CN116648263A - Pharmaceutical composition comprising englitazone co-crystals - Google Patents
Pharmaceutical composition comprising englitazone co-crystals Download PDFInfo
- Publication number
- CN116648263A CN116648263A CN202180077817.7A CN202180077817A CN116648263A CN 116648263 A CN116648263 A CN 116648263A CN 202180077817 A CN202180077817 A CN 202180077817A CN 116648263 A CN116648263 A CN 116648263A
- Authority
- CN
- China
- Prior art keywords
- pharmaceutical composition
- pharmaceutical
- pharmaceutical formulation
- crystal
- formulation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000008194 pharmaceutical composition Substances 0.000 title claims abstract description 47
- 239000013078 crystal Substances 0.000 title claims abstract description 28
- MVDXXGIBARMXSA-PYUWXLGESA-N 5-[[(2r)-2-benzyl-3,4-dihydro-2h-chromen-6-yl]methyl]-1,3-thiazolidine-2,4-dione Chemical compound S1C(=O)NC(=O)C1CC1=CC=C(O[C@@H](CC=2C=CC=CC=2)CC2)C2=C1 MVDXXGIBARMXSA-PYUWXLGESA-N 0.000 title description 3
- 229950002375 englitazone Drugs 0.000 title description 3
- 239000000203 mixture Substances 0.000 claims abstract description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 24
- 239000011248 coating agent Substances 0.000 claims abstract description 13
- 238000000576 coating method Methods 0.000 claims abstract description 13
- 239000000463 material Substances 0.000 claims abstract description 13
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 claims abstract description 12
- 239000008101 lactose Substances 0.000 claims abstract description 12
- 239000003085 diluting agent Substances 0.000 claims description 18
- 239000003814 drug Substances 0.000 claims description 17
- 229940079593 drug Drugs 0.000 claims description 15
- 239000003826 tablet Substances 0.000 claims description 12
- ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 9
- 229930182821 L-proline Natural products 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 9
- 239000003112 inhibitor Substances 0.000 claims description 9
- 229960002429 proline Drugs 0.000 claims description 9
- 229940077274 Alpha glucosidase inhibitor Drugs 0.000 claims description 8
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 8
- 229940100389 Sulfonylurea Drugs 0.000 claims description 8
- 229940123464 Thiazolidinedione Drugs 0.000 claims description 8
- 239000003888 alpha glucosidase inhibitor Substances 0.000 claims description 8
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 8
- YROXIXLRRCOBKF-UHFFFAOYSA-N sulfonylurea Chemical class OC(=N)N=S(=O)=O YROXIXLRRCOBKF-UHFFFAOYSA-N 0.000 claims description 8
- 150000001467 thiazolidinediones Chemical class 0.000 claims description 8
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 7
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 7
- 150000005846 sugar alcohols Chemical class 0.000 claims description 7
- 206010007558 Cardiac failure chronic Diseases 0.000 claims description 6
- SWLAMJPTOQZTAE-UHFFFAOYSA-N 4-[2-[(5-chloro-2-methoxybenzoyl)amino]ethyl]benzoic acid Chemical class COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(C(O)=O)C=C1 SWLAMJPTOQZTAE-UHFFFAOYSA-N 0.000 claims description 5
- 208000002249 Diabetes Complications Diseases 0.000 claims description 5
- 206010012655 Diabetic complications Diseases 0.000 claims description 5
- 206010012601 diabetes mellitus Diseases 0.000 claims description 5
- 239000003960 organic solvent Substances 0.000 claims description 5
- 229940123208 Biguanide Drugs 0.000 claims description 4
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 4
- 108010067722 Dipeptidyl Peptidase 4 Proteins 0.000 claims description 4
- 102100025012 Dipeptidyl peptidase 4 Human genes 0.000 claims description 4
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 claims description 4
- 229930195725 Mannitol Natural products 0.000 claims description 4
- 108091006277 SLC5A1 Proteins 0.000 claims description 4
- 102000058090 Sodium-Glucose Transporter 1 Human genes 0.000 claims description 4
- 229940123518 Sodium/glucose cotransporter 2 inhibitor Drugs 0.000 claims description 4
- 150000004283 biguanides Chemical class 0.000 claims description 4
- 239000011230 binding agent Substances 0.000 claims description 4
- 239000007884 disintegrant Substances 0.000 claims description 4
- 230000009977 dual effect Effects 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- 239000000594 mannitol Substances 0.000 claims description 4
- 235000010355 mannitol Nutrition 0.000 claims description 4
- 108091006269 SLC5A2 Proteins 0.000 claims description 3
- 239000007941 film coated tablet Substances 0.000 claims description 3
- 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 3
- 238000004898 kneading Methods 0.000 claims description 3
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 claims description 2
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 claims description 2
- 239000004386 Erythritol Substances 0.000 claims description 2
- UNXHWFMMPAWVPI-UHFFFAOYSA-N Erythritol Natural products OCC(O)C(O)CO UNXHWFMMPAWVPI-UHFFFAOYSA-N 0.000 claims description 2
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 claims description 2
- 239000000654 additive Substances 0.000 claims description 2
- 230000000996 additive effect Effects 0.000 claims description 2
- 239000002775 capsule Substances 0.000 claims description 2
- 235000019414 erythritol Nutrition 0.000 claims description 2
- UNXHWFMMPAWVPI-ZXZARUISSA-N erythritol Chemical compound OC[C@H](O)[C@H](O)CO UNXHWFMMPAWVPI-ZXZARUISSA-N 0.000 claims description 2
- 229940009714 erythritol Drugs 0.000 claims description 2
- 239000008187 granular material Substances 0.000 claims description 2
- 239000000832 lactitol Substances 0.000 claims description 2
- 235000010448 lactitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-JVCRWLNRSA-N lactitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@@H]1O[C@H](CO)[C@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-JVCRWLNRSA-N 0.000 claims description 2
- 229960003451 lactitol Drugs 0.000 claims description 2
- 239000000845 maltitol Substances 0.000 claims description 2
- 235000010449 maltitol Nutrition 0.000 claims description 2
- VQHSOMBJVWLPSR-WUJBLJFYSA-N maltitol Chemical compound OC[C@H](O)[C@@H](O)[C@@H]([C@H](O)CO)O[C@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O VQHSOMBJVWLPSR-WUJBLJFYSA-N 0.000 claims description 2
- 229940035436 maltitol Drugs 0.000 claims description 2
- 229960001855 mannitol Drugs 0.000 claims description 2
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 claims description 2
- 239000008188 pellet Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims description 2
- 239000000600 sorbitol Substances 0.000 claims description 2
- 235000010356 sorbitol Nutrition 0.000 claims description 2
- 229960002920 sorbitol Drugs 0.000 claims description 2
- 239000000811 xylitol Substances 0.000 claims description 2
- 235000010447 xylitol Nutrition 0.000 claims description 2
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 claims description 2
- 229960002675 xylitol Drugs 0.000 claims description 2
- 102000058081 Sodium-Glucose Transporter 2 Human genes 0.000 claims 1
- 230000000903 blocking effect Effects 0.000 abstract description 5
- 230000000694 effects Effects 0.000 abstract description 3
- 238000002360 preparation method Methods 0.000 abstract 1
- 230000000052 comparative effect Effects 0.000 description 14
- 230000005496 eutectics Effects 0.000 description 9
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 6
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 5
- YASAKCUCGLMORW-UHFFFAOYSA-N Rosiglitazone Chemical compound C=1C=CC=NC=1N(C)CCOC(C=C1)=CC=C1CC1SC(=O)NC1=O YASAKCUCGLMORW-UHFFFAOYSA-N 0.000 description 4
- 238000012790 confirmation Methods 0.000 description 4
- HYAFETHFCAUJAY-UHFFFAOYSA-N pioglitazone Chemical compound N1=CC(CC)=CC=C1CCOC(C=C1)=CC=C1CC1C(=O)NC(=O)S1 HYAFETHFCAUJAY-UHFFFAOYSA-N 0.000 description 4
- BOVGTQGAOIONJV-BETUJISGSA-N 1-[(3ar,6as)-3,3a,4,5,6,6a-hexahydro-1h-cyclopenta[c]pyrrol-2-yl]-3-(4-methylphenyl)sulfonylurea Chemical compound C1=CC(C)=CC=C1S(=O)(=O)NC(=O)NN1C[C@H]2CCC[C@H]2C1 BOVGTQGAOIONJV-BETUJISGSA-N 0.000 description 3
- 102100020888 Sodium/glucose cotransporter 2 Human genes 0.000 description 3
- 229960001667 alogliptin Drugs 0.000 description 3
- ZSBOMTDTBDDKMP-OAHLLOKOSA-N alogliptin Chemical compound C=1C=CC=C(C#N)C=1CN1C(=O)N(C)C(=O)C=C1N1CCC[C@@H](N)C1 ZSBOMTDTBDDKMP-OAHLLOKOSA-N 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 229960000346 gliclazide Drugs 0.000 description 3
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 3
- XUFXOAAUWZOOIT-SXARVLRPSA-N (2R,3R,4R,5S,6R)-5-[[(2R,3R,4R,5S,6R)-5-[[(2R,3R,4S,5S,6R)-3,4-dihydroxy-6-methyl-5-[[(1S,4R,5S,6S)-4,5,6-trihydroxy-3-(hydroxymethyl)-1-cyclohex-2-enyl]amino]-2-oxanyl]oxy]-3,4-dihydroxy-6-(hydroxymethyl)-2-oxanyl]oxy]-6-(hydroxymethyl)oxane-2,3,4-triol Chemical compound O([C@H]1O[C@H](CO)[C@H]([C@@H]([C@H]1O)O)O[C@H]1O[C@@H]([C@H]([C@H](O)[C@H]1O)N[C@@H]1[C@@H]([C@@H](O)[C@H](O)C(CO)=C1)O)C)[C@@H]1[C@@H](CO)O[C@@H](O)[C@H](O)[C@H]1O XUFXOAAUWZOOIT-SXARVLRPSA-N 0.000 description 2
- NIXOWILDQLNWCW-UHFFFAOYSA-N Acrylic acid Chemical compound OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-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
- JVHXJTBJCFBINQ-ADAARDCZSA-N Dapagliflozin Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)=CC=C1Cl JVHXJTBJCFBINQ-ADAARDCZSA-N 0.000 description 2
- 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 2
- IBAQFPQHRJAVAV-ULAWRXDQSA-N Miglitol Chemical compound OCCN1C[C@H](O)[C@@H](O)[C@H](O)[C@H]1CO IBAQFPQHRJAVAV-ULAWRXDQSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- DBMJMQXJHONAFJ-UHFFFAOYSA-M Sodium laurylsulphate Chemical compound [Na+].CCCCCCCCCCCCOS([O-])(=O)=O DBMJMQXJHONAFJ-UHFFFAOYSA-M 0.000 description 2
- 102000000070 Sodium-Glucose Transport Proteins Human genes 0.000 description 2
- 108010080361 Sodium-Glucose Transport Proteins Proteins 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- 229920002472 Starch Polymers 0.000 description 2
- FZNCGRZWXLXZSZ-CIQUZCHMSA-N Voglibose Chemical compound OCC(CO)N[C@H]1C[C@](O)(CO)[C@@H](O)[C@H](O)[C@H]1O FZNCGRZWXLXZSZ-CIQUZCHMSA-N 0.000 description 2
- 229960002632 acarbose Drugs 0.000 description 2
- XUFXOAAUWZOOIT-UHFFFAOYSA-N acarviostatin I01 Natural products OC1C(O)C(NC2C(C(O)C(O)C(CO)=C2)O)C(C)OC1OC(C(C1O)O)C(CO)OC1OC1C(CO)OC(O)C(O)C1O XUFXOAAUWZOOIT-UHFFFAOYSA-N 0.000 description 2
- 239000001506 calcium phosphate Substances 0.000 description 2
- OSGAYBCDTDRGGQ-UHFFFAOYSA-L calcium sulfate Chemical compound [Ca+2].[O-]S([O-])(=O)=O OSGAYBCDTDRGGQ-UHFFFAOYSA-L 0.000 description 2
- 229960001713 canagliflozin Drugs 0.000 description 2
- VHOFTEAWFCUTOS-TUGBYPPCSA-N canagliflozin hydrate Chemical compound O.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1.CC1=CC=C([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O2)O)C=C1CC(S1)=CC=C1C1=CC=C(F)C=C1 VHOFTEAWFCUTOS-TUGBYPPCSA-N 0.000 description 2
- 229960001631 carbomer Drugs 0.000 description 2
- 229960000913 crospovidone Drugs 0.000 description 2
- 229960003834 dapagliflozin Drugs 0.000 description 2
- 229960004346 glimepiride Drugs 0.000 description 2
- WIGIZIANZCJQQY-RUCARUNLSA-N glimepiride Chemical compound O=C1C(CC)=C(C)CN1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)N[C@@H]2CC[C@@H](C)CC2)C=C1 WIGIZIANZCJQQY-RUCARUNLSA-N 0.000 description 2
- 229960001381 glipizide Drugs 0.000 description 2
- ZJJXGWJIGJFDTL-UHFFFAOYSA-N glipizide Chemical compound C1=NC(C)=CN=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZJJXGWJIGJFDTL-UHFFFAOYSA-N 0.000 description 2
- 208000038003 heart failure with preserved ejection fraction Diseases 0.000 description 2
- 208000038002 heart failure with reduced ejection fraction Diseases 0.000 description 2
- 229960002397 linagliptin Drugs 0.000 description 2
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 2
- 238000012423 maintenance Methods 0.000 description 2
- 229960001110 miglitol Drugs 0.000 description 2
- 229960005095 pioglitazone Drugs 0.000 description 2
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 2
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 229940069328 povidone Drugs 0.000 description 2
- 229960004586 rosiglitazone Drugs 0.000 description 2
- 229960004937 saxagliptin Drugs 0.000 description 2
- 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 2
- 108010033693 saxagliptin Proteins 0.000 description 2
- 235000019333 sodium laurylsulphate Nutrition 0.000 description 2
- 239000008107 starch Substances 0.000 description 2
- 235000019698 starch Nutrition 0.000 description 2
- 229940032147 starch Drugs 0.000 description 2
- 229940124597 therapeutic agent Drugs 0.000 description 2
- 229960001254 vildagliptin Drugs 0.000 description 2
- SYOKIDBDQMKNDQ-XWTIBIIYSA-N vildagliptin Chemical compound C1C(O)(C2)CC(C3)CC1CC32NCC(=O)N1CCC[C@H]1C#N SYOKIDBDQMKNDQ-XWTIBIIYSA-N 0.000 description 2
- 229960001729 voglibose Drugs 0.000 description 2
- QKDRXGFQVGOQKS-CRSSMBPESA-N (2s,3r,4r,5s,6r)-2-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]-6-methylsulfanyloxane-3,4,5-triol Chemical compound C1=CC(OCC)=CC=C1CC1=CC([C@H]2[C@@H]([C@@H](O)[C@H](O)[C@@H](SC)O2)O)=CC=C1Cl QKDRXGFQVGOQKS-CRSSMBPESA-N 0.000 description 1
- OKMWKBLSFKFYGZ-UHFFFAOYSA-N 1-behenoylglycerol Chemical compound CCCCCCCCCCCCCCCCCCCCCC(=O)OCC(O)CO OKMWKBLSFKFYGZ-UHFFFAOYSA-N 0.000 description 1
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-UHFFFAOYSA-N 2-(hydroxymethyl)-6-[4,5,6-trihydroxy-2-(hydroxymethyl)oxan-3-yl]oxyoxane-3,4,5-triol Chemical compound OCC1OC(OC2C(O)C(O)C(O)OC2CO)C(O)C(O)C1O GUBGYTABKSRVRQ-UHFFFAOYSA-N 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 229920002307 Dextran Polymers 0.000 description 1
- 208000008960 Diabetic foot Diseases 0.000 description 1
- 235000019739 Dicalciumphosphate Nutrition 0.000 description 1
- 239000001856 Ethyl cellulose Substances 0.000 description 1
- 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 1
- 229930091371 Fructose Natural products 0.000 description 1
- 239000005715 Fructose Substances 0.000 description 1
- RFSUNEUAIZKAJO-ARQDHWQXSA-N Fructose Chemical compound OC[C@H]1O[C@](O)(CO)[C@@H](O)[C@@H]1O RFSUNEUAIZKAJO-ARQDHWQXSA-N 0.000 description 1
- 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 1
- FAEKWTJYAYMJKF-QHCPKHFHSA-N GlucoNorm Chemical compound C1=C(C(O)=O)C(OCC)=CC(CC(=O)N[C@@H](CC(C)C)C=2C(=CC=CC=2)N2CCCCC2)=C1 FAEKWTJYAYMJKF-QHCPKHFHSA-N 0.000 description 1
- 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 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 1
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 1
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- DLSWIYLPEUIQAV-UHFFFAOYSA-N Semaglutide Chemical compound CCC(C)C(NC(=O)C(Cc1ccccc1)NC(=O)C(CCC(O)=O)NC(=O)C(CCCCNC(=O)COCCOCCNC(=O)COCCOCCNC(=O)CCC(NC(=O)CCCCCCCCCCCCCCCCC(O)=O)C(O)=O)NC(=O)C(C)NC(=O)C(C)NC(=O)C(CCC(N)=O)NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(CC(C)C)NC(=O)C(Cc1ccc(O)cc1)NC(=O)C(CO)NC(=O)C(CO)NC(=O)C(NC(=O)C(CC(O)=O)NC(=O)C(CO)NC(=O)C(NC(=O)C(Cc1ccccc1)NC(=O)C(NC(=O)CNC(=O)C(CCC(O)=O)NC(=O)C(C)(C)NC(=O)C(N)Cc1cnc[nH]1)C(C)O)C(C)O)C(C)C)C(=O)NC(C)C(=O)NC(Cc1c[nH]c2ccccc12)C(=O)NC(CC(C)C)C(=O)NC(C(C)C)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CCCNC(N)=N)C(=O)NCC(O)=O DLSWIYLPEUIQAV-UHFFFAOYSA-N 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 101710103228 Sodium/glucose cotransporter 2 Proteins 0.000 description 1
- 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 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 206010067584 Type 1 diabetes mellitus Diseases 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000001133 acceleration Effects 0.000 description 1
- DPXJVFZANSGRMM-UHFFFAOYSA-N acetic acid;2,3,4,5,6-pentahydroxyhexanal;sodium Chemical compound [Na].CC(O)=O.OCC(O)C(O)C(O)C(O)C=O DPXJVFZANSGRMM-UHFFFAOYSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000853 adhesive Substances 0.000 description 1
- 230000001070 adhesive effect Effects 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- LDXYBEHACFJIEL-HNNXBMFYSA-N anagliptin Chemical compound C=1N2N=C(C)C=C2N=CC=1C(=O)NCC(C)(C)NCC(=O)N1CCC[C@H]1C#N LDXYBEHACFJIEL-HNNXBMFYSA-N 0.000 description 1
- 229950009977 anagliptin Drugs 0.000 description 1
- -1 and preferably Chemical compound 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229910000019 calcium carbonate Inorganic materials 0.000 description 1
- 229960003563 calcium carbonate Drugs 0.000 description 1
- 235000010216 calcium carbonate Nutrition 0.000 description 1
- 229940095672 calcium sulfate Drugs 0.000 description 1
- 235000011132 calcium sulphate Nutrition 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 1
- 239000008112 carboxymethyl-cellulose Substances 0.000 description 1
- 239000001913 cellulose Substances 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 229940096516 dextrates Drugs 0.000 description 1
- 239000008121 dextrose Substances 0.000 description 1
- NEFBYIFKOOEVPA-UHFFFAOYSA-K dicalcium phosphate Chemical compound [Ca+2].[Ca+2].[O-]P([O-])([O-])=O NEFBYIFKOOEVPA-UHFFFAOYSA-K 0.000 description 1
- 229940038472 dicalcium phosphate Drugs 0.000 description 1
- 229910000390 dicalcium phosphate Inorganic materials 0.000 description 1
- 238000002845 discoloration Methods 0.000 description 1
- RRPFCKLVOUENJB-UHFFFAOYSA-L disodium;2-aminoacetic acid;carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O.NCC(O)=O RRPFCKLVOUENJB-UHFFFAOYSA-L 0.000 description 1
- 229960003345 empagliflozin Drugs 0.000 description 1
- OBWASQILIWPZMG-QZMOQZSNSA-N empagliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(Cl)C(CC=2C=CC(O[C@@H]3COCC3)=CC=2)=C1 OBWASQILIWPZMG-QZMOQZSNSA-N 0.000 description 1
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- 229960002458 gemigliptin Drugs 0.000 description 1
- 229960004580 glibenclamide Drugs 0.000 description 1
- ZNNLBTZKUZBEKO-UHFFFAOYSA-N glyburide Chemical compound COC1=CC=C(Cl)C=C1C(=O)NCCC1=CC=C(S(=O)(=O)NC(=O)NC2CCCCC2)C=C1 ZNNLBTZKUZBEKO-UHFFFAOYSA-N 0.000 description 1
- 229940049654 glyceryl behenate Drugs 0.000 description 1
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 1
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 1
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 229950000991 ipragliflozin Drugs 0.000 description 1
- AHFWIQIYAXSLBA-RQXATKFSSA-N ipragliflozin Chemical compound O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1C1=CC=C(F)C(CC=2SC3=CC=CC=C3C=2)=C1 AHFWIQIYAXSLBA-RQXATKFSSA-N 0.000 description 1
- 208000017169 kidney disease Diseases 0.000 description 1
- 230000003902 lesion Effects 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229950004994 meglitinide Drugs 0.000 description 1
- XZWYZXLIPXDOLR-UHFFFAOYSA-N metformin Chemical compound CN(C)C(=N)NC(N)=N XZWYZXLIPXDOLR-UHFFFAOYSA-N 0.000 description 1
- 229960003105 metformin Drugs 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 229960000698 nateglinide Drugs 0.000 description 1
- OELFLUMRDSZNSF-BRWVUGGUSA-N nateglinide Chemical compound C1C[C@@H](C(C)C)CC[C@@H]1C(=O)N[C@@H](C(O)=O)CC1=CC=CC=C1 OELFLUMRDSZNSF-BRWVUGGUSA-N 0.000 description 1
- 201000001119 neuropathy Diseases 0.000 description 1
- 230000007823 neuropathy Effects 0.000 description 1
- 208000033808 peripheral neuropathy Diseases 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920003124 powdered cellulose Polymers 0.000 description 1
- 235000019814 powdered cellulose Nutrition 0.000 description 1
- 229960002354 repaglinide Drugs 0.000 description 1
- 229950011186 semaglutide Drugs 0.000 description 1
- 108010060325 semaglutide Proteins 0.000 description 1
- 229960004034 sitagliptin Drugs 0.000 description 1
- 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 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 1
- 229950005268 sotagliflozin Drugs 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical compound [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 1
- 229940078499 tricalcium phosphate Drugs 0.000 description 1
- 229910000391 tricalcium phosphate Inorganic materials 0.000 description 1
- 235000019731 tricalcium phosphate Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 229920001285 xanthan gum Polymers 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
-
- 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
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/351—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom not condensed with another ring
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/04—Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
Abstract
The present invention provides a pharmaceutical composition comprising an englitz co-crystal and having a water content of 3% or less in the composition, and a pharmaceutical formulation comprising the pharmaceutical composition. The pharmaceutical composition of the invention can maintain the englitz co-crystal and prevent browning phenomenon when lactose is used in the preparation of the englitz co-crystal. Furthermore, the pharmaceutical formulation of the present invention can exert the effect of blocking hygroscopicity to the maximum by including a coating material capable of blocking hygroscopicity of the englitant co-crystal.
Description
Technical Field
The present invention relates to pharmaceutical compositions comprising an enggliflozin (empagliflozin) co-crystal and pharmaceutical formulations comprising said pharmaceutical compositions.
Background
Engliflozin is a sodium glucose cotransporter 2 (SGLT 2) inhibitor, represented by the following chemical formula (I), commercially available as a therapeutic agent for type 2 diabetes, and is also being developed as a therapeutic agent for chronic heart failure:
[ formula I ]
Engliflozin in crystalline or amorphous form of the free base or the like may be used as the active ingredient, and an Engliflozin co-crystal may also be used.
It has been found that it is difficult to maintain the structure of the englitz co-crystal due to the structural characteristics of the co-crystal and external factors (moisture, temperature, etc.), and in particular, to maintain its structure due to moisture. When the englitz co-crystal cannot be maintained, the physicochemical properties may change, which may affect in vivo absorption. Therefore, there is a need to develop a pharmaceutical technology capable of maintaining a eutectic.
Furthermore, during the formulation of the englitz co-crystal, browning was observed when lactose was used (lactose is the diluent used in the reference drug and is also one of the most commonly used diluents in the formulation). Therefore, there is a need for pharmaceutical technology that can also ameliorate these problems.
Disclosure of Invention
Technical problem
It is an object of the present invention to provide a pharmaceutical composition capable of maintaining the co-crystal form of englitz.
It is another object of the present invention to provide a pharmaceutical composition that prevents browning that occurs when lactose is used in the co-crystal formulation of englitz, which is the diluent used in the reference drug and is also one of the most commonly used diluents in formulation.
It is a further object of the present invention to provide a pharmaceutical formulation comprising a coating material capable of blocking the eutectic hygroscopicity of englitde.
Solution to the problem
The present invention will be described in detail below. Meanwhile, each of the descriptions and embodiments disclosed in the present invention may be applied to each of the other descriptions and embodiments. In other words, all combinations of the various elements disclosed in the invention are within the scope of the invention. Furthermore, the scope of the invention should not be considered limited by the following detailed description.
According to one embodiment of the present invention, there is provided a pharmaceutical composition comprising an englitjing co-crystal and having a water content of 3% or less in the composition.
In the pharmaceutical composition of the present invention, the amount of the englitjing co-crystals may be 0.1 to 30 wt%, preferably 0.3 to 20 wt%, based on the total weight of the composition. Furthermore, the englitz co-crystal may be englitz L-proline.
In the pharmaceutical composition of the present invention, the water content in the composition can be reduced to a minimum of 3% or less, so that the structure of the englitjing co-crystal can be maintained. In other words, it is more preferable that the water content is minimized, and thus, the present invention has technical features on the upper limit of the numerical range. However, the water content may be 0.1% to 3%.
In the pharmaceutical composition of the present invention, an organic solvent having a water content of less than 5% may be used as a binding solvent during kneading with the englitant co-crystal to prepare the pharmaceutical composition. Specifically, the organic solvent may be absolute ethanol (e.g., USP 99.5% or higher) or isopropanol, but any organic solvent having less than 5% water may be used without limitation.
In the pharmaceutical composition of the present invention, the pharmaceutical composition may further include at least one additive selected from the group consisting of diluents, binders, disintegrants and lubricants.
In the pharmaceutical composition of the present invention, the diluent may not include lactose. In addition, the diluent may include sugar alcohols. For example, the sugar alcohol may be at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol, and maltitol, and preferably, mannitol may be used. When sugar alcohol is used as a diluent instead of lactose, browning phenomenon observed in the case of formulation including lactose can be prevented. Meanwhile, the amount of the sugar alcohol may be 30 to 70 wt%, specifically 40 to 60 wt%, based on the total weight of the composition.
In addition, the diluent may further include at least one selected from the group consisting of: microcrystalline cellulose, powdered cellulose, starch, pregelatinized starch, calcium carbonate, dicalcium phosphate, tricalcium phosphate, calcium sulfate, silicified microcrystalline cellulose, dextrates (dextran), dextrose, fructose, and sucrose, but are not limited thereto. Meanwhile, the amount of the other diluents to be added other than sugar alcohol may be 10 to 40% by weight, specifically 15 to 30% by weight, based on the total weight of the composition.
Further, the binder may be at least one selected from the group consisting of: hydroxypropyl methylcellulose (hypromellose), hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, starch, pregelatinized starch, carbomer (carbomer), xanthan gum, polyvinyl alcohol, vinylpyrrolidone and povidone (povidone), but are not limited thereto. Meanwhile, the amount of the binder may be 0.5 to 10 wt%, specifically, 1 to 4 wt%, based on the total weight of the composition.
Further, the disintegrant may be at least one selected from the group consisting of: crospovidone (crospovidone), calcium carboxymethyl cellulose, sodium alginate, sodium glycine carbonate, sodium lauryl sulfate, sodium starch glycolate, croscarmellose sodium and low-substituted hydroxypropyl cellulose, but are not limited thereto. Meanwhile, the amount of the disintegrant may be 2 to 20% by weight, specifically, 4 to 12% by weight, based on the total weight of the composition.
Further, the lubricant may be at least one selected from the group consisting of: talc, colloidal silica, sodium stearyl fumarate, magnesium stearate, sodium lauryl sulfate and glyceryl behenate, but are not limited thereto. Meanwhile, the amount of the lubricant may be 0.1 to 10 wt%, specifically, 0.5 to 4 wt%, based on the total weight of the composition.
In another general aspect, the present invention provides a pharmaceutical formulation comprising the pharmaceutical composition of the present invention.
In the pharmaceutical formulation of the present invention, the formulation may be a tablet, capsule, pellet, granule or powder, preferably a tablet. Furthermore, the tablets may be film coated tablets.
In the pharmaceutical formulation of the present invention, particularly in the film coated tablet of the present invention, the coating material may not include hydroxypropyl methylcellulose. Alternatively, the coating material may include polyvinyl alcohol (PVA). Engliflozin L-proline has a problem of strong hygroscopicity, and thus a polyvinyl alcohol coating material can be used to block hygroscopicity to moisture as much as possible.
Meanwhile, the pharmaceutical preparation of the present invention can be used for treating diabetes, diabetic complications or chronic heart failure. The diabetes may be type 1 diabetes or type 2 diabetes, preferably type 2 diabetes. Further, the diabetic complication may be retinopathy, nephropathy or neuropathy, diabetic foot ulcers, tumors or macrovascular lesions. Furthermore, chronic heart failure may be heart failure with reduced ejection fraction (HFrEF) or heart failure with preserved ejection fraction (HFpEF).
Furthermore, according to one embodiment of the present invention, the pharmaceutical formulation of the present invention may further comprise at least one drug for treating diabetes, diabetic complications or chronic heart failure. Specifically, the drug may be at least one drug selected from the group consisting of: biguanides, thiazolidinediones (TZDs), DPP-IV inhibitors, SGLT2 inhibitors, SGLT1/SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylurea (SU) drugs, meglitinide (meglitinide) analogs, and alpha-glucosidase inhibitors (AGI).
Examples of biguanides, thiazolidinediones (TZDs), DPP-IV inhibitors, SGLT2 inhibitors, SGLT1/SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylurea (SU) drugs, meglitinide analogs, and alpha-glucosidase inhibitors (AGI) are provided below:
biguanides drugs: metformin (meta) or the like;
thiazolidinediones (TZDs) class of drugs: lobemidone (lobemidone), rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), and the like;
DPP-IV inhibitors: sitagliptin, vildagliptin (vildagliptin), saxagliptin (saxagliptin), linagliptin (linagliptin), alogliptin (alogliptin), gemigliptin (gemigipiptin), tenagliptin (teneigliptin), alogliptin (anagliptin), and evagliptin (evagliptin);
SGLT-2 inhibitors: dapagliflozin (dapagliflozin), canagliflozin (canagliflozin), irigliflozin (ipragliflozin), and the like;
dual inhibitors of SGLT1/SGLT 2: sotagliflozin (sotalozin) and the like;
GLP-1 receptor agonists: cord Ma Lutai (semaglutide), etc.;
sulfonylurea (SU) drugs: glimepiride (glimepiride), glibenclamide (gliclazide), gliclazide (gliclazide), glipizide (glipizide), etc.;
a meglitinide analog: nateglinide, repaglinide, and the like; and
alpha-glucosidase inhibitor (AGI): acarbose (acarbose), voglibose (voglibose), miglitol (miglitol), and the like.
Advantageous effects of the invention
The pharmaceutical composition of the invention can maintain the eutectic form of the englitazone.
In addition, the pharmaceutical composition of the present invention prevents browning phenomenon occurring when lactose, which is a diluent used in reference medicines and is also one of the most commonly used diluents in formulation, is used in the formulation of the englitant co-crystal.
Furthermore, the pharmaceutical formulation of the present invention can exert the effect of blocking hygroscopicity to the maximum by including a coating material capable of blocking hygroscopicity of the englitant co-crystal.
Drawings
Fig. 1 shows XRD results obtained by observing whether the eutectic is maintained or changed in experimental example 1.
Fig. 2 and 3 show XRD results (fig. 2: ethanol, fig. 3: isopropanol) obtained by observing whether the eutectic is maintained or changed in experimental example 2.
Fig. 4 is an image obtained by observing whether or not browning phenomenon occurs depending on the type of diluent in experimental example 3.
Detailed Description
Hereinafter, the present invention will be described in more detail via examples and experimental examples. However, these examples and experimental examples are provided to illustrate the present invention, and the scope of the present invention is not limited to these examples and experimental examples.
Experimental example 1 confirmation test of eutectic maintenance depending on Water content
The coated tablets of example 1 were prepared with the compositions shown in table 1 below. The water content of example 1 was 1.6%.
TABLE 1
Furthermore, coated tablets of examples 2 and 3 were prepared with the same composition as in example 1, except that the water content was adjusted to 2.6% and 2.9%, respectively. Further, coated tablets of comparative examples 1 to 3 were prepared with the same composition as in example 1, except that the water contents were adjusted to 3.2%, 3.6% and 4.0%, respectively.
Depending on the water content in examples 1 to 3 and comparative examples 1 to 3, the results of whether the eutectic is maintained or changed are summarized in table 2 below.
TABLE 2
As confirmed in table 2 and fig. 1 above, it was observed that the coated tablets of examples 1 to 3 remained with the enggliflozin co-crystal (L-proline), whereas in the coated tablets of comparative examples 1 to 3, the enggliflozin co-crystal (L-proline) was changed.
Experimental example 2 confirmation test of eutectic maintenance depending on the water content in organic solvent
The composition of example 4 was prepared with the composition shown in table 3 below. When the composition of example 4 was prepared, absolute ethanol was used during kneading.
TABLE 3
Further, the compositions of comparative examples 4 and 5 were prepared with the same composition as in example 4, except that the water content of the binding solution was adjusted to 5% and 10%, respectively. Further, the compositions of example 5, comparative examples 6 and 7 were prepared with the same composition as in example 4, except that isopropanol was used instead of ethanol and the water content of the adhesive solution was adjusted to 0%, 5% and 10%, respectively.
The results of whether the eutectic was maintained or changed in examples 4 and 5 and comparative examples 4 to 7 are summarized in table 4 below.
TABLE 4
As confirmed in table 4 above and fig. 2 and 3, it was observed that the compositions of examples 4 and 5 maintained with the enggliflozin co-crystal (L-proline), whereas the enggliflozin co-crystal (L-proline) was changed in the compositions of comparative examples 4 to 7.
Experimental example 3 confirmation test of browning phenomenon depending on the type of diluent
The compositions of example 6 and comparative example 8 were prepared with the compositions shown in Table 5 below.
TABLE 5
As shown in fig. 4, discoloration was observed in comparative example 8 using lactose as a diluent. This is presumably due to browning phenomenon caused by the reaction between the amino group of L-proline and the reducing sugar of lactose (maillard reaction (Maillard reaction)).
On the other hand, no browning phenomenon was observed in example 6 using mannitol instead of lactose.
Experimental example 4 confirmation test of hygroscopicity depending on the type of coating material
A coated tablet of example 7 having a water content of 2.3% was prepared with the same composition as in example 1. Further, coated tablets of comparative example 9 having a water content of 2.3% were prepared with the compositions shown in table 6 below.
TABLE 6
The hygroscopicity of example 7 and comparative example 9 under acceleration conditions (40±2 ℃/RH 75±5%, close to 6M) was compared, and the results are shown in table 7 below.
TABLE 7
| Examples/comparative examples | Coating material | Variation of Water content (%) |
| Example 7 | PVA | 2.3→2.6 |
| Comparative example 9 | HPMC | 2.3→4.5 |
As confirmed in table 7 above, in view of the variation in water content, it was observed that the water content of comparative example 9 using HPMC as a coating material was increased by about 2.2% (from 2.3% to 4.5%), whereas the water content of example 7 using PVA as a coating material was increased only slightly by about 0.3% (from 2.3% to 2.6%). Therefore, in order to block the hygroscopicity of englitine L-proline, it is preferable to use PVA instead of HPMC as coating material.
From the above description, it will be understood by those skilled in the art that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the above-described embodiments are illustrative in all respects and not restrictive. With respect to the scope of the invention, it is to be understood that all changes or modifications that come within the meaning and range of equivalency of the appended claims and their equivalents are intended to be embraced therein.
Claims (16)
1. A pharmaceutical composition comprising an englitz co-crystal and having a water content in the composition of 3% or less.
2. The pharmaceutical composition of claim 1, wherein the englitjing co-crystal is englitjing L-proline.
3. The pharmaceutical composition of claim 1, wherein the water content in the composition is 0.1% to 3%.
4. The pharmaceutical composition according to claim 1, wherein an organic solvent having a water content of less than 5% is used as a binding solvent during kneading with the englitz co-crystal.
5. The pharmaceutical composition according to claim 1, further comprising at least one additive selected from the group consisting of diluents, binders, disintegrants and lubricants.
6. The pharmaceutical composition of claim 5, wherein the diluent does not comprise lactose.
7. The pharmaceutical composition of claim 6, wherein the diluent comprises a sugar alcohol.
8. The pharmaceutical composition according to claim 7, wherein the sugar alcohol is at least one selected from the group consisting of mannitol, sorbitol, erythritol, xylitol, lactitol and maltitol.
9. A pharmaceutical formulation comprising the pharmaceutical composition according to any one of claims 1 to 8.
10. The pharmaceutical formulation of claim 9, wherein the formulation is a tablet, capsule, pellet, granule, or powder.
11. The pharmaceutical formulation of claim 10, wherein the tablet is a film coated tablet.
12. The pharmaceutical formulation of claim 11, wherein the coating material does not comprise hydroxypropyl methylcellulose.
13. The pharmaceutical formulation of claim 12, wherein the coating material comprises polyvinyl alcohol.
14. The pharmaceutical formulation of claim 9, wherein the pharmaceutical formulation is for use in treating diabetes, diabetic complications, or chronic heart failure.
15. The pharmaceutical formulation of claim 14, further comprising at least one drug for treating diabetes, diabetic complications, or chronic heart failure.
16. The pharmaceutical formulation of claim 15, wherein the drug is at least one drug selected from the group consisting of: biguanides, thiazolidinediones (TZDs), DPP-IV inhibitors, SGLT2 inhibitors, SGLT1/SGLT2 dual inhibitors, GLP-1 receptor agonists, sulfonylurea (SU) drugs, meglitinide analogs, and alpha-glucosidase inhibitors (AGI).
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR10-2020-0170136 | 2020-12-08 | ||
| KR1020200170136A KR20220080880A (en) | 2020-12-08 | 2020-12-08 | Pharmaceutical composition comprising empagliflozin co-crystal |
| PCT/KR2021/018414 WO2022124749A1 (en) | 2020-12-08 | 2021-12-07 | Pharmaceutical composition comprising empagliflozin co-crystal |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN116648263A true CN116648263A (en) | 2023-08-25 |
Family
ID=81973432
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202180077817.7A Pending CN116648263A (en) | 2020-12-08 | 2021-12-07 | Pharmaceutical composition comprising englitazone co-crystals |
Country Status (5)
| Country | Link |
|---|---|
| JP (1) | JP2023552817A (en) |
| KR (2) | KR20220080880A (en) |
| CN (1) | CN116648263A (en) |
| TW (1) | TW202222322A (en) |
| WO (1) | WO2022124749A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2024062310A1 (en) * | 2022-09-22 | 2024-03-28 | Savoi Guilherme | Co-crystals derived from empagliflozin and dapagliflozin with l-proline |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| UA91546C2 (en) | 2005-05-03 | 2010-08-10 | Бьорінгер Інгельхайм Інтернаціональ Гмбх | Crystalline form of 1-chloro-4-(я-d-glucopyranos-1-yl)-2-[4-((s)-tetrahydrofuran-3-yloxy)-benzyl]-benzene, a method for its preparation and the use thereof for preparing medicaments |
| CZ2015110A3 (en) * | 2015-02-18 | 2016-08-31 | Zentiva, K.S. | Empagliflozin solid forms |
| US10428053B2 (en) * | 2015-09-15 | 2019-10-01 | Laurus Labs Limited | Co-crystals of SGLT2 inhibitors, process for their preparation and pharmaceutical compositions thereof |
| WO2020058095A1 (en) * | 2018-09-19 | 2020-03-26 | Galenicum Health S.L.U. | Pharmaceutical compositions of empagliflozin |
| KR102111248B1 (en) * | 2019-12-30 | 2020-05-14 | 유니셀랩 주식회사 | New Empagliflozin cocrystal |
-
2020
- 2020-12-08 KR KR1020200170136A patent/KR20220080880A/en not_active IP Right Cessation
-
2021
- 2021-12-07 TW TW110145722A patent/TW202222322A/en unknown
- 2021-12-07 CN CN202180077817.7A patent/CN116648263A/en active Pending
- 2021-12-07 WO PCT/KR2021/018414 patent/WO2022124749A1/en active Application Filing
- 2021-12-07 JP JP2023534902A patent/JP2023552817A/en active Pending
-
2024
- 2024-01-08 KR KR1020240003010A patent/KR20240010065A/en active Application Filing
Also Published As
| Publication number | Publication date |
|---|---|
| KR20220080880A (en) | 2022-06-15 |
| WO2022124749A1 (en) | 2022-06-16 |
| KR20240010065A (en) | 2024-01-23 |
| JP2023552817A (en) | 2023-12-19 |
| TW202222322A (en) | 2022-06-16 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| ES2334933T3 (en) | COVERED OR GRANULATED TABLET CONTAINING A PYRIDYL PIRIMIDINE. | |
| KR20240010065A (en) | Pharmaceutical composition comprising empagliflozin co-crystal | |
| KR20150067153A (en) | A solid oral pharmaceutical formulation containing ticagrelor | |
| EA024699B1 (en) | Pharmaceutical immediate release tablet comprising sevelamer carbonate | |
| WO2021123165A1 (en) | Dosage form comprising amorphous solid solution of empagliflozin with polymer | |
| EP2468268B1 (en) | Combination composition of vildagliptin and gliclazide | |
| KR20140045271A (en) | Combination drug comprising gemigliptin and metformin and method for the preparation thereof | |
| KR20230056789A (en) | Pharmaceutical composition of dapagliflozin co-crystal | |
| US20150283248A1 (en) | Pharmaceutical compositions of Linagliptin and process for preparation thereof | |
| KR102330597B1 (en) | Novel Pharmaceutical Formulation with Improved Stability Comprising Amorphous Empagliflozin | |
| WO2012093972A1 (en) | Water soluble dosage forms | |
| WO2013077824A1 (en) | Preparation process for a formulation comprising metformin | |
| WO2013077819A1 (en) | Pharmaceutical formulations comprising nateglinide | |
| EP4171533A1 (en) | A film coated tablet comprising vildagliptin and metformin hci | |
| WO2013077825A1 (en) | Preparation process for a formulation comprising metformin | |
| WO2013115739A1 (en) | Production method for formulations comprising comprising nateglinide and lipoic acid | |
| WO2014096983A1 (en) | Stable pharmaceutical compositions of saxagliptin or salts thereof | |
| EP4008316A1 (en) | A film coated tablet formulation comprising dapagliflozin and metformin hydrochloride | |
| WO2022119540A2 (en) | A process for formulations of dapagliflozin and metformin hydrochloride | |
| US11096945B2 (en) | Pharmaceutical compositions of linagliptin and process for preparation thereof | |
| US20230346817A1 (en) | Composition and use of sglt-2 inhibitor and angiotensin receptor blockers | |
| EP4285893A1 (en) | A combination comprising empagliflozin and metformin hydrochloride | |
| EP4285894A1 (en) | A formulation of empagliflozin and metformin hydrochloride | |
| WO2021262115A1 (en) | A stable combination of vildagliptin and metformin hci | |
| TR2022013357A2 (en) | ORAL THERAPEUTIC FORMULATIONS |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |