출을 나타내어야 한다. The dissolution evaluation of metformin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 100 rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours.
실시예 5 내지 7 및 비교예 3의 에보글립틴 용출 평가 결과는 아래 [표 7] 및 [도 1]에 나타내었고, 메트포르민 용출 평가 결과는 [표 8]에 나타내었다.The evogliptin dissolution evaluation results of Examples 5 to 7 and Comparative Example 3 are shown in [Table 7] and [Figure 1] below, and the metformin dissolution evaluation results are shown in [Table 8].
| 항목item | 실시예 5Example 5 | 실시예 6Example 6 | 실시예 7Example 7 | 비교예 3Comparative Example 3 |
| 30분 용출률 (%)30 minutes dissolution rate (%) | 89.4 %89.4% | 92.6 %92.6% | 93.8 %93.8% | 27.5 %27.5% |
| 시간hour | 실시예 5Example 5 | 실시예 6Example 6 | 실시예 7Example 7 | 비교예 3Comparative Example 3 |
| 1시간1 hours | 29.1 %29.1% | 28.4 %28.4% | 28.7 %28.7% | 27.9 %27.9% |
| 3시간3 hours | 50.4 %50.4% | 50.1 %50.1% | 51.0 %51.0% | 50.6 %50.6% |
| 10시간10 hours | 91.8 %91.8% | 93.3 %93.3% | 92.9 %92.9% | 92.8 %92.8% |
상기 [표 7] 및 [도 1]의 결과에서 볼 수 있듯이 실시예 5 내지 7의 에보글립틴은 빠른 속방 용출을 나타내었으나, 비교예 3의 경우에는 속방용출을 나타내지 못하는 것을 알 수 있었다.As can be seen from the results in [Table 7] and [Figure 1], evogliptin in Examples 5 to 7 showed rapid immediate release, but in the case of Comparative Example 3, it was found that it did not show immediate release.
[표 8]의 결과에서 볼 수 있듯이 에보글립틴의 속방성 과립에 포함되는 붕해제는 메트포르민의 서방 용출에는 영향을 주지 않음을 알 수 있었다.As can be seen from the results in [Table 8], it was found that the disintegrant contained in the immediate-release granules of evogliptin did not affect the sustained dissolution of metformin.
실험예 3. 복합제제의 용출평가 및 함량균일성 평가Experimental Example 3. Dissolution evaluation and content uniformity evaluation of combination preparation
실시예 5, 8 내지 10 및 비교예 4 내지 6의 제제에 대하여 에보글립틴 성분의 함량균일성 및 용출, 그리고 메트포르민 성분의 용출평가를 진행하였다.The preparations of Examples 5, 8 to 10 and Comparative Examples 4 to 6 were evaluated for content uniformity and dissolution of the evogliptin component and the dissolution of the metformin component.
에보글립틴의 용출평가는 pH 1.2액, 37℃, 900mL, 50rpm조건에서 30분에 샘플링하여 분석을 진행하였다. 에보글립틴은 속방용출을 나타내어야 하므로 30분이내에 용출률이 80% 이상을 나타내어야 한다.The dissolution evaluation of evogliptin was conducted by sampling for 30 minutes in a pH 1.2 solution, 37°C, 900mL, and 50rpm. Evogliptin must exhibit immediate release, so the dissolution rate must be at least 80% within 30 minutes.
메트포르민의 용출평가는 pH 1.2액, 37℃, 900mL, 100rpm에서 진행하였다. 메트포르민 성분은 서방 용출을 나타내기 때문에 1시간에 15~45%, 3시간에 35~65%, 10시간에 80% 이상의 용출을 나타내어야 한다.The dissolution evaluation of metformin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 100 rpm. Since the metformin ingredient exhibits sustained release, it must exhibit a release rate of 15-45% in 1 hour, 35-65% in 3 hours, and 80% or more in 10 hours.
에보글립틴의 용출 및 함량균일성의 RSD% 결과는 [표 9]에 나타내었고, 메트포르민 용출 결과는 [표 10] 에 나타내었다.The RSD% results of evogliptin dissolution and content uniformity are shown in [Table 9], and the metformin dissolution results are shown in [Table 10].
| 항목item |
실시예 5.Example 5. |
실시예 8.Example 8. |
실시예 9.Example 9. |
실시예 10.Example 10. |
비교예 4.Comparative example 4. |
비교예 5.Comparative example 5. |
비교예 6.Comparative example 6. |
| 용출 (%)Dissolution (%) | 91.3 %91.3% | 87.1 %87.1% | 89.5 %89.5% | 84.6 %84.6% | 63.7 %63.7% | 70.3 %70.3% | 18.9 %18.9% |
| 함량균일성 RSD%Content uniformity RSD% | 1.371.37 | 1.181.18 | 0.420.42 | 0.530.53 | 0.680.68 | 0.360.36 | 0.310.31 |
| 항목item |
실시예 5Example 5 |
실시예 8Example 8 |
실시예 9Example 9 |
실시예 10.Example 10. |
비교예 4.Comparative example 4. |
비교예 5.Comparative example 5. |
비교예 6.Comparative example 6. |
| 1시간1 hours | 28.3 %28.3% | 29.1 %29.1% | 33.6 %33.6% | 31.1 %31.1% | 30.7 %30.7% | 37.1 %37.1% | 31.7 %31.7% |
| 3시간3 hours | 50.1 %50.1% | 51.2 %51.2% | 54.9 %54.9% | 53.8 %53.8% | 51.5 %51.5% | 59.6 %59.6% | 54.0 %54.0% |
| 10시간10 hours | 90.3 %90.3% | 90.4 %90.4% | 93.6 %93.6% | 92.5 %92.5% | 91.1 %91.1% | 95.2 %95.2% | 93.1 %93.1% |
상기 [표 9]의 결과에서 볼 수 있듯이 실시예 5, 8 내지 10의 에보글립틴 용출은 모두 빠른 속방 용출을 나타내었다. 그러나 붕해제가 없거나, 서방성 과립과의 혼합비율이 높은 비교예 4, 5의 경우는 용출 저하가 일어났다. 더구나, 이층정으로 제조하지 않고 두 과립을 섞어서 타정할 경우 에보글립틴은 30분에 20% 정도의 매우 낮은 용출일 나타내었다. 에보글립틴의 함량균일성은 모두 RSD 3% 이내로 양호한 균일성을 나타내었지만, 혼합비율을 높여 이층부의 중량이 높아질수록 균일성이 좋아지는 양상을 보였다.As can be seen from the results in [Table 9], the dissolution of evogliptin in Examples 5, 8 to 10 all showed rapid immediate release. However, in Comparative Examples 4 and 5, which did not contain a disintegrant or had a high mixing ratio with sustained-release granules, dissolution decreased. Moreover, when the two granules were mixed and compressed instead of being manufactured as a double-layer tablet, evogliptin showed a very low dissolution rate of about 20% in 30 minutes. The content uniformity of evogliptin was all within RSD 3%, showing good uniformity, but as the mixing ratio was increased and the weight of the double layer increased, uniformity improved.
메트포르민 용출의 경우 [표 10]에서 볼 수 있듯이 메트포르민의 서방용출을 나타내기는 했으나, 서방성 과립이 에보글립틴 속방성 과립과 혼합되는 비율이 높아질수록 용출이 약간 빨리지는 양상을 나타내었다.In the case of metformin dissolution, as can be seen in [Table 10], metformin showed sustained release, but as the ratio of sustained-release granules mixed with evogliptin immediate-release granules increased, dissolution became slightly faster.
실험예 4. 복합제제의 함량, 함량 균일성 및 용출 평가Experimental Example 4. Evaluation of content, content uniformity, and dissolution of composite preparation
실시예 6, 11, 12 및 비교예 7에 대해 함량 및 함량균일성 평가를 진행하였다. 또한 에보글립틴 성분에 대한 용출 평가를 진행하였다. 에보글립틴의 용출평가는 pH 1.2액, 37℃, 900mL, 50rpm에서 진행하였다. 에보글립틴은 속방용출을 나타내어야 하므로 30분이내에 용출률이 80% 이상을 나타내어야 한다. 그 결과는 아래 [표 11]에 나타내었다.Content and content uniformity were evaluated for Examples 6, 11, 12, and Comparative Example 7. Additionally, dissolution evaluation of the evogliptin component was conducted. The dissolution evaluation of evogliptin was conducted in a pH 1.2 solution, 37°C, 900 mL, and 50 rpm. Evogliptin must exhibit immediate release, so the dissolution rate must be at least 80% within 30 minutes. The results are shown in [Table 11] below.
| 항목item | 실시예 6Example 6 | 실시예 11Example 11 | 실시예 12Example 12 | 비교예 7Comparative Example 7 |
| 함량 (%)content (%) | 98.9 %98.9% | 97.3 %97.3% | 102.5 %102.5% | 101.2 %101.2% |
| 함량균일성 RSD%Content uniformity RSD% | 1.491.49 | 2.332.33 | 1.031.03 | 8.798.79 |
| 30분 용출률 (%)30 minutes dissolution rate (%) | 92.6 %92.6% | 84.9 %84.9% | 94.4 %94.4% | 61.5 %61.5% |
[표 11]의 결과에서 확인할 수 있듯이 실시예 6, 11, 12 및 비교예 7의 제제 모두 함량은 100% 수준으로 적합하였으나, 2층부 중량이 작은 비교예 7의 경우 함량균일성이 좋지 않은 결과를 나타내었다.As can be seen from the results in [Table 11], the contents of all preparations of Examples 6, 11, 12 and Comparative Example 7 were suitable at the 100% level, but in the case of Comparative Example 7, where the weight of the second layer was small, the content uniformity was poor. indicated.
에보글립틴 용출 평가 결과를 통해 볼 때, 실시예 6, 11 및 12의 경우 모두 30분 용출률이 80% 이상의 속방 용출을 나타내었으나, 비교예 7의 경우 2층부의 두께가 너무 얇아져 상대적으로 1층부인 메트포르민 서방층과의 접촉 비율이 커짐에 따라 메트포르민 서방층의 서방화제의 영향으로 용출이 느려지는 것을 확인하였다.Looking at the results of evogliptin dissolution evaluation, in the case of Examples 6, 11, and 12, all showed immediate dissolution with a 30-minute dissolution rate of 80% or more, but in the case of Comparative Example 7, the thickness of the second layer was too thin, so it was relatively one layer. It was confirmed that as the contact ratio with the metformin sustained-release layer increased, dissolution slowed down due to the influence of the sustained-release agent of the metformin sustained-release layer.
실험예 5. 복합제의 단면 확인Experimental Example 5. Confirmation of cross section of composite agent
실시예 6 및 비교예 7의 복합제에 대하여 정제의 단면을 확인하였고, 이를 [도 2]에 나타내었다. [도 2]에서 확인할 수 있듯이, 에보글립틴 속방층의 경우 메트포르민 서방층보다 중량이 매우 작기 때문에 실제 단면에서도 매우 얇은 두께를 나타내고 있음을 알 수 있다. 특히, 비교예 7의 경우 매우 낮은 중량으로 메트포르민 서방층 위에 겨우 덮여 이러한 얇은 두께로 인해 좋지 않은 함량 균일성 및 낮은 용출을 나타내는 것을 알 수 있었다.The cross-section of the tablets of the combination preparations of Example 6 and Comparative Example 7 was confirmed, and this is shown in [Figure 2]. As can be seen in [Figure 2], the weight of the evogliptin immediate-release layer is much less than that of the metformin sustained-release layer, so it can be seen that the actual cross-section shows a very thin thickness. In particular, in the case of Comparative Example 7, it was found that the metformin sustained-release layer was barely covered with a very low weight, showing poor content uniformity and low dissolution due to this thin thickness.
Claims (22)
- 메트포르민 염산염 및 서방화제를 포함하는 메트포르민 함유 서방성 과립; 및 Metformin-containing sustained-release granules comprising metformin hydrochloride and a sustained-release agent; and에보글립틴 또는 약제학적으로 허용가능한 그의 염과 붕해제를 포함하는 에보글립틴 함유 속방성 과립;을 포함하는 복합제제.A combination preparation comprising: immediate-release granules containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant.
- 제1항에 있어서, 상기 복합제제는 이층정인 것인, 복합제제.The combination preparation according to claim 1, wherein the combination preparation is a double-layer tablet.
- 제1항에 있어서, 상기 복합제제에 포함된 메트포르민 함유 서방성 과립 100 중량부를 기준으로 에보글립틴 함유 속방성 과립이 5 내지 30 중량부로 포함되는 것인, 복합제제.The combination preparation according to claim 1, wherein 5 to 30 parts by weight of immediate-release granules containing evogliptin are included based on 100 parts by weight of metformin-containing sustained-release granules included in the combination preparation.
- 제1항에 있어서, 상기 메트포르민 함유 서방성 과립 및 상기 에보글립틴 함유 속방성 과립이 각각 별개의 층에 포함되는 것을 특징으로 하는, 복합제제.The combination preparation according to claim 1, wherein the metformin-containing sustained-release granules and the evogliptin-containing immediate-release granules are each contained in separate layers.
- 제1항에 있어서, 메트포르민 함유 서방성 과립만을 포함하는 제1층; 및The method of claim 1, further comprising: a first layer comprising only metformin-containing sustained-release granules; and메트포르민 함유 서방성 과립 및 에보글립틴 함유 속방성 과립을 포함하는 제2층을 포함하는 것을 특징으로 하는, 복합제제.A combination preparation comprising a second layer comprising metformin-containing sustained-release granules and evogliptin-containing immediate-release granules.
- 제5항에 있어서, 상기 제2층에 포함된 메트포르민 함유 서방성 과립 및 상기 제2층에 포함된 에보글립틴 함유 속방성 과립 전체 100중량% 기준으로, 상기 제2층의 메트포르민 함유 서방성 과립의 함량은 20중량% 미만인, 복합제제.The method of claim 5, wherein, based on 100% by weight of the total metformin-containing sustained-release granules contained in the second layer and the evogliptin-containing immediate-release granules contained in the second layer, the metformin-containing sustained-release granules in the second layer A composite preparation with a content of less than 20% by weight.
- 제1항에 있어서, 상기 복합제제는 용출시험 시 에보글립틴의 30분 이내 용출률이 80% 이상인 것을 특징으로 하는 복합제제.The combination preparation according to claim 1, wherein the combination preparation has a dissolution rate of 80% or more within 30 minutes during a dissolution test.
- 제1항에 있어서, 상기 복합제제는 용출시험 시 메트포르민의 용출률이 1 시간에 15 내지 45%, 3 시간에 35 내지 65% 및 10시간에 80% 이상인 것을 특징으로 하는 복합제제.The combination preparation according to claim 1, wherein the combination preparation has a dissolution rate of 15 to 45% in 1 hour, 35 to 65% in 3 hours, and 80% or more in 10 hours in a dissolution test.
- 제1항에 있어서, 상기 메트포르민 또는 이의 약학적으로 허용가능한 염은 복합제제 당 약 500 내지 1,000mg이 포함되는 것인, 복합제제.The combination preparation according to claim 1, wherein the metformin or a pharmaceutically acceptable salt thereof is contained in an amount of about 500 to 1,000 mg per combination preparation.
- 제1항에 있어서, 상기 에보글립틴 또는 이의 약학적으로 허용가능한 염은 복합제제 당 2.5 내지 10mg이 포함되는 것인, 복합제제.The combination preparation according to claim 1, wherein the evogliptin or a pharmaceutically acceptable salt thereof is contained in an amount of 2.5 to 10 mg per combination preparation.
- 제1항에 있어서, 상기 붕해제는 저치환도 히드록시프로필셀룰로오스, 크로스카멜로오스나트륨, 크로스포비돈 및 이의 혼합물로 이루어지는 군으로부터 선택되는 것인, 복합제제.The combination preparation according to claim 1, wherein the disintegrant is selected from the group consisting of low-substituted hydroxypropylcellulose, croscarmellose sodium, crospovidone, and mixtures thereof.
- 제1항에 있어서, 상기 붕해제의 양은 에보글립틴 함유 속방성 과립의 총 중량의 1 내지 40 중량%로 포함되는 것인, 복합제제.The combination preparation according to claim 1, wherein the amount of the disintegrant is 1 to 40% by weight of the total weight of the immediate-release granules containing evogliptin.
- 제1항에 있어서, 상기 서방화제는 메타아크릴산공중합체, 히프로멜로오스, 카보머, 히드록시프로필메틸셀룰로오스 및 이의 혼합물로 이루어지는 군으로부터 선택되는 것인, 복합제제.The combination preparation according to claim 1, wherein the sustained-release agent is selected from the group consisting of methacrylic acid copolymer, hypromellose, carbomer, hydroxypropylmethylcellulose, and mixtures thereof.
- 제1항에 있어서, 상기 서방화제의 양은 메트포르민 함유 서방성 과립 총 중량의 11 내지 30 중량%로 포함되는 것인, 복합제제.The combination preparation according to claim 1, wherein the amount of the sustained-release agent is 11 to 30% by weight of the total weight of the metformin-containing sustained-release granules.
- 제1항에 있어서, 상기 에보글립틴 함유 속방성 과립은 희석제, 활택제, 결합제, 가소제, 분산제 및 착색제로 이루어지는 군으로부터 선택되는 약학적으로 허용가능한 첨가제를 더 포함하는 것인, 복합제제.The combination preparation according to claim 1, wherein the evogliptin-containing immediate-release granules further comprise a pharmaceutically acceptable additive selected from the group consisting of diluents, lubricants, binders, plasticizers, dispersants, and colorants.
- 제1항에 있어서, 상기 메트포르민 함유 서방성 과립은 활택제, 희석제 및 결합제로 이루어지는 군으로부터 선택되는 약학적으로 허용가능한 첨가제를 더 포함하는 것인, 복합제제.The combination preparation according to claim 1, wherein the metformin-containing sustained-release granules further include a pharmaceutically acceptable additive selected from the group consisting of a lubricant, a diluent, and a binder.
- (a) 메트포르민 또는 이의 약학적으로 허용가능한 염과 서방화제를 포함하는 메트포르민 함유 서방성 과립을 제조하는 단계;(a) preparing metformin-containing sustained-release granules comprising metformin or a pharmaceutically acceptable salt thereof and a sustained-release agent;(b) 에보글립틴 또는 이의 약학적으로 허용가능한 염과 붕해제를 포함하는 에보글립틴 함유 속방성 과립을 제조하는 단계; 및(b) preparing immediate-release granules containing evogliptin containing evogliptin or a pharmaceutically acceptable salt thereof and a disintegrant; and(c) 상기 단계 (a) 및 (b)에서 각각 제조된 메트포르민 함유 서방성 과립 및 에보글립틴 함유 속방성 과립을 타정하여 이층정으로 제조하는 단계;(c) compressing the metformin-containing sustained-release granules and evogliptin-containing immediate-release granules prepared in steps (a) and (b), respectively, into two-layer tablets;를 포함하는 제1항에 따른 복합제제의 제조방법.A method for manufacturing a combination preparation according to claim 1 comprising.
- 제17항에 있어서, 상기 단계 (a) 또는 (b)는 습식과립법 또는 건식과립법에 의해 수행되는 것을 특징으로 하는, 복합제제의 제조방법.The method of claim 17, wherein step (a) or (b) is performed by a wet granulation method or a dry granulation method.
- 제17항에 있어서, 메트포르민 함유 서방성 과립 100 중량부를 기준으로 에보글립틴 함유 과립이 5 내지 30 중량부로 포함되는 것을 특징으로 하는 복합제제의 제조방법.The method of claim 17, wherein 5 to 30 parts by weight of evogliptin-containing granules are included based on 100 parts by weight of metformin-containing sustained-release granules.
- 제17항에 있어서, 상기 단계 (c)는The method of claim 17, wherein step (c) is상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립만을 사용하여 제1층을 타정한 후, 타정된 제1층 상에 상기 단계 (b)에서 제조된 에보글립틴 함유 속방성 과립만을 사용하여 제2층을 타정하여 수행되는 것인, 복합제제의 제조방법.After compressing the first layer into tablets using only the sustained-release granules containing metformin prepared in step (a), a tablet was prepared on the compressed first layer using only the immediate-release granules containing evogliptin prepared in step (b). A method for manufacturing a composite formulation, which is performed by compressing two layers.
- 제17항에 있어서, 상기 단계 (c)는The method of claim 17, wherein step (c) is상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립만을 사용하여 제1층을 타정한 후, 타정된 제1층 상에 상기 단계 (a)에서 제조된 메트포르민 함유 서방성 과립 및 단계 (b)에서 제조된 에보글립틴 함유 속방성 과립의 혼합물을 사용하여 제2층을 타정하여 수행되는 것인 복합제제의 제조방법.After compressing the first layer using only the metformin-containing sustained-release granules prepared in step (a), the metformin-containing sustained-release granules prepared in step (a) and the sustained-release granules containing metformin prepared in step (b) are placed on the compressed first layer. A method for producing a composite formulation, which is performed by compressing the second layer into tablets using a mixture of the prepared evogliptin-containing immediate-release granules.
- 제21항에 있어서,According to clause 21,제2층의 에보글립틴 함유 속방성 과립 및 메트포르민 함유 서방성 과립의 전체 중량에 대한 메트포르민 함유 서방성 과립의 중량비는 20중량% 미만인 것인, 복합제제의 제조방법.A method for producing a combination formulation, wherein the weight ratio of the metformin-containing sustained-release granules to the total weight of the evogliptin-containing immediate-release granules and the metformin-containing sustained-release granules of the second layer is less than 20% by weight.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2022/012670 WO2024043358A1 (en) | 2022-08-24 | 2022-08-24 | Oral composite formulation comprising evogliptin and metformin and method for preparing same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| PCT/KR2022/012670 WO2024043358A1 (en) | 2022-08-24 | 2022-08-24 | Oral composite formulation comprising evogliptin and metformin and method for preparing same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| WO2024043358A1 true WO2024043358A1 (en) | 2024-02-29 |
Family
ID=90013567
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| PCT/KR2022/012670 WO2024043358A1 (en) | 2022-08-24 | 2022-08-24 | Oral composite formulation comprising evogliptin and metformin and method for preparing same |
Country Status (1)
| Country | Link |
|---|---|
| WO (1) | WO2024043358A1 (en) |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220004026A (en) * | 2019-03-25 | 2022-01-11 | 더 조지 인스티튜트 포 글로벌 헬스 | Low-dose 3-type combination formulation |
| US20220087958A1 (en) * | 2020-09-22 | 2022-03-24 | Elite Pharmaceutical Solution Inc. | Antidiabetic pharmaceutical compositions and preparation method thereof |
-
2022
- 2022-08-24 WO PCT/KR2022/012670 patent/WO2024043358A1/en unknown
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20220004026A (en) * | 2019-03-25 | 2022-01-11 | 더 조지 인스티튜트 포 글로벌 헬스 | Low-dose 3-type combination formulation |
| US20220087958A1 (en) * | 2020-09-22 | 2022-03-24 | Elite Pharmaceutical Solution Inc. | Antidiabetic pharmaceutical compositions and preparation method thereof |
Non-Patent Citations (4)
| Title |
|---|
| BAJAJ, SARITA; AIWALE, AMOL; TRAILOKYA, ABHIJIT; SHARMA, AKHILESH: "Clinical Evidence of Evogliptin plus Metformin in Management of Type 2 Diabetes mellitus", JOURNAL OF THE ASSOCIATION OF PHYSICIANS OF INDIA, vol. 69, no. 2, 1 February 2021 (2021-02-01), IN , pages 25 - 29, XP009553231, ISSN: 0004-5772 * |
| HAN WON DONG; PARK HEEJUN; SEO JEONG-WOONG; WOO JANG SUN; HA EUN-SOL; KIM MIN-SOO: "Active coating of immediate-release evogliptin tartrate to prepare fixed dose combination tablet with sustained-release metformin HCl", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 623, 15 June 2022 (2022-06-15), NL , XP087112504, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2022.121927 * |
| WON DONG HAN; PARK HEEJUN; HA EUN-SOL; KIM HWAN-HO; JANG SUN WOO; KIM MIN-SOO: "Optimization of bilayer tablet manufacturing process for fixed dose combination of sustained release high-dose drug and immediate release low-dose drug based on quality by design (QbD)", INTERNATIONAL JOURNAL OF PHARMACEUTICS, ELSEVIER, NL, vol. 605, 28 June 2021 (2021-06-28), NL , XP086713308, ISSN: 0378-5173, DOI: 10.1016/j.ijpharm.2021.120838 * |
| YU KYUNG-SANG, RHEE SU-JIN, LEE SEUNG HWAN, YOON SEO HYUN, CHO JOO-YOUN, JANG IN-JIN: "Pharmacokinetics of the evogliptin/metformin extended-release (5/1,000 mg) fixed-dose combination formulation compared to the corresponding loose combination, and food effect in healthy subjects", DRUG DESIGN, DEVELOPMENT AND THERAPY, DOVE MEDICAL PRESS LTD., UNITED KINGDOM, vol. 10, 1 January 2016 (2016-01-01), United Kingdom , pages 1411 - 1418, XP093142894, ISSN: 1177-8881, DOI: 10.2147/DDDT.S102459 * |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US8486453B2 (en) | Controlled release compositions with reduced food effect | |
| WO2018124497A1 (en) | Pharmaceutical composite preparation containing dapagliflozin l-proline and antidiabetic agent | |
| US9351937B2 (en) | Controlled release pharmaceutical formulations of nitazoxanide | |
| WO2012005500A2 (en) | Time-delayed sustained release pharmaceutical composition comprising dapoxetine for oral administration | |
| MXPA00012957A (en) | Extended release oral dosage composition. | |
| WO2013147462A1 (en) | Pharmaceutical composition comprising olmesartan medoxomil and rosuvastatin or its salt | |
| WO2016105084A2 (en) | Pharmaceutical composition for treating diabetes | |
| WO2019059557A2 (en) | Medicinal composition comprising sglt-2 inhibitor and angiotensin receptor blocker | |
| KR20070053221A (en) | Anti-histaminic composition | |
| KR20140045271A (en) | Combination drug comprising gemigliptin and metformin and method for the preparation thereof | |
| WO2020242413A1 (en) | A combination comprising alogliptin and metformin | |
| WO2021201461A1 (en) | Oral complex tablet comprising sitagliptin, dapagliflozin, and metformin | |
| WO2021261837A1 (en) | Oral pharmaceutical composition comprising nafamostat mesylate as active ingredient | |
| WO2018062685A1 (en) | Composite formed into single layer, comprising candesartan and amlodipine | |
| WO2019240699A2 (en) | Tablet formulations comprising metformin and sitagliptin processed with hot-melt extrusion | |
| EP3784672A2 (en) | Tablet formulations comprising metformin and sitagliptin | |
| WO2024043358A1 (en) | Oral composite formulation comprising evogliptin and metformin and method for preparing same | |
| WO2012077968A2 (en) | Complex formulation comprising lercanidipine hydrochloride and valsartan and method for the preparation thereof | |
| WO2020050677A1 (en) | Pharmaceutical composition having improved stability | |
| WO2021221288A1 (en) | Combination drug comprising mosapride and proton pump inhibitor | |
| WO2014157852A1 (en) | Sustained-release medicinal composition containing eperisone as active ingredient | |
| WO2021157883A1 (en) | Hard capsule agent comprising enteric proton pump inhibitor and mosapride sustained-release formulation | |
| WO2013032206A1 (en) | Controlled-release oral composition containing itopride hydrochloride, and preparation method thereof | |
| CA3185535A1 (en) | The process for the preparation of a film coated tablet comprising linagliptin and metformin | |
| WO2016137266A2 (en) | Pharmaceutical composition containing eperisone and pelubiprofen |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| 121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22956564 Country of ref document: EP Kind code of ref document: A1 |