KR20200079957A - Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same - Google Patents
Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same Download PDFInfo
- Publication number
- KR20200079957A KR20200079957A KR1020180169706A KR20180169706A KR20200079957A KR 20200079957 A KR20200079957 A KR 20200079957A KR 1020180169706 A KR1020180169706 A KR 1020180169706A KR 20180169706 A KR20180169706 A KR 20180169706A KR 20200079957 A KR20200079957 A KR 20200079957A
- Authority
- KR
- South Korea
- Prior art keywords
- acid
- edoxaban
- pharmaceutical composition
- oral pharmaceutical
- water
- Prior art date
Links
- 229960000622 edoxaban Drugs 0.000 title claims abstract description 82
- HGVDHZBSSITLCT-JLJPHGGASA-N Edoxaban Chemical compound N([C@H]1CC[C@@H](C[C@H]1NC(=O)C=1SC=2CN(C)CCC=2N=1)C(=O)N(C)C)C(=O)C(=O)NC1=CC=C(Cl)C=N1 HGVDHZBSSITLCT-JLJPHGGASA-N 0.000 title claims abstract description 80
- 239000008203 oral pharmaceutical composition Substances 0.000 title claims abstract description 27
- 239000004480 active ingredient Substances 0.000 title description 4
- 238000002360 preparation method Methods 0.000 title description 2
- 239000007962 solid dispersion Substances 0.000 claims abstract description 45
- 150000007524 organic acids Chemical class 0.000 claims abstract description 31
- 229920003169 water-soluble polymer Polymers 0.000 claims abstract description 28
- 150000003839 salts Chemical class 0.000 claims abstract description 15
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 23
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 17
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 16
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 16
- 239000011259 mixed solution Substances 0.000 claims description 16
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical group CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 15
- 239000000243 solution Substances 0.000 claims description 13
- 238000000034 method Methods 0.000 claims description 11
- OFOBLEOULBTSOW-UHFFFAOYSA-N Malonic acid Chemical compound OC(=O)CC(O)=O OFOBLEOULBTSOW-UHFFFAOYSA-N 0.000 claims description 9
- -1 hydroxybutyl Chemical group 0.000 claims description 9
- WNLRTRBMVRJNCN-UHFFFAOYSA-N adipic acid Chemical compound OC(=O)CCCCC(O)=O WNLRTRBMVRJNCN-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-UHFFFAOYSA-N trans-butenedioic acid Natural products OC(=O)C=CC(O)=O VZCYOOQTPOCHFL-UHFFFAOYSA-N 0.000 claims description 8
- VZCYOOQTPOCHFL-OWOJBTEDSA-N Fumaric acid Chemical compound OC(=O)\C=C\C(O)=O VZCYOOQTPOCHFL-OWOJBTEDSA-N 0.000 claims description 7
- 239000002253 acid Substances 0.000 claims description 7
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 7
- 235000015165 citric acid Nutrition 0.000 claims description 7
- 239000003960 organic solvent Substances 0.000 claims description 7
- 239000008194 pharmaceutical composition Substances 0.000 claims description 7
- CIWBSHSKHKDKBQ-JLAZNSOCSA-N Ascorbic acid Chemical compound OC[C@H](O)[C@H]1OC(=O)C(O)=C1O CIWBSHSKHKDKBQ-JLAZNSOCSA-N 0.000 claims description 6
- 229920002678 cellulose Polymers 0.000 claims description 6
- 239000001913 cellulose Substances 0.000 claims description 6
- 235000010980 cellulose Nutrition 0.000 claims description 6
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 4
- 239000001361 adipic acid Substances 0.000 claims description 4
- 235000011037 adipic acid Nutrition 0.000 claims description 4
- BJEPYKJPYRNKOW-UHFFFAOYSA-N alpha-hydroxysuccinic acid Natural products OC(=O)C(O)CC(O)=O BJEPYKJPYRNKOW-UHFFFAOYSA-N 0.000 claims description 4
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 4
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 4
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 4
- 239000000314 lubricant Substances 0.000 claims description 4
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 claims description 4
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 4
- 238000001694 spray drying Methods 0.000 claims description 4
- BJEPYKJPYRNKOW-REOHCLBHSA-N (S)-malic acid Chemical compound OC(=O)[C@@H](O)CC(O)=O BJEPYKJPYRNKOW-REOHCLBHSA-N 0.000 claims description 3
- 239000005711 Benzoic acid Substances 0.000 claims description 3
- WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 3
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 claims description 3
- 239000004354 Hydroxyethyl cellulose Substances 0.000 claims description 3
- CKLJMWTZIZZHCS-REOHCLBHSA-N L-aspartic acid Chemical compound OC(=O)[C@@H](N)CC(O)=O CKLJMWTZIZZHCS-REOHCLBHSA-N 0.000 claims description 3
- WHUUTDBJXJRKMK-VKHMYHEASA-N L-glutamic acid Chemical compound OC(=O)[C@@H](N)CCC(O)=O WHUUTDBJXJRKMK-VKHMYHEASA-N 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- 239000004372 Polyvinyl alcohol Substances 0.000 claims description 3
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 3
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 3
- 235000010323 ascorbic acid Nutrition 0.000 claims description 3
- 239000011668 ascorbic acid Substances 0.000 claims description 3
- 229960005070 ascorbic acid Drugs 0.000 claims description 3
- 235000003704 aspartic acid Nutrition 0.000 claims description 3
- 235000010233 benzoic acid Nutrition 0.000 claims description 3
- OQFSQFPPLPISGP-UHFFFAOYSA-N beta-carboxyaspartic acid Natural products OC(=O)C(N)C(C(O)=O)C(O)=O OQFSQFPPLPISGP-UHFFFAOYSA-N 0.000 claims description 3
- KDYFGRWQOYBRFD-NUQCWPJISA-N butanedioic acid Chemical compound O[14C](=O)CC[14C](O)=O KDYFGRWQOYBRFD-NUQCWPJISA-N 0.000 claims description 3
- 239000007884 disintegrant Substances 0.000 claims description 3
- BEFDCLMNVWHSGT-UHFFFAOYSA-N ethenylcyclopentane Chemical compound C=CC1CCCC1 BEFDCLMNVWHSGT-UHFFFAOYSA-N 0.000 claims description 3
- 239000001530 fumaric acid Substances 0.000 claims description 3
- 239000004220 glutamic acid Substances 0.000 claims description 3
- 235000013922 glutamic acid Nutrition 0.000 claims description 3
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 claims description 3
- 229920003063 hydroxymethyl cellulose Polymers 0.000 claims description 3
- 229940031574 hydroxymethyl cellulose Drugs 0.000 claims description 3
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical group 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
- 239000011976 maleic acid Substances 0.000 claims description 3
- 239000001630 malic acid Substances 0.000 claims description 3
- 235000011090 malic acid Nutrition 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920002451 polyvinyl alcohol Polymers 0.000 claims description 3
- 239000004334 sorbic acid Substances 0.000 claims description 3
- 235000010199 sorbic acid Nutrition 0.000 claims description 3
- 229940075582 sorbic acid Drugs 0.000 claims description 3
- 235000002906 tartaric acid Nutrition 0.000 claims description 3
- 239000011975 tartaric acid Substances 0.000 claims description 3
- 235000011087 fumaric acid Nutrition 0.000 claims description 2
- 229920002554 vinyl polymer Polymers 0.000 claims description 2
- HNJBEVLQSNELDL-UHFFFAOYSA-N pyrrolidin-2-one Chemical compound O=C1CCCN1 HNJBEVLQSNELDL-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 10
- 239000000203 mixture Substances 0.000 description 18
- 230000000052 comparative effect Effects 0.000 description 17
- 229940079593 drug Drugs 0.000 description 14
- 239000003814 drug Substances 0.000 description 14
- 239000003826 tablet Substances 0.000 description 12
- 238000012360 testing method Methods 0.000 description 10
- 229920002785 Croscarmellose sodium Polymers 0.000 description 7
- 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 7
- 239000003146 anticoagulant agent Substances 0.000 description 7
- 229960001681 croscarmellose sodium Drugs 0.000 description 7
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 7
- MVPICKVDHDWCJQ-UHFFFAOYSA-N ethyl 3-pyrrolidin-1-ylpropanoate Chemical compound CCOC(=O)CCN1CCCC1 MVPICKVDHDWCJQ-UHFFFAOYSA-N 0.000 description 7
- 229940045902 sodium stearyl fumarate Drugs 0.000 description 7
- 238000010521 absorption reaction Methods 0.000 description 6
- 239000000654 additive Substances 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 230000007935 neutral effect Effects 0.000 description 5
- 239000012085 test solution Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 5
- 230000000996 additive effect Effects 0.000 description 4
- 229940127219 anticoagulant drug Drugs 0.000 description 4
- 238000007922 dissolution test Methods 0.000 description 4
- 239000007921 spray Substances 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 238000004458 analytical method Methods 0.000 description 3
- 230000002429 anti-coagulating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000009472 formulation Methods 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 239000008363 phosphate buffer Substances 0.000 description 3
- 239000000843 powder Substances 0.000 description 3
- QNZCBYKSOIHPEH-UHFFFAOYSA-N Apixaban Chemical compound C1=CC(OC)=CC=C1N1C(C(=O)N(CC2)C=3C=CC(=CC=3)N3C(CCCC3)=O)=C2C(C(N)=O)=N1 QNZCBYKSOIHPEH-UHFFFAOYSA-N 0.000 description 2
- 229920002261 Corn starch Polymers 0.000 description 2
- 241001301450 Crocidium multicaule Species 0.000 description 2
- 208000005189 Embolism Diseases 0.000 description 2
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 2
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 229960003886 apixaban Drugs 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 150000007514 bases Chemical class 0.000 description 2
- 239000011248 coating agent Substances 0.000 description 2
- 239000008120 corn starch Substances 0.000 description 2
- 229960003850 dabigatran Drugs 0.000 description 2
- YBSJFWOBGCMAKL-UHFFFAOYSA-N dabigatran Chemical compound N=1C2=CC(C(=O)N(CCC(O)=O)C=3N=CC=CC=3)=CC=C2N(C)C=1CNC1=CC=C(C(N)=N)C=C1 YBSJFWOBGCMAKL-UHFFFAOYSA-N 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 229940093915 gynecological organic acid Drugs 0.000 description 2
- 150000004677 hydrates Chemical class 0.000 description 2
- 229940031703 low substituted hydroxypropyl cellulose 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
- 230000014759 maintenance of location Effects 0.000 description 2
- 239000008108 microcrystalline cellulose Substances 0.000 description 2
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 2
- 229940016286 microcrystalline cellulose Drugs 0.000 description 2
- 235000005985 organic acids Nutrition 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 210000000813 small intestine Anatomy 0.000 description 2
- 238000013112 stability test Methods 0.000 description 2
- 210000002784 stomach Anatomy 0.000 description 2
- 239000000126 substance Substances 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- PGOHTUIFYSHAQG-LJSDBVFPSA-N (2S)-6-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-4-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-5-amino-2-[[(2S)-2-[[(2S)-2-[[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-5-amino-2-[[(2S)-1-[(2S,3R)-2-[[(2S)-2-[[(2S)-2-[[(2R)-2-[[(2S)-2-[[(2S)-2-[[2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-amino-4-methylsulfanylbutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]propanoyl]pyrrolidine-2-carbonyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-methylpentanoyl]amino]acetyl]amino]-3-hydroxypropanoyl]amino]-4-methylpentanoyl]amino]-3-sulfanylpropanoyl]amino]-4-methylsulfanylbutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-hydroxybutanoyl]pyrrolidine-2-carbonyl]amino]-5-oxopentanoyl]amino]-3-hydroxypropanoyl]amino]-3-hydroxypropanoyl]amino]-3-(1H-imidazol-5-yl)propanoyl]amino]-4-methylpentanoyl]amino]-3-hydroxybutanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-5-carbamimidamidopentanoyl]amino]-5-oxopentanoyl]amino]-3-hydroxybutanoyl]amino]-3-hydroxypropanoyl]amino]-3-carboxypropanoyl]amino]-3-hydroxypropanoyl]amino]-5-oxopentanoyl]amino]-5-oxopentanoyl]amino]-3-phenylpropanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-methylbutanoyl]amino]-4-methylpentanoyl]amino]-4-oxobutanoyl]amino]-5-carbamimidamidopentanoyl]amino]-3-(1H-indol-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-5-oxopentanoyl]amino]hexanoic acid Chemical compound CSCC[C@H](N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N1CCC[C@H]1C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(=O)NCC(=O)N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CS)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1CCC[C@H]1C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CO)C(=O)N[C@@H](Cc1cnc[nH]1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CC(O)=O)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](Cc1ccccc1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CCCCN)C(O)=O PGOHTUIFYSHAQG-LJSDBVFPSA-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
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 1
- GUBGYTABKSRVRQ-XLOQQCSPSA-N Alpha-Lactose Chemical compound O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O GUBGYTABKSRVRQ-XLOQQCSPSA-N 0.000 description 1
- WSVLPVUVIUVCRA-KPKNDVKVSA-N Alpha-lactose monohydrate Chemical compound O.O[C@@H]1[C@@H](O)[C@@H](O)[C@@H](CO)O[C@H]1O[C@@H]1[C@@H](CO)O[C@H](O)[C@H](O)[C@H]1O WSVLPVUVIUVCRA-KPKNDVKVSA-N 0.000 description 1
- 244000144725 Amygdalus communis Species 0.000 description 1
- 206010003658 Atrial Fibrillation Diseases 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- 229940123900 Direct thrombin inhibitor Drugs 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
- 108010014173 Factor X Proteins 0.000 description 1
- 229940123583 Factor Xa inhibitor Drugs 0.000 description 1
- 229920003114 HPC-L Polymers 0.000 description 1
- HTTJABKRGRZYRN-UHFFFAOYSA-N Heparin Chemical compound OC1C(NC(=O)C)C(O)OC(COS(O)(=O)=O)C1OC1C(OS(O)(=O)=O)C(O)C(OC2C(C(OS(O)(=O)=O)C(OC3C(C(O)C(O)C(O3)C(O)=O)OS(O)(=O)=O)C(CO)O2)NS(O)(=O)=O)C(C(O)=O)O1 HTTJABKRGRZYRN-UHFFFAOYSA-N 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 1
- CPELXLSAUQHCOX-UHFFFAOYSA-N Hydrogen bromide Chemical compound Br CPELXLSAUQHCOX-UHFFFAOYSA-N 0.000 description 1
- GUBGYTABKSRVRQ-QKKXKWKRSA-N Lactose Natural products OC[C@H]1O[C@@H](O[C@H]2[C@H](O)[C@@H](O)C(O)O[C@@H]2CO)[C@H](O)[C@@H](O)[C@H]1O GUBGYTABKSRVRQ-QKKXKWKRSA-N 0.000 description 1
- OFOBLEOULBTSOW-UHFFFAOYSA-L Malonate Chemical compound [O-]C(=O)CC([O-])=O OFOBLEOULBTSOW-UHFFFAOYSA-L 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 1
- 229920000881 Modified starch Polymers 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- 208000012902 Nervous system disease Diseases 0.000 description 1
- 208000025966 Neurological disease Diseases 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- MUBZPKHOEPUJKR-UHFFFAOYSA-N Oxalic acid Chemical compound OC(=O)C(O)=O MUBZPKHOEPUJKR-UHFFFAOYSA-N 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 108010094028 Prothrombin Proteins 0.000 description 1
- 102100027378 Prothrombin Human genes 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-L Sulfate Chemical compound [O-]S([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-L 0.000 description 1
- 208000001435 Thromboembolism Diseases 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 239000003698 antivitamin K Substances 0.000 description 1
- 230000008901 benefit Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 230000006931 brain damage Effects 0.000 description 1
- 231100000874 brain damage Toxicity 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- FUFJGUQYACFECW-UHFFFAOYSA-L calcium hydrogenphosphate Chemical compound [Ca+2].OP([O-])([O-])=O FUFJGUQYACFECW-UHFFFAOYSA-L 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 238000007906 compression Methods 0.000 description 1
- 230000006835 compression Effects 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 238000004132 cross linking Methods 0.000 description 1
- 235000019700 dicalcium phosphate Nutrition 0.000 description 1
- 229920001249 ethyl cellulose Polymers 0.000 description 1
- 235000019325 ethyl cellulose Nutrition 0.000 description 1
- 230000001747 exhibiting effect Effects 0.000 description 1
- 239000012530 fluid Substances 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 239000012458 free base Substances 0.000 description 1
- JFCQEDHGNNZCLN-UHFFFAOYSA-N glutaric acid Chemical compound OC(=O)CCCC(O)=O JFCQEDHGNNZCLN-UHFFFAOYSA-N 0.000 description 1
- 125000003976 glyceryl group Chemical group [H]C([*])([H])C(O[H])([H])C(O[H])([H])[H] 0.000 description 1
- 229960002897 heparin Drugs 0.000 description 1
- 229920000669 heparin Polymers 0.000 description 1
- XMBWDFGMSWQBCA-UHFFFAOYSA-N hydrogen iodide Chemical compound I XMBWDFGMSWQBCA-UHFFFAOYSA-N 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 239000004615 ingredient Substances 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- SUMDYPCJJOFFON-UHFFFAOYSA-N isethionic acid Chemical compound OCCS(O)(=O)=O SUMDYPCJJOFFON-UHFFFAOYSA-N 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 229960001375 lactose Drugs 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- 229940049920 malate Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 229960001855 mannitol Drugs 0.000 description 1
- 230000010534 mechanism of action Effects 0.000 description 1
- 229920000609 methyl cellulose Polymers 0.000 description 1
- 239000001923 methylcellulose Substances 0.000 description 1
- 235000010981 methylcellulose Nutrition 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 235000010482 polyoxyethylene sorbitan monooleate Nutrition 0.000 description 1
- 229920000053 polysorbate 80 Polymers 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 229940039716 prothrombin Drugs 0.000 description 1
- 238000010298 pulverizing process Methods 0.000 description 1
- 230000035484 reaction time Effects 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229920003109 sodium starch glycolate Polymers 0.000 description 1
- 229940079832 sodium starch glycolate Drugs 0.000 description 1
- 239000008109 sodium starch glycolate Substances 0.000 description 1
- 239000007909 solid dosage form Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 229940032147 starch Drugs 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-L succinate(2-) Chemical compound [O-]C(=O)CCC([O-])=O KDYFGRWQOYBRFD-UHFFFAOYSA-L 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 235000012222 talc Nutrition 0.000 description 1
- 229940095064 tartrate Drugs 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000003868 thrombin inhibitor Substances 0.000 description 1
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 1
- 229940019333 vitamin k antagonists Drugs 0.000 description 1
Images
Classifications
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
-
- 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
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
- A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
-
- 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
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1617—Organic compounds, e.g. phospholipids, fats
-
- 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
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
- A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Engineering & Computer Science (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Medicinal Chemistry (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Biophysics (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Physiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
Description
본 발명은 에독사반 또는 그의 약제학적으로 허용되는 염을 함유한 경구용 의약 조성물 및 그의 제조방법에 관한 것이다. 구체적으로는, 에독사반 또는 그의 약제학적으로 허용되는 염이 수용성 폴리머 내에 분산되어 존재하는 것을 특징으로 하는 고체분산체를 포함하는 경구용 의약 조성물에 관한 것이다. 보다 특별하게는, 고체분산체에 유기산을 추가로 포함하여 에독사반의 인체 내 넓은 pH 범위에서의 용해도 및 용출성을 개선함과 동시에 약물의 안정성 확보가 가능하여 높은 생체이용률을 확보할 수 있는 효과가 있다. The present invention relates to an oral pharmaceutical composition containing edoxaban or a pharmaceutically acceptable salt thereof and a method for preparing the same. Specifically, it relates to an oral pharmaceutical composition comprising a solid dispersion, characterized in that edoxaban or a pharmaceutically acceptable salt thereof is dispersed in a water-soluble polymer. More specifically, the solid dispersion may further include an organic acid to improve the solubility and dissolution properties of edoxaban in a wide pH range in the human body, and at the same time, ensure the stability of the drug, thereby securing a high bioavailability. There is.
비판막성 심방세동(non-valvular atrial fibrillation) 환자의 경우 정상인에 비해 뇌졸중의 빈도가 5배나 높고 뇌졸중이 발생하면 다른 원인에 의한 경우보다 뇌손상의 범위가 크고 신경학적 장애가 심하여 사망이나 중증 장애로 이어질 위험이 높아 항혈전 치료에 대한 중요성이 꾸준히 강조되고 있다. 장기간 투여가 인정된 거의 유일한 경구용 항응고제는 비타민 K 길항제인 와파린(Warfarin)이었으나, 와파린은 작용이 나타날 때까지 걸리는 시간(International Normalized, INR)이 길어서 빠른 시간 내에 항응고 효과가 필요한 경우에는 헤파린과 같은 약제를 교가요법으로 사용해야 하며, 반감기가 길어 수술 또는 시술 전에 수일간 복용을 중지하고 프로트롬빈 시간이 낮아졌는지 여부를 측정해야 하는 불편이 있었다. 또한, 다른 약물이나 음식과의 상호작용도 많기 때문에 복용시 주의가 필요하였다. In patients with non-valvular atrial fibrillation, the frequency of stroke is 5 times higher than in normal people, and if stroke occurs, the range of brain damage is greater than that of other causes and severe neurological disorders lead to death or severe disability. Due to the high risk, the importance of antithrombotic treatment is steadily emphasized. The only oral anticoagulant approved for long-term administration was vitamin K antagonist, Warfarin, but warfarin had a long time to take action (International Normalized (INR)), so if anticoagulant effect was required within a short period of time, heparin The same drug should be used as a cross-linking therapy, and it had a long half-life, so it was inconvenient to stop taking the drug for several days before surgery or procedure and measure whether prothrombin time was lowered. In addition, because there are many interactions with other drugs and food, caution was required when taking it.
이와 같은 불편함을 해소하는 비용경제적인 대안으로 새로운 경구 항응고제(novel oral anticoagulant, NOAC)가 개발되었으며, 작용기전에 따라 직접적인 트롬빈억제제(direct thrombin inhibitor) 계열인 다비가트란(dabigatran), 혈액응고인자 Xa 억제제(factor Xa inhibitor) 계열인 아픽사반(apixaban), 에독사반(edoxaban) 등이 있다. 이 중 다비가트란, 아픽사반의 경우 하루에 두 번 복약해야 하는 번거로움이 있는데 반해, 에독사반의 경우 하루 한번 복용해도 되는 장점으로 인해 부각되고 있다. A novel oral anticoagulant (NOAC) has been developed as a cost-effective alternative to alleviating this discomfort, and according to the mechanism of action, a direct thrombin inhibitor family, dabigatran and blood coagulation factor Xa. There are a family of factor Xa inhibitors such as apixaban and edoxaban. Among them, dabigatran and apixaban have the hassle of taking medication twice a day, whereas edoxaban is being emphasized due to the advantage of taking it once a day.
본 발명의 유효성분인 에독사반(Edoxaban)은 화합물명이 N1-(5-클로로피리딘-2-일)-N2-((1S,2R,4S)-4-[(디메틸아미노)카르보닐]-2-{[(5-메틸-4,5,6,7-테트라하이드로티아졸로[5,4-c]피리딘-2-일)카르보닐]아미노}시클로헥실)에탄디아미드로 하기 화학식 1로 표시되는 구조를 가진다The active ingredient of the present invention, Edoxaban, has a compound name of N1-(5-chloropyridin-2-yl)-N2-((1S,2R,4S)-4-[(dimethylamino)carbonyl]- 2-{[(5-methyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridin-2-yl)carbonyl]amino}cyclohexyl)ethane diamide to formula (1) Have the structure shown
상기 화학식 1로 표시되는 에독사반은 국제공개특허 WO2003/000680호에 활성화 혈액응고 제X인자로 개시되어 있고, 강력한 항응고작용 및 항혈전작용을 나타내기 때문에 혈전·색전에 기인하는 여러 질병의 예방약 및 치료약으로 유용한 것으로 공지되어 있다. Edoxaban represented by Chemical Formula 1 is disclosed as an active blood coagulation factor X in International Publication No. WO2003/000680, and exhibits strong anticoagulant and antithrombotic actions, thereby preventing various diseases caused by thromboembolism and embolism. It is known to be useful as a prophylactic and therapeutic drug.
상기 화학식 1로 표시되는 에독사반은 염기성 화합물로, 강산성 수용액에서는 양호한 용해성을 나타내지만, 중성의 수용액(중성의 완충액 등)에서는 용해성이 저하되어 흡수 부위인 소장 상부(pH가 약 6)에서의 흡수율 개선을 위해서는 중성 영역에서의 용출성 개선을 위한 용해도 개선이 필요하다. 국제공개특허 WO 2008/129846호에는 에독사반 및 그의 약제학적으로 염, 또는 그 수화물, 당알콜류 및 수팽윤성 첨가제를 함유하는 정제를 히프로멜로오스, 메틸셀룰로오스, 에틸셀룰로오스, 히드록시프로필셀룰로오스 및 폴리비닐알코올로부터 선택되는 1종 이상을 포함하는 코팅제에 의해 코팅하여 용출성을 개선한 의약 조성물이 기재되어 있다. Edoxaban represented by Chemical Formula 1 is a basic compound, and exhibits good solubility in a strongly acidic aqueous solution, but has a low solubility in a neutral aqueous solution (such as a neutral buffer), in the upper portion of the small intestine (pH is about 6) as an absorption site. To improve the absorption rate, it is necessary to improve the solubility to improve the dissolution properties in the neutral region. International Publication No. WO 2008/129846 discloses tablets containing edoxaban and its pharmaceutically salts, or hydrates, sugar alcohols and water-swellable additives thereof, as hypromellose, methylcellulose, ethylcellulose, hydroxypropylcellulose and A pharmaceutical composition having improved dissolution properties by coating with a coating agent containing at least one selected from polyvinyl alcohol is described.
또한, 국제공개특허 WO 2011/115067호에는 에독사반, 그의 약학적으로 허용가능한 염 또는 그의 용매화물을 함유하는 조립물을 조립(造粒) 중의 조립물의 최대 수분값을 10% 이하로 유지하는 조건하에서 제조함으로써 용출성을 개선한 제조공정이 기재되어 있다. In addition, in International Publication No. WO 2011/115067, the granules containing edoxaban, a pharmaceutically acceptable salt thereof, or a solvate thereof are maintained at a maximum moisture value of granules in granules of 10% or less. A manufacturing process in which elution is improved by manufacturing under conditions is described.
본 발명자는 상기와 같은 문제를 해결하기 위하여 연구한 결과, 인체 내 허용가능한 범위의 pH에서 용해도 분석시 pH 4.0 보다 높은 중성에서 에독사반의 용해도가 현저히 떨어지고, 그로 인해 제제에 함유되는 약물의 용출성이 떨어지는 것을 확인하였으며, 이를 극복하고자 산 성분을 첨가하면 에독사반 주변 pH 변화에 의해 용해도와 약물의 용출성은 개선되나 가혹시험 결과 산(위 체류액) 및 염기 조건에서 에독사반 자체의 안정성이 현저히 떨어짐을 최초로 확인하였다. As a result of research to solve the above problems, the present inventors significantly lower the solubility of edoxaban at a neutrality higher than pH 4.0 when analyzing solubility at a pH in an allowable range in the human body, thereby dissolving the drug contained in the formulation It was confirmed that the dropping, and to overcome this, adding the acid component improves the solubility and dissolution of the drug by changing the pH around the edoxaban, but as a result of severe testing, the stability of the edoxaban itself under acid (stomach retention) and basic conditions It was first confirmed that the drop was significantly.
이에, 본 발명자는 에독사반을 수용성 폴리머에 분산되어 존재하도록 고체분산체 형태로 제조하는 경우 특히, 이 고체분산체에 유기산을 추가 혼합하는 경우 에독사반의 인체 내 넓은 pH 범위에서의 용해도 및 용출성을 개선할 수 있음과 동시에 약물의 안정성 확보가 가능하여 생체이용률을 증가시킬 수 있다는 것을 확인하여, 본 발명을 완성하였다. Thus, the present inventors, when prepared in the form of a solid dispersion such that the edoxaban is dispersed in a water-soluble polymer, especially when the organic acid is further mixed with the solid dispersion, the solubility and elution of the edoxaban at a wide pH range in the human body The present invention was completed by confirming that the bioavailability can be increased by improving the sex and at the same time securing the stability of the drug.
본 발명은 항혈액응고제로 투여될 수 있는 경구용 의약 조성물을 제공하는 것을 해결과제로 하며, 유효성분으로 에독사반을 포함하고, 유효성분이 수용성 폴리머 내에 분산되어 존재하는 고체분산체를 포함하는 경구용 의약 조성물을 제공하는 것을 구체적인 해결과제로 한다. The present invention is to solve the problem of providing an oral pharmaceutical composition that can be administered as an anticoagulant, an oral composition comprising a solid dispersion in which the active ingredient is dispersed in a water-soluble polymer and contains edoxaban. A specific solution is to provide a pharmaceutical composition.
나아가, 본 발명은 상기 고체분산체에 유기산을 추가함으로써 유효성분인 에독사반의 인체 내 넓은 pH 범위에서의 용해도 및 용출성이 개선되고, 우수한 안정성을 나타내는 경구용 의약 조성물을 제공하는 것을 본 발명의 특별한 해결과제로 한다. Furthermore, the present invention provides an oral pharmaceutical composition exhibiting excellent stability and improved solubility and dissolution in the wide range of pH in the human body of edoxaban as an active ingredient by adding an organic acid to the solid dispersion. Make it a special solution.
상기 과제를 해결하기 위하여, 본 발명에서는 하기와 같은 수단을 개시한다. In order to solve the above problems, the present invention discloses the following means.
일 양태에서, 에독사반, 그의 약제학적으로 허용되는 염 또는 그들의 수화물이 수용성 폴리머 내에 분산되어 존재하는 것을 특징으로 하는 고체분산체를 포함하는 경구용 의약 조성물을 개시한다. In one aspect, an oral pharmaceutical composition comprising a solid dispersion, characterized in that edoxaban, a pharmaceutically acceptable salt thereof, or a hydrate thereof is present dispersed in a water-soluble polymer.
상기 고체분산체는 유기산을 추가로 포함할 수 있다. The solid dispersion may further include an organic acid.
상기 수용성 폴리머는 히드록시프로필메틸셀룰로오스, 히드록시프로빌부틸셀룰로오스, 히드록시메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시부틸셀룰로오스, 히드록시펜틸셀룰로오스, 폴리비닐피롤리돈, 폴리비닐알코올 및 폴리에칠렌글리콜로 구성된 그룹으로부터 선택된 1종 이상일 수 있다. The water-soluble polymer is hydroxypropyl methylcellulose, hydroxyprobyl cellulose, hydroxymethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxybutyl cellulose, hydroxypentyl cellulose, polyvinylpyrrolidone, polyvinyl It may be one or more selected from the group consisting of alcohol and polyethylene glycol.
상기 수용성 폴리머의 함량은 에독사반 100 중량부를 기준으로 50 ~ 300 중량부일 수 있다. The content of the water-soluble polymer may be 50 to 300 parts by weight based on 100 parts by weight of edoxaban.
상기 유기산은 아디프산, 아스파르트산, 벤조산, 글루탐산, 숙신산, 소르브산, 말론산, 아스코르브산, 시트르산, 타르타르산, 푸마르산, 말레산 및 말산으로 구성된 그룹으로부터 선택된 1종 이상일 수 있다. The organic acid may be at least one selected from the group consisting of adipic acid, aspartic acid, benzoic acid, glutamic acid, succinic acid, sorbic acid, malonic acid, ascorbic acid, citric acid, tartaric acid, fumaric acid, maleic acid and malic acid.
상기 유기산의 함량은 에독사반 100 중량부를 기준으로 15 ~ 100 중량부일 수 있다. The content of the organic acid may be 15 to 100 parts by weight based on 100 parts by weight of edoxaban.
상기 경구용 의약 조성물은 수팽윤성 부형제, 붕해제 및 활택제 중에서 선택되는 1종 이상을 추가로 포함할 수 있다.The oral pharmaceutical composition may further include at least one selected from water-swellable excipients, disintegrants, and lubricants.
다른 양태에서, 본 발명은 에독사반, 그의 약제학적으로 허용되는 염 또는 그들의 수화물을 유기용매에 용해시키는 단계; 상기 용액에 수용성 폴리머를 첨가하여 혼합 용액을 제조하는 단계; 및 상기 혼합 용액을 분무건조하여 에독사반, 그의 약제학적으로 허용되는 염 또는 그들의 수화물이 수용성 폴리머에 분산되어 존재하는 것을 특징으로 하는 고체분산체를 제조하는 단계를 포함하는 경구용 의약 조성물 제조방법을 개시한다. In another aspect, the present invention comprises dissolving edoxaban, a pharmaceutically acceptable salt thereof or a hydrate thereof in an organic solvent; Preparing a mixed solution by adding a water-soluble polymer to the solution; And spray-driing the mixed solution to prepare a solid dispersion, characterized in that edoxaban, a pharmaceutically acceptable salt thereof, or a hydrate thereof is dispersed in a water-soluble polymer. Disclosed.
상기 혼합 용액을 제조하는 단계에 유기산을 추가로 첨가할 수 있다.An organic acid may be additionally added to the step of preparing the mixed solution.
상기 유기용매는 에탄올, 디클로로메탄 또는 이들의 조합일 수 있다.The organic solvent may be ethanol, dichloromethane or a combination thereof.
상기 혼합 용액의 농도는 5∼20%(w/w)일 수 있다. The concentration of the mixed solution may be 5 to 20% (w/w).
본 발명에 따른 경구용 의약 조성물은 항혈액응고제로 투여될 수 있다. 보다 특별하게는, 에독사반을 수용성 폴리머와 혼합하여 에독사반을 수용성 폴리머에 분산되어 존재하도록 고체분산체 형태로 제조하고, 특히 고체분산체에 유기산을 추가함으로써 에독사반이 인체 내 넓은 pH 범위에서 용해도 및 용출성을 개선함과 동시에 에독사반 자체의 안정성도 유지될 수 있어서 결과적으로 생체이용률을 향상시킬 수 있는 효과가 있다. The pharmaceutical composition for oral administration according to the present invention may be administered as an anticoagulant. More specifically, edoxaban is mixed with a water-soluble polymer to prepare edoxaban in the form of a solid dispersion such that it is dispersed in a water-soluble polymer, and in particular, by adding an organic acid to the solid dispersion, edoxaban has a wide pH in the human body. In addition to improving solubility and dissolution in the range, stability of edoxaban itself can be maintained, and as a result, there is an effect of improving bioavailability.
도 1(1)은 pH 1 내지 8 범위에서 에독사반의 용해도 결과를 나타낸 그래프이고, 도 1(2)는 의약품동등성시험 고시 기준에 따른 에독사반의 용해도 결과를 나타낸 그래프이다.
도 2는 본 발명의 고체분산체, 유기산을 포함하지 않는 고체분산체, 유기산을 포함하는 혼합물의 용해도 시험 결과를 나타낸 그래프이다.
도 3은 유기산 함량별 고체분산체의 용해도 시험 결과를 나타낸 그래프이다.
도 4는 에독사반 화합물, 본 발명의 고체분산체, 단순 혼합물에 대한 인체내 흡수조건 pH에서 가혹시험(안정성 시험) 결과를 나타낸 그래프이다.
도 5는 본 발명의 고체분산체를 포함하는 정제와 고체분산체를 포함하지 않는 정제에 대한 용출시험 결과를 나타낸 그래프이다. 1 (1) is a graph showing the results of solubility of edoxaban in the range of
2 is a graph showing the solubility test results of the solid dispersion of the present invention, a solid dispersion not containing an organic acid, and a mixture containing an organic acid.
Figure 3 is a graph showing the solubility test results of the solid dispersion by organic acid content.
4 is a graph showing the results of a harsh test (stability test) at pH of the absorption conditions in the human body for the edoxaban compound, the solid dispersion of the present invention, and a simple mixture.
5 is a graph showing the dissolution test results for a tablet containing a solid dispersion and a tablet not containing a solid dispersion of the present invention.
본 발명은, 에독사반이 염기성 화합물로, pH 4.0 보다 높은 중성에서 용해도가 현저히 저하되고, 그로 인해 약물의 용출성이 떨어져 소장 상부(흡수부위, pH가 약 6)에서의 흡수율이 떨어지게 되는데, 이를 극복하기 위해 제제에 산 성분을 첨가하면 산(위 체류액) 및 염기 조건에서 에독사반 약물 자체의 안정성이 현저히 떨어지는 문제가 발생하는데 반해, 에독사반을 수용성 폴리머에 분산되어 존재하도록 고체분산체 형태로 제조하면서 고체분산체에 유기산을 추가 혼합하는 경우 에독사반의 중성 용액에서의 용해도 및 용출성을 개선함과 동시에 약물 자체의 안정성 확보가 가능하다는 것에 기초하여 이루어진 것이다. In the present invention, edoxaban is a basic compound, solubility is significantly lowered at a neutrality higher than pH 4.0, and thus, the dissolution rate of the drug is lowered, leading to a decrease in absorption rate at the upper part of the small intestine (absorption site, pH about 6). To overcome this, when the acid component is added to the formulation, a problem occurs in that the stability of the edoxaban drug itself is significantly lowered under acid (stomach retention) and base conditions, whereas solid dispersion is carried out so that edoxaban is dispersed in a water-soluble polymer. When the organic acid is additionally mixed with the solid dispersion while being prepared in a sieve form, the solubility and dissolution properties of the neutral solution of edoxaban are improved, and the stability of the drug itself can be secured.
본 발명에 따라, 항혈액응고 경구용 의약 조성물은 에독사반, 그의 약제학적으로 허용되는 염 또는 그들의 수화물이 수용성 폴리머 내에 분산되어 존재하는 것을 고체분산체를 포함하는 조성물 및 그 제조방법을 포함한다. According to the present invention, the anticoagulant oral pharmaceutical composition includes a composition comprising a solid dispersion in which edoxaban, a pharmaceutically acceptable salt thereof, or a hydrate thereof is dispersed in a water-soluble polymer and a method for preparing the same .
또한, 본 발명에 따라, 상기 고체분산체는 유기산을 추가로 포함할 수 있다.Further, according to the present invention, the solid dispersion may further include an organic acid.
본 발명의 경구용 의약 조성물에 사용가능한 에독사반은 에독사반 유리 염기 또는 약제학적으로 허용가능한 그의 산부가염, 또는 그들의 수화물(이하, 명세서에서는, 특별히 다르게 표시되지 않는 한, 에독사반, 그의 약제학적으로 허용되는 염 또는 그들의 수화물을 '에독사반'으로 통칭한다)이 포함될 수 있으며, 예를 들어, 염산염, 황산염, 브롬화수소산염, 요오드화수소산염, 인산염, 질산염, 안식향산염, 메탄설폰산염, 2-히드록시에탄설폰산염, p-톨루엔설폰산염, 초산염, 프로판산염, 옥살산염, 말론산염, 숙신산염, 글루타르산염, 아디프산염, 타르타르산염, 말레산염, 푸마르산염, 말산염, 만델산염 등을 들 수 있다. The edoxaban usable in the oral pharmaceutical composition of the present invention is edoxaban free base or a pharmaceutically acceptable acid addition salt thereof, or a hydrate thereof (hereinafter, unless otherwise indicated otherwise in the specification, edoxaban, Pharmaceutically acceptable salts or their hydrates are collectively referred to as'edoxaban'), for example, hydrochloride, sulfate, hydrobromide, hydroiodide, phosphate, nitrate, benzoate, methanesulfonate , 2-hydroxyethanesulfonate, p-toluenesulfonate, acetate, propanate, oxalate, malonate, succinate, glutarate, adipic acid, tartrate, maleate, fumarate, malate, mandel And acid salts.
본 발명의 경구용 의약 조성물에 사용가능한 수용성 폴리머는 히드록시프로필메틸셀룰로오스, 히드록시프로필부틸셀룰로오스, 히드록시메틸셀룰로오스, 히드록시에틸셀룰로오스, 히드록시프로필셀룰로오스, 히드록시부틸셀룰로오스, 히드록시펜틸셀룰로오스, 폴리비닐피롤리돈, 폴리비닐알코올 및 폴리에칠렌글리콜로 구성된 그룹으로부터 선택된 1종 또는 2종 이상의 혼합물일 수 있다. 바람직하게는 히드록시프로필셀룰로오스이다.Water-soluble polymers usable in the oral pharmaceutical composition of the present invention include hydroxypropylmethylcellulose, hydroxypropylbutylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxybutylcellulose, hydroxypentylcellulose, It may be one or a mixture of two or more selected from the group consisting of polyvinylpyrrolidone, polyvinyl alcohol, and polyethylene glycol. It is preferably hydroxypropyl cellulose.
상기 수용성 폴리머는 고체분산체 내의 약물을 분산시키는 베이스로서의 역할을 하는 것으로, 수용성 폴리머 함량이 과도할 경우 상대적으로 에독사반의 용해도를 저하시킬 수 있으며, 수용성 폴리머 함량이 소량일 경우 고체분산체가 제대로 형성 되기 어려우므로, 상기 에독사반 100 중량부를 기준으로 50 ~ 300 중량부인 것이 바람직하다.The water-soluble polymer serves as a base for dispersing the drug in the solid dispersion. When the water-soluble polymer content is excessive, the solubility of edoxaban can be relatively reduced. When the water-soluble polymer content is small, the solid dispersion is properly formed. Since it is difficult to be, it is preferable that it is 50 to 300 parts by weight based on 100 parts by weight of the edoxaban.
본 발명의 경구용 의약 조성물에 사용가능한 유기산은 아디프산, 아스파르트산, 벤조산, 글루탐산, 숙신산, 소르브산, 말론산, 아스코르브산. 시트르산, 타르타르산, 푸마르산, 말레산 및 말산으로 구성된 그룹으로부터 선택된 1종 또는 2종 이상의 혼합물일 수 있다. 바람직하게는 시트르산이 사용될 수 있으며, 유기산의 함량이 과도할 경우 에독사반의 안정성이 문제가 되고 그 함량이 소량일 경우 요구되는 용해도를 확보할 수 없으므로 안정성과 용해도 향상을 고려시 에독사반 100 중량부를 기준으로 15 ~ 100 중량부인 것이 바람직하다. Organic acids that can be used in the oral pharmaceutical composition of the present invention are adipic acid, aspartic acid, benzoic acid, glutamic acid, succinic acid, sorbic acid, malonic acid and ascorbic acid. It may be one or a mixture of two or more selected from the group consisting of citric acid, tartaric acid, fumaric acid, maleic acid and malic acid. Preferably, citric acid can be used, and if the content of organic acid is excessive, stability of edoxaban becomes a problem, and if the content is small, the required solubility cannot be secured, so considering stability and solubility improvement, edoxaban 100 weight It is preferably 15 to 100 parts by weight based on parts.
본 발명의 경구용 의약 조성물은 추가적으로 약제학적으로 허용되는 첨가제, 예를 들어 부형제, 붕해제, 활택제 등을 더 포함할 수 있다. The pharmaceutical composition for oral use of the present invention may further include a pharmaceutically acceptable additive, for example, excipients, disintegrants, lubricants, and the like.
상기 부형제는 타정의 용이성을 향상시키고 정제의 형태를 유지하는 역할을 하는 첨가제로, 전분, 미결정셀룰로오스, 유당, 만니톨, 무수인산수소칼슘 등이 단독 또는 혼합되어 사용될 수 있으며, 수팽윤성 미결정셀룰로오스가 특히 바람직하다. The excipient is an additive that improves the ease of tableting and maintains the form of tablets. Starch, microcrystalline cellulose, lactose, mannitol, calcium hydrogen phosphate, and the like can be used alone or in combination, and water-swellable microcrystalline cellulose is particularly useful. desirable.
상기 붕해제는 생체 투여 후 고체 제형의 붕괴 또는 붕해를 용이하게 하는 첨가제로, 옥수수전분, 전분글리콜산나트륨, 전호화전분, 저치환도히드록시프로필셀룰로오스, 크로스카멜로스나트륨, 크로스포비돈 등이 단독 또는 혼합되어 사용 될 수 있으며, 크로스카멜로스나트륨과 저치환도히드록시프로필셀룰로오스가 특히 바림직하다. The disintegrating agent is an additive that facilitates disintegration or disintegration of the solid dosage form after administration in vivo. Corn starch, sodium starch glycolate, pregelatinized starch, low-substituted hydroxypropyl cellulose, croscarmellose sodium, crospovidone, etc. alone Alternatively, it can be used in combination, and croscarmellose sodium and low-substituted hydroxypropyl cellulose are particularly preferred.
상기 활택제는 분립체의 유동성을 향상과 분립체와 타정기의 마찰을 감소시켜 정제의 압축 및 방출을 용이하게 하는 첨가제로, 이산화규소, 탈크, 스테아르산마그네슘, 푸마르산스테아릴나트륨, 글리세릴베네히트 등이 단독 또는 혼합되어 사용 될 수 있으며, 푸마르산스테아릴나트륨이 특히 바람직하다.The lubricant is an additive that facilitates compression and release of tablets by improving the fluidity of the powder and reducing friction between the powder and the tableting machine, silicon dioxide, talc, magnesium stearate, sodium stearyl fumarate, glyceryl benehit Etc. can be used alone or in combination, and sodium stearyl fumarate is particularly preferred.
본 발명의 경구용 의약 조성물은 경구로 투여가 가능한 제형 예를 들어, 정제, 캡슐제, 액제 등으로 제조될 수 있으며, 정제가 가장 바람직하다. The oral pharmaceutical composition of the present invention may be prepared in a form that can be administered orally, for example, tablets, capsules, liquids, and the like, and tablets are most preferred.
본 발명의 경구용 의약 조성물의 바람직한 투여량은 환자의 상태 및 체중, 질병의 정도, 약물형태, 투여기간에 따라 다르지만, 당업자에 의해 적절하게 선택될 수 있다. 바람직한 효과를 위해서, 본 발명의 경구용 의약 조성물은 1일 30 내지 60mg으로 투여할 수 있다. 투여는 하루에 한번 투여할 수 있고, 수회 나누어 투여할 수 있다. 상기 투여량은 어떠한 면으로든 본 발명의 범위를 한정하는 것은 아니다. The preferred dosage of the oral pharmaceutical composition of the present invention depends on the patient's condition and body weight, the degree of disease, the drug type, and the administration period, but can be appropriately selected by those skilled in the art. For a desired effect, the pharmaceutical composition for oral administration of the present invention may be administered at 30 to 60 mg per day. The administration may be administered once a day, and may be divided into several times. The above dosage does not limit the scope of the present invention in any way.
본 발명은 또한 경구용 의약 조성물의 제조 방법을 제공한다. 한 구체예로서, 본 발명의 경구용 의약 조성물의 제조 방법은The present invention also provides a method for preparing an oral pharmaceutical composition. In one embodiment, the method for preparing an oral pharmaceutical composition of the present invention
(1) 에독사반을 유기용매에 용해시키는 단계; (2) 상기 용액에 수용성 폴리머를 첨가하여 혼합 용액을 제조하는 단계; 및 (3) 상기 혼합 용액을 분무건조하여 에독사반이 수용성 폴리머에 분산되어 존재하는 것을 특징으로 하는 고체분산체를 제조하는 단계를 포함하며, 상기 혼합 용액을 제조하는 단계에 유기산을 추가로 첨가할 수 있다.(1) dissolving edoxaban in an organic solvent; (2) adding a water-soluble polymer to the solution to prepare a mixed solution; And (3) spray-drying the mixed solution to prepare a solid dispersion, characterized in that edoxaban is dispersed in a water-soluble polymer, and further adding an organic acid to the preparing the mixed solution. can do.
상기 제조방법의 에독사반, 수용성 폴리머, 유기산에 대한 세부적인 사항은 앞서 기재한 바와 같다.Details of edoxaban, water-soluble polymer, and organic acid in the above-described production method are as described above.
상기 유기 용매는 물에 대한 용해도가 낮은 에독사반을 용해시키기 위해 사용되는 것으로, 에탄올 및 디클로로메탄의 혼합된 것이 바람직하다. 상기 유기용매의 양은 난용성 에독사반을 충분히 용해시킬 수 있는 적절한 범위 일 수 있으며, 에독사반 기준 상기 혼합 용액에서의 농도 범위는 5 ~ 20%(w/w)가 바람직하다.The organic solvent is used to dissolve edoxaban, which has low solubility in water, and is preferably a mixture of ethanol and dichloromethane. The amount of the organic solvent may be a suitable range capable of sufficiently dissolving poorly soluble edoxaban, and the concentration range in the mixed solution based on edoxaban is preferably 5 to 20% (w/w).
이하, 본 발명을 실시예에 의해 상세히 설명한다. 단, 하기 실시예는 본 발명을 예시하는 것일 뿐, 본 발명의 내용이 하기 실시예에 한정되는 것은 아니다. Hereinafter, the present invention will be described in detail by examples. However, the following examples are merely illustrative of the present invention, and the contents of the present invention are not limited to the following examples.
실시예Example 1 내지 4. 1 to 4. 고체분산체의Solid dispersion 제조 Produce
에독사반 6g을 디클로로메탄과 에탄올을 6:1의 부피비로 혼합한 용액 210g에 용해시켰다. 이 용액에 수용성 폴리머인 히드록시프로필셀룰로오스(HPC) 6g을 첨가하여 혼합하고, 여기에 유기산 해당량을 첨가하여 농도가 7~ 12%(w/w)인 혼합 용액을 제조하였다. 6 g of edoxaban was dissolved in 210 g of a solution in which dichloromethane and ethanol were mixed at a volume ratio of 6:1. To this solution, 6 g of hydroxypropyl cellulose (HPC), a water-soluble polymer, was added and mixed, and an equivalent amount of organic acid was added thereto to prepare a mixed solution having a concentration of 7 to 12% (w/w).
상기 혼합 용액을 분무건조기에 투입하고 분무건조하여 고체분산체를 제조하였다. 이때, 상기 분무 건조는 공기 주입온도(Inlet temperature) 72℃, 챔버온도 50℃, 유속 0.12m2/min Automizing 80Kpa의 조건으로 실시하였다. 실시예 1 내지 4의 고체분산체의 조성비는 하기 표 1에 기재하였다. The mixed solution was introduced into a spray dryer and spray dried to prepare a solid dispersion. At this time, the spray drying was performed under conditions of
비교예Comparative example 1. 유기산을 포함하지 않는 1. Does not contain organic acids 고체분산체의Solid dispersion 제조 Produce
에독사반 6g을 디클로로메탄과 에탄올을 6:1의 부피비로 혼합한 용액 210g에 용해시켰다. 이 용액에 수용성 폴리머인 히드록시프로필셀룰로오스(HPC) 6g을 첨가하여 혼합 용액을 제조하였다. 6 g of edoxaban was dissolved in 210 g of a solution in which dichloromethane and ethanol were mixed at a volume ratio of 6:1. To this solution, 6 g of hydroxypropyl cellulose (HPC), a water-soluble polymer, was added to prepare a mixed solution.
상기 혼합 용액을 분무건조기에 투입하고 분무건조하여 고체분산체를 제조하였다. 이때, 상기 분무 건조는 공기 주입온도(Inlet temperature) 72℃, 챔버온도 50℃, 유속 0.12m2/min Automizing 80Kpa의 조건으로 실시하였다. 비교예 1의 고체분산체의 조성비는 하기 표 1에 기재하였다. The mixed solution was introduced into a spray dryer and spray dried to prepare a solid dispersion. At this time, the spray drying was performed under conditions of
비교예Comparative example 2. 혼합물의 제조 2. Preparation of the mixture
에독사반 6g, 수용성 폴리머인 히드록시프로필셀룰로오스(HPC) 6g, 유기산 6g을 혼합하여 제조하였다. 비교예 2의 혼합물의 조성비는 하기 표 1에 기재하였다. It was prepared by mixing 6 g of edoxaban, 6 g of hydroxypropyl cellulose (HPC), a water-soluble polymer, and 6 g of an organic acid. The composition ratio of the mixture of Comparative Example 2 is shown in Table 1 below.
(g)Edoxaban
(g)
(g)HPC
(g)
(g)Citric acid
(g)
(w : w : w)Content ratio of each composition
(w: w: w)
실험예Experimental Example 1. One. 에독사반Edoxaban 자체의 용해도 분석 Analysis of its own solubility
분말상태의 에독사반 10mg을 정확하게 취해 pH 1 내지 8 범위의 시험액 10mL에 1mg/mL 농도로 녹인 다음 해당 pH 조건에서 용해도를 측정하였으며, 그 결과를 도 1(1)에 나타내었다. 또한, 의약품동등성시험 기준 수용성 제제의 시험액 4개 media에서 에독사반을 5mg/mL로 녹인 다음 용해도를 측정하였으며, 그 결과를 도 1(2)에 나타내었다. 그 결과 pH4.0 초과의 중성 시험액에서는 에독사반의 용해도가 낮음을 확인하였다.10 mg of Edoxaban in powder form was accurately taken, dissolved in 10 mL of the test solution in the range of
실험예Experimental Example 2. 유기산에 의한 용해도 분석 2. Solubility analysis by organic acid
에독사반 25mg에 해당하는 실시예 2, 비교예 1 및 비교예 2를 각각 취하여 의약품동등성시험 고시 기준의 시험액 100mL에 녹인 후 용해도를 측정하였으며, 그 결과를 도 2에 나타내었다. 그 결과 유기산이 포함된 실시예 2와 비교예 2가 유기산이 포함되지 않은 비교예 1에 비해 용해도가 2배 이상 증가함을 확인하였다. Example 2, Comparative Example 1, and Comparative Example 2 corresponding to 25 mg of edoxaban were taken and dissolved in 100 mL of the test solution based on the notification criteria for the pharmaceutical equivalence test, and solubility was measured, and the results are shown in FIG. 2. As a result, it was confirmed that the solubility of Example 2 and Comparative Example 2 in which the organic acid was included was more than twice that of Comparative Example 1 in which the organic acid was not included.
실험예Experimental Example 3. 유기산 함량에 따른 3. According to organic acid content 고체분산체의Solid dispersion 용해도 분석 Solubility analysis
에독사반 25mg에 해당하는 실시예 1 내지 4 및 비교예 1을 각각 취하여 의약품동등성시험 고시 기준의 시험액 100 mL에 녹인 후 용해도를 측정하였으며, 그 결과는 도 3에 나타내었다. 그 결과 유기산 투입에 의한 영향으로 용해도는 증가하나, 에독사반과 비율이 1:1을 초과하는 경우에는 유기산 함량에 비례하여 효과를 나타내지 않았다.Each of Examples 1 to 4 and Comparative Example 1 corresponding to 25 mg of edoxaban was taken and dissolved in 100 mL of the test solution based on the notification criteria of the pharmaceutical equivalence test to measure solubility, and the results are shown in FIG. 3. As a result, the solubility increased due to the influence of the organic acid input, but when the ratio with edoxaban exceeds 1:1, it did not show an effect in proportion to the organic acid content.
실험예Experimental Example 4. 4. 에독사반Edoxaban 및 And 고체분산체의Solid dispersion 안정성 시험 Stability test
에독사반, 실시예 2, 비교예 2에 대하여 인체내 흡수조건 pH에서 가혹시험을 진행하여 안정성에 대한 결과를 확인하였다. 구체적으로, 에독사반 10mg에 해당하는 에독사반 화합물, 실시예 2, 비교예 2를 취하여 10mL 플라스크에 넣고, 여기에 5mL 아세토니트릴을 넣고 초음파 분쇄하여 녹여서 각각 3개씩 준비하였다. 그 후 이 용액에 물, pH1.2, pH6.0 용액(solution)을 각각 5mL씩 넣어 60℃에 보관하여 최초 함량 대비 시간이 지남에 따라 최종 5일까지 시간 변화에 따른 함량 변화를 확인하였으며, 그 결과를 표 2와 도 4에 나타내었다. 그 결과 에독사반 화합물과 고체분산체 형태가 아닌 단순 혼합물인 비교예 2의 경우 에독사반 약물의 함량이 현저히 감소하여 안정성에 문제가 발생함을 확인할 수 있었다. For edoxaban, Example 2 and Comparative Example 2, a harsh test was conducted at pH under absorption conditions in the human body to confirm the results for stability. Specifically, the edoxaban compound corresponding to 10 mg of edoxaban, Example 2, and Comparative Example 2 were taken and placed in a 10 mL flask, 5 mL acetonitrile was added thereto, and then crushed and dissolved by ultrasonic pulverization to prepare three each. Thereafter, 5 mL of water, pH 1.2, and pH 6.0 solutions were added to the solution and stored at 60° C., respectively, to confirm the change in content over time until the last 5 days compared to the initial content. The results are shown in Table 2 and FIG. 4. As a result, it was confirmed that in the case of Comparative Example 2, which is a simple mixture that is not in the form of an edoxaban compound and a solid dispersion, the content of the edoxaban drug is significantly reduced, leading to stability problems.
시험항목 Test Items
실험예Experimental Example 5. 정제에서의 용출시험 결과 5. Dissolution test results in tablets
[처방 A][Prescription A]
하기 표 3에 기재된 처방 중, 히드록시프로필셀룰로오스, 크로스카멜로오스나트륨 절반 해당량, 푸마르산스테아릴나트륨을 제외한 성분을 혼합하고, 히드록시프로필셀룰로오스 수용액으로 조립하였다. 이 과립에 크로스카멜로오스나트륨 절반과 푸마르산스테아릴나트륨을 첨가하여 혼합하고, 타정용 과립으로 한 후 이것을 타정기(KT15SS, 금성 제조)로 압축성형함으로써, 제정을 실시하여 정제를 얻었다. 소정의 pH6.8 인산염 완충액에서 용출 시험을 진행하였으며, 그 결과를 도 5에 나타내었다. Among the prescriptions listed in Table 3 below, hydroxypropylcellulose, half equivalent of croscarmellose sodium, and components other than sodium stearyl fumarate were mixed and assembled into an aqueous hydroxypropylcellulose solution. To the granules, half of croscarmellose sodium and sodium stearyl fumarate were added and mixed, followed by tableting with a tableting machine (KT15SS, manufactured by Goldstar) to obtain tablets. Dissolution test was conducted in a predetermined pH6.8 phosphate buffer, and the results are shown in FIG. 5.
[처방 B 및 C][Prescription B and C]
하기 표 3에 기재된 처방 중, 히드록시프로필셀룰로오스, 크로스카멜로오스나트륨 절반 해당량, 에독사반 해당량, 푸마르산스테아릴나트륨을 제외한 성분을 혼합하고, 유동층 건조기를 사용하여 히드록시프로필셀룰로오스, 에독사반, 시트르산 수용액을 분무하여 조립하였다. 이 과립에 크로스카멜로오스나트륨 절반과 푸마르산스테아릴나트륨을 첨가하여 혼합하고, 타정용 과립으로 한 후 이것을 타정기(KT15SS, 금성 제조)로 압축성형함으로써, 제정을 실시하여 정제를 얻었다. 소정의 pH6.8 인산염 완충액에서 용출 시험을 진행하였으며, 그 결과를 도 5에 나타내었다. In the prescriptions listed in Table 3 below, hydroxypropyl cellulose, half equivalent of croscarmellose sodium, equivalent of edoxaban, and components except sodium stearyl fumarate were mixed, and hydroxypropyl cellulose and edoxa were used using a fluid bed dryer. Half, the citric acid aqueous solution was sprayed and assembled. To the granules, half of croscarmellose sodium and sodium stearyl fumarate were added and mixed, followed by tableting with a tableting machine (KT15SS, manufactured by Goldstar) to obtain tablets. Dissolution test was conducted in a predetermined pH6.8 phosphate buffer, and the results are shown in FIG. 5.
그 결과 정제에 함유되는 에독사반의 일부를 고체분산화한 경우 pH6.8 인산염 완충액에서 정제에서 에독사반의 용출성이 향상되는 것을 확인하였다. As a result, it was confirmed that, when a part of edoxaban contained in the tablet was solid-dispersed, the dissolution property of edoxaban in the tablet was improved in a pH6.8 phosphate buffer.
(mg)(mg)
본 발명에 따른 경구용 의약 조성물은 항혈액응고 효과를 나타내므로, 제약산업 및 의료현장에서 의약품으로서 이용 가능하다. Since the pharmaceutical composition for oral use according to the present invention exhibits an anticoagulant effect, it can be used as a pharmaceutical in the pharmaceutical industry and the medical field.
Claims (12)
상기 용액에 수용성 폴리머를 첨가하여 혼합 용액을 제조하는 단계; 및
상기 혼합 용액을 분무건조하여 에독사반 또는 그의 약제학적으로 허용되는 염이 수용성 폴리머에 분산되어 존재하는 것을 특징으로 하는 고체분산체를 제조하는 단계를 포함하는 경구용 의약 조성물 제조방법Dissolving edoxaban, a pharmaceutically acceptable salt or hydrate thereof in an organic solvent;
Preparing a mixed solution by adding a water-soluble polymer to the solution; And
Method for preparing an oral pharmaceutical composition comprising the step of preparing a solid dispersion, characterized in that the mixed solution is spray-dried and edoxaban or a pharmaceutically acceptable salt thereof is dispersed in a water-soluble polymer.
The method according to claim 9, wherein the concentration of the mixed solution is 5 to 20% (w/w).
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180169706A KR20200079957A (en) | 2018-12-26 | 2018-12-26 | Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020180169706A KR20200079957A (en) | 2018-12-26 | 2018-12-26 | Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| KR20200079957A true KR20200079957A (en) | 2020-07-06 |
Family
ID=71571179
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1020180169706A KR20200079957A (en) | 2018-12-26 | 2018-12-26 | Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same |
Country Status (1)
| Country | Link |
|---|---|
| KR (1) | KR20200079957A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022119300A1 (en) * | 2020-12-01 | 2022-06-09 | 주식회사 삼양홀딩스 | Olaparib solid dispersion composition with improved stability and bioavailability |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008129846A1 (en) | 2007-03-29 | 2008-10-30 | Daiichi Sankyo Company, Limited | Pharmaceutical composition |
| WO2011115067A1 (en) | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | Method for improving dissolvability of anticoagulant |
| WO2013022059A1 (en) | 2011-08-10 | 2013-02-14 | 第一三共株式会社 | Pharmaceutical composition containing diamine derivative |
-
2018
- 2018-12-26 KR KR1020180169706A patent/KR20200079957A/en not_active Application Discontinuation
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008129846A1 (en) | 2007-03-29 | 2008-10-30 | Daiichi Sankyo Company, Limited | Pharmaceutical composition |
| WO2011115067A1 (en) | 2010-03-19 | 2011-09-22 | 第一三共株式会社 | Method for improving dissolvability of anticoagulant |
| WO2013022059A1 (en) | 2011-08-10 | 2013-02-14 | 第一三共株式会社 | Pharmaceutical composition containing diamine derivative |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2022119300A1 (en) * | 2020-12-01 | 2022-06-09 | 주식회사 삼양홀딩스 | Olaparib solid dispersion composition with improved stability and bioavailability |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| KR101424843B1 (en) | Pharmaceutical composition | |
| KR101940840B1 (en) | Pharmaceutical composition containing diamine derivative | |
| JP5390014B2 (en) | Anticoagulant dissolution improvement method | |
| WO2010147169A1 (en) | Pharmaceutical composition having improved solubility | |
| JPWO2016136849A1 (en) | Solid preparation | |
| JP5714562B2 (en) | Oral sustained-release solid preparation | |
| JP2011207873A (en) | Pharmaceutical composition containing irbesartan and amlodipine or salt of the same | |
| JP4805234B2 (en) | Oral solid medicine | |
| TW201827049A (en) | Orally disintegrating tablet containing diamine derivative | |
| TW202038917A (en) | Extended release formulation containing tofacitinib or pharmaceutically acceptable salts thereof and preparation method for the same | |
| JP6814886B2 (en) | A novel formulation containing a benzimidazole derivative | |
| KR20200079957A (en) | Oral pharmaceutical composition containing edoxaban as an active ingredient and the preparation method for the same | |
| KR102222774B1 (en) | Pharmaceutical formulation comprising edoxaban and preparation method thereof | |
| RU2308941C1 (en) | Solid medicinal formulation possessing histamine-like effect and method for its preparing | |
| KR20150075959A (en) | Capsule containing mini-tablets comprising mosapride citrate for sustained-releasing formulation improving gastrointestinal disease and preparing the method thereof | |
| KR20130024644A (en) | Controlled-release oral drug preparations and it's manufacturing process containing itopride hydrochloride | |
| KR101938872B1 (en) | Composition comprising complex for prevention and treatment of dementia and cognitive impairment | |
| JP2022020459A (en) | Nilotinib tablet | |
| JP2020520892A (en) | Tablet containing dabigatran etexilate or a pharmaceutically acceptable salt thereof and method for producing the same | |
| KR101428149B1 (en) | Granules containing imatinib mesylate, immediate-release tablet composition for oral use comprising said granules and method for preparing thereof | |
| EP3335703A1 (en) | Pharmaceutical composition comprising omarigliptin | |
| KR20190028109A (en) | Sustained Release Formulation Comprising Blonanserin | |
| JP2022140430A (en) | Rivaroxaban-containing tablet | |
| KR20160082170A (en) | An oral solid formulation containing rivaroxaban | |
| EP2803352A1 (en) | High dose imatinib tablets |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| N231 | Notification of change of applicant | ||
| A201 | Request for examination | ||
| E902 | Notification of reason for refusal | ||
| E601 | Decision to refuse application |