WO2022222886A1 - 一种噁拉戈利钠组合物 - Google Patents
一种噁拉戈利钠组合物 Download PDFInfo
- Publication number
- WO2022222886A1 WO2022222886A1 PCT/CN2022/087432 CN2022087432W WO2022222886A1 WO 2022222886 A1 WO2022222886 A1 WO 2022222886A1 CN 2022087432 W CN2022087432 W CN 2022087432W WO 2022222886 A1 WO2022222886 A1 WO 2022222886A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- composition
- alkalizing agent
- sodium
- elagolix
- magnesium oxide
- Prior art date
Links
- 239000000203 mixture Substances 0.000 title claims abstract description 117
- HEAUOKZIVMZVQL-VWLOTQADSA-N Elagolix Chemical compound COC1=CC=CC(C=2C(N(C[C@H](NCCCC(O)=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F HEAUOKZIVMZVQL-VWLOTQADSA-N 0.000 title description 31
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 58
- 230000003113 alkalizing effect Effects 0.000 claims abstract description 54
- 238000002360 preparation method Methods 0.000 claims abstract description 25
- -1 alkali metal salt Chemical class 0.000 claims abstract description 7
- 239000000945 filler Substances 0.000 claims abstract description 7
- 239000000853 adhesive Substances 0.000 claims abstract description 3
- 230000001070 adhesive effect Effects 0.000 claims abstract description 3
- 229910052783 alkali metal Inorganic materials 0.000 claims abstract description 3
- 150000008044 alkali metal hydroxides Chemical class 0.000 claims abstract description 3
- 229910052784 alkaline earth metal Inorganic materials 0.000 claims abstract description 3
- 229910000287 alkaline earth metal oxide Inorganic materials 0.000 claims abstract description 3
- 150000001413 amino acids Chemical class 0.000 claims abstract description 3
- 150000007530 organic bases Chemical class 0.000 claims abstract description 3
- DQYGXRQUFSRDCH-UQIIZPHYSA-M sodium;4-[[(1r)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoate Chemical compound [Na+].COC1=CC=CC(C=2C(N(C[C@H](NCCCC([O-])=O)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F DQYGXRQUFSRDCH-UQIIZPHYSA-M 0.000 claims abstract 6
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 30
- 239000000395 magnesium oxide Substances 0.000 claims description 20
- CPLXHLVBOLITMK-UHFFFAOYSA-N magnesium oxide Inorganic materials [Mg]=O CPLXHLVBOLITMK-UHFFFAOYSA-N 0.000 claims description 20
- 235000012245 magnesium oxide Nutrition 0.000 claims description 20
- AXZKOIWUVFPNLO-UHFFFAOYSA-N magnesium;oxygen(2-) Chemical group [O-2].[Mg+2] AXZKOIWUVFPNLO-UHFFFAOYSA-N 0.000 claims description 20
- MBBZMMPHUWSWHV-BDVNFPICSA-N N-methylglucamine Chemical compound CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO MBBZMMPHUWSWHV-BDVNFPICSA-N 0.000 claims description 18
- 229960003194 meglumine Drugs 0.000 claims description 18
- 239000004475 Arginine Substances 0.000 claims description 14
- 229920000881 Modified starch Polymers 0.000 claims description 14
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical group C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 claims description 14
- ODKSFYDXXFIFQN-UHFFFAOYSA-N arginine Natural products OC(=O)C(N)CCCNC(N)=N ODKSFYDXXFIFQN-UHFFFAOYSA-N 0.000 claims description 14
- 239000003814 drug Substances 0.000 claims description 14
- 239000011248 coating agent Substances 0.000 claims description 13
- 238000000576 coating method Methods 0.000 claims description 13
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical group OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 claims description 12
- ODKSFYDXXFIFQN-BYPYZUCNSA-P L-argininium(2+) Chemical compound NC(=[NH2+])NCCC[C@H]([NH3+])C(O)=O ODKSFYDXXFIFQN-BYPYZUCNSA-P 0.000 claims description 12
- 229930195725 Mannitol Natural products 0.000 claims description 12
- 239000000594 mannitol Substances 0.000 claims description 12
- 235000010355 mannitol Nutrition 0.000 claims description 12
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 8
- 239000007884 disintegrant Substances 0.000 claims description 8
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 8
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 8
- 229940069328 povidone Drugs 0.000 claims description 8
- 239000001506 calcium phosphate Substances 0.000 claims description 6
- 229910000389 calcium phosphate Inorganic materials 0.000 claims description 6
- 235000011010 calcium phosphates Nutrition 0.000 claims description 6
- 239000000314 lubricant Substances 0.000 claims description 6
- 239000001488 sodium phosphate Substances 0.000 claims description 6
- 229910000162 sodium phosphate Inorganic materials 0.000 claims description 6
- 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 claims description 6
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical compound [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 claims description 6
- 239000011230 binding agent Substances 0.000 claims description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 4
- 201000009273 Endometriosis Diseases 0.000 claims description 3
- 239000002202 Polyethylene glycol Substances 0.000 claims description 3
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 3
- 206010046798 Uterine leiomyoma Diseases 0.000 claims description 3
- 201000010260 leiomyoma Diseases 0.000 claims description 3
- 229920001223 polyethylene glycol Polymers 0.000 claims description 3
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 claims description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 claims description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 claims description 2
- XNEYCQMMVLAXTN-UHFFFAOYSA-N carbonic acid;magnesium Chemical compound [Mg].OC(O)=O XNEYCQMMVLAXTN-UHFFFAOYSA-N 0.000 claims 1
- NFIYTPYOYDDLGO-UHFFFAOYSA-N phosphoric acid;sodium Chemical compound [Na].OP(O)(O)=O NFIYTPYOYDDLGO-UHFFFAOYSA-N 0.000 claims 1
- 238000004090 dissolution Methods 0.000 abstract description 31
- 239000012535 impurity Substances 0.000 abstract description 11
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 abstract description 6
- 239000000126 substance Substances 0.000 abstract description 6
- BVKZGUZCCUSVTD-UHFFFAOYSA-L Carbonate Chemical compound [O-]C([O-])=O BVKZGUZCCUSVTD-UHFFFAOYSA-L 0.000 abstract description 3
- 239000001569 carbon dioxide Substances 0.000 abstract description 3
- 229910002092 carbon dioxide Inorganic materials 0.000 abstract description 3
- 210000002784 stomach Anatomy 0.000 abstract description 2
- 230000000052 comparative effect Effects 0.000 description 28
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical group [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 description 28
- 238000000034 method Methods 0.000 description 24
- 238000009472 formulation Methods 0.000 description 23
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 18
- 235000019359 magnesium stearate Nutrition 0.000 description 14
- 239000000463 material Substances 0.000 description 13
- 239000000243 solution Substances 0.000 description 13
- 238000012360 testing method Methods 0.000 description 13
- 229940079593 drug Drugs 0.000 description 12
- 239000012738 dissolution medium Substances 0.000 description 11
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 8
- 239000008351 acetate buffer Substances 0.000 description 7
- MQRJBSHKWOFOGF-UHFFFAOYSA-L disodium;carbonate;hydrate Chemical compound O.[Na+].[Na+].[O-]C([O-])=O MQRJBSHKWOFOGF-UHFFFAOYSA-L 0.000 description 7
- 229940076133 sodium carbonate monohydrate Drugs 0.000 description 7
- WZFUQSJFWNHZHM-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)N1CC2=C(CC1)NN=N2 WZFUQSJFWNHZHM-UHFFFAOYSA-N 0.000 description 6
- 229960000913 crospovidone Drugs 0.000 description 6
- 238000002156 mixing Methods 0.000 description 6
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 6
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 6
- VZSRBBMJRBPUNF-UHFFFAOYSA-N 2-(2,3-dihydro-1H-inden-2-ylamino)-N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]pyrimidine-5-carboxamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C(=O)NCCC(N1CC2=C(CC1)NN=N2)=O VZSRBBMJRBPUNF-UHFFFAOYSA-N 0.000 description 5
- OUCSEDFVYPBLLF-KAYWLYCHSA-N 5-(4-fluorophenyl)-1-[2-[(2r,4r)-4-hydroxy-6-oxooxan-2-yl]ethyl]-n,4-diphenyl-2-propan-2-ylpyrrole-3-carboxamide Chemical compound C=1C=CC=CC=1C1=C(C=2C=CC(F)=CC=2)N(CC[C@H]2OC(=O)C[C@H](O)C2)C(C(C)C)=C1C(=O)NC1=CC=CC=C1 OUCSEDFVYPBLLF-KAYWLYCHSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 238000001879 gelation Methods 0.000 description 5
- 239000008187 granular material Substances 0.000 description 5
- 229920003081 Povidone K 30 Polymers 0.000 description 4
- 239000003153 chemical reaction reagent Substances 0.000 description 4
- 238000005469 granulation Methods 0.000 description 4
- 230000003179 granulation Effects 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 229940001593 sodium carbonate Drugs 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 4
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 3
- 229940075614 colloidal silicon dioxide Drugs 0.000 description 3
- 229950004823 elagolix Drugs 0.000 description 3
- 239000007888 film coating Substances 0.000 description 3
- 238000009501 film coating Methods 0.000 description 3
- ZLNQQNXFFQJAID-UHFFFAOYSA-L magnesium carbonate Chemical compound [Mg+2].[O-]C([O-])=O ZLNQQNXFFQJAID-UHFFFAOYSA-L 0.000 description 3
- 239000001095 magnesium carbonate Substances 0.000 description 3
- 229910000021 magnesium carbonate Inorganic materials 0.000 description 3
- 239000000047 product Substances 0.000 description 3
- 238000007873 sieving Methods 0.000 description 3
- OHVLMTFVQDZYHP-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[4-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]piperazin-1-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CN1CCN(CC1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O OHVLMTFVQDZYHP-UHFFFAOYSA-N 0.000 description 2
- KZEVSDGEBAJOTK-UHFFFAOYSA-N 1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)-2-[5-[2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]ethanone Chemical compound N1N=NC=2CN(CCC=21)C(CC=1OC(=NN=1)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)=O KZEVSDGEBAJOTK-UHFFFAOYSA-N 0.000 description 2
- JQMFQLVAJGZSQS-UHFFFAOYSA-N 2-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-N-(2-oxo-3H-1,3-benzoxazol-6-yl)acetamide Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)CC(=O)NC1=CC2=C(NC(O2)=O)C=C1 JQMFQLVAJGZSQS-UHFFFAOYSA-N 0.000 description 2
- YJLUBHOZZTYQIP-UHFFFAOYSA-N 2-[5-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]-1,3,4-oxadiazol-2-yl]-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)C1=NN=C(O1)CC(=O)N1CC2=C(CC1)NN=N2 YJLUBHOZZTYQIP-UHFFFAOYSA-N 0.000 description 2
- CONKBQPVFMXDOV-QHCPKHFHSA-N 6-[(5S)-5-[[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]methyl]-2-oxo-1,3-oxazolidin-3-yl]-3H-1,3-benzoxazol-2-one Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C[C@H]1CN(C(O1)=O)C1=CC2=C(NC(O2)=O)C=C1 CONKBQPVFMXDOV-QHCPKHFHSA-N 0.000 description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 2
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 2
- 238000010521 absorption reaction Methods 0.000 description 2
- 239000011247 coating layer Substances 0.000 description 2
- 238000007906 compression Methods 0.000 description 2
- 230000006835 compression Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 239000002474 gonadorelin antagonist Substances 0.000 description 2
- 229940121381 gonadotrophin releasing hormone (gnrh) antagonists Drugs 0.000 description 2
- 238000004128 high performance liquid chromatography Methods 0.000 description 2
- 238000000338 in vitro Methods 0.000 description 2
- 238000004806 packaging method and process Methods 0.000 description 2
- 239000002245 particle Substances 0.000 description 2
- 229920003023 plastic Polymers 0.000 description 2
- 239000004033 plastic Substances 0.000 description 2
- 239000000843 powder Substances 0.000 description 2
- 238000003825 pressing Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- 238000005550 wet granulation Methods 0.000 description 2
- HMUNWXXNJPVALC-UHFFFAOYSA-N 1-[4-[2-(2,3-dihydro-1H-inden-2-ylamino)pyrimidin-5-yl]piperazin-1-yl]-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethanone Chemical compound C1C(CC2=CC=CC=C12)NC1=NC=C(C=N1)N1CCN(CC1)C(CN1CC2=C(CC1)NN=N2)=O HMUNWXXNJPVALC-UHFFFAOYSA-N 0.000 description 1
- AEOBYHAZFRJFPZ-QFIPXVFZSA-N 3-[(2r)-2-amino-2-phenylethyl]-5-(2-fluoro-3-methoxyphenyl)-1-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-6-methylpyrimidine-2,4-dione Chemical compound COC1=CC=CC(C=2C(N(C[C@H](N)C=3C=CC=CC=3)C(=O)N(CC=3C(=CC=CC=3F)C(F)(F)F)C=2C)=O)=C1F AEOBYHAZFRJFPZ-QFIPXVFZSA-N 0.000 description 1
- HWYCCACGKNRWJX-NDEPHWFRSA-N 4-[3-carboxypropyl-[(1R)-2-[5-(2-fluoro-3-methoxyphenyl)-3-[[2-fluoro-6-(trifluoromethyl)phenyl]methyl]-4-methyl-2,6-dioxopyrimidin-1-yl]-1-phenylethyl]amino]butanoic acid Chemical compound FC1=C(C=CC=C1OC)C1=C(N(C(N(C1=O)C[C@@H](C1=CC=CC=C1)N(CCCC(=O)O)CCCC(=O)O)=O)CC1=C(C=CC=C1C(F)(F)F)F)C HWYCCACGKNRWJX-NDEPHWFRSA-N 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- 206010015137 Eructation Diseases 0.000 description 1
- 102000001895 Gonadotropin Receptors Human genes 0.000 description 1
- 108010040490 Gonadotropin Receptors Proteins 0.000 description 1
- 101001062093 Homo sapiens RNA-binding protein 15 Proteins 0.000 description 1
- DGAQECJNVWCQMB-PUAWFVPOSA-M Ilexoside XXIX Chemical compound C[C@@H]1CC[C@@]2(CC[C@@]3(C(=CC[C@H]4[C@]3(CC[C@@H]5[C@@]4(CC[C@@H](C5(C)C)OS(=O)(=O)[O-])C)C)[C@@H]2[C@]1(C)O)C)C(=O)O[C@H]6[C@@H]([C@H]([C@@H]([C@H](O6)CO)O)O)O.[Na+] DGAQECJNVWCQMB-PUAWFVPOSA-M 0.000 description 1
- 239000007836 KH2PO4 Substances 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 239000004368 Modified starch Substances 0.000 description 1
- MKYBYDHXWVHEJW-UHFFFAOYSA-N N-[1-oxo-1-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propan-2-yl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(C(C)NC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 MKYBYDHXWVHEJW-UHFFFAOYSA-N 0.000 description 1
- NIPNSKYNPDTRPC-UHFFFAOYSA-N N-[2-oxo-2-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)ethyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 NIPNSKYNPDTRPC-UHFFFAOYSA-N 0.000 description 1
- AFCARXCZXQIEQB-UHFFFAOYSA-N N-[3-oxo-3-(2,4,6,7-tetrahydrotriazolo[4,5-c]pyridin-5-yl)propyl]-2-[[3-(trifluoromethoxy)phenyl]methylamino]pyrimidine-5-carboxamide Chemical compound O=C(CCNC(=O)C=1C=NC(=NC=1)NCC1=CC(=CC=C1)OC(F)(F)F)N1CC2=C(CC1)NN=N2 AFCARXCZXQIEQB-UHFFFAOYSA-N 0.000 description 1
- 239000004372 Polyvinyl alcohol Substances 0.000 description 1
- 102100029244 RNA-binding protein 15 Human genes 0.000 description 1
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 description 1
- 229960000583 acetic acid Drugs 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
- 239000003146 anticoagulant agent Substances 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- 239000012736 aqueous medium Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 235000009697 arginine Nutrition 0.000 description 1
- 208000027687 belching Diseases 0.000 description 1
- 239000008119 colloidal silica Substances 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 238000010586 diagram Methods 0.000 description 1
- 238000007922 dissolution test Methods 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 238000001035 drying Methods 0.000 description 1
- 238000010828 elution Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000007789 gas Substances 0.000 description 1
- 210000004211 gastric acid Anatomy 0.000 description 1
- 230000027119 gastric acid secretion Effects 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000003349 gelling agent Substances 0.000 description 1
- 239000012362 glacial acetic acid Substances 0.000 description 1
- 239000000745 gonadal hormone Substances 0.000 description 1
- 239000008240 homogeneous mixture Substances 0.000 description 1
- QAOWNCQODCNURD-UHFFFAOYSA-M hydrogensulfate Chemical compound OS([O-])(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-M 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- JEIPFZHSYJVQDO-UHFFFAOYSA-N iron(III) oxide Inorganic materials O=[Fe]O[Fe]=O JEIPFZHSYJVQDO-UHFFFAOYSA-N 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 229910052749 magnesium Inorganic materials 0.000 description 1
- 239000011777 magnesium Substances 0.000 description 1
- 229960000869 magnesium oxide Drugs 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- QEQBINKVWYLHGD-BTVCFUMJSA-N methanamine;(2r,3s,4r,5r)-2,3,4,5,6-pentahydroxyhexanal Chemical compound NC.OC[C@@H](O)[C@@H](O)[C@H](O)[C@@H](O)C=O QEQBINKVWYLHGD-BTVCFUMJSA-N 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 235000019426 modified starch Nutrition 0.000 description 1
- 150000004682 monohydrates Chemical class 0.000 description 1
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 1
- 235000019796 monopotassium phosphate Nutrition 0.000 description 1
- 239000007800 oxidant agent Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- GNSKLFRGEWLPPA-UHFFFAOYSA-M potassium dihydrogen phosphate Chemical compound [K+].OP(O)([O-])=O GNSKLFRGEWLPPA-UHFFFAOYSA-M 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 238000012216 screening Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000001632 sodium acetate Substances 0.000 description 1
- 235000017281 sodium acetate Nutrition 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000004408 titanium dioxide Substances 0.000 description 1
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
- A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
- A61K31/513—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim having oxo groups directly attached to the heterocyclic ring, e.g. cytosine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/02—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
-
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/02—Drugs for disorders of the endocrine system of the hypothalamic hormones, e.g. TRH, GnRH, CRH, GRH, somatostatin
Definitions
- the invention relates to the field of pharmaceutical preparations, in particular to an elagolix sodium composition.
- Elagolix sodium (molecular structure shown in formula I) is an oral GnRH antagonist developed by Abbvie and Neurocrine Biosciences. It lowers the levels of circulating gonadal hormones by inhibiting the pituitary gonadotropin receptors. Elagolix, as a new type of GnRH antagonist, has good curative effect on uterine fibroids and endometriosis, and has great market prospects.
- Elagolix sodium is easy to form a gel in an aqueous medium, which affects the disintegration of the preparation and the dissolution rate of the drug, thereby affecting the absorption of the drug in the body.
- elagolix sodium has poor stability in preparations and has a short period of validity.
- Patent CN201880067969.7 discloses a composition of elagolix sodium, in which an antigelling agent (alkalizing agent) is used to solve the above problems of elagolix sodium tablets.
- an antigelling agent alkalizing agent
- sodium carbonate monohydrate is added as anti-gelling agent and stabilizer in the prescription, and a dry or wet granulation process is adopted.
- up to 104mg of sodium carbonate monohydrate is added to the prescription of a 200mg tablet. After oral administration, the sodium carbonate monohydrate in the tablet reacts with gastric acid and will generate carbon dioxide, which may cause belching and secondary Increased gastric acid secretion.
- the object of the present invention is to provide a novel composition containing elagolix sodium.
- a first aspect of the present invention provides an elagolix sodium composition, the composition comprising: elagolix sodium as shown in formula (I), and a pharmaceutically acceptable alkalizing agent, filler agent, adhesive;
- the alkalizing agent is selected from the group consisting of alkali metal hydroxides, alkali metal salts, organic bases, amino acids, alkaline earth metal salts, and alkaline earth metal oxides;
- the alkalizing agent includes a first alkalizing agent and a second alkalizing agent, and at least one of the first alkalizing agent and the second alkalizing agent is magnesium oxide.
- the alkalizing agent does not contain carbonate, such as sodium carbonate.
- the alkalizing agent is selected from the group consisting of arginine, sodium phosphate, sodium bicarbonate, sodium hydroxide, calcium carbonate, meglumine, calcium phosphate, magnesium carbonate, and magnesium oxide.
- the first alkalizing agent is magnesium oxide
- the second alkalizing agent is selected from one or more of the following group: arginine, sodium phosphate, sodium hydroxide, glucose Methylamine and calcium phosphate.
- the first alkalizing agent is magnesium oxide
- the second alkalizing agent is meglumine and/or arginine
- the filler is selected from the group consisting of mannitol and pregelatinized starch.
- the binder is selected from the group consisting of povidone, polyethylene glycol, and hydroxypropyl cellulose.
- composition comprises the following components:
- composition comprises the following components:
- the weight ratio of the alkalizing agent to the elagolix sodium is 0.1-0.9, preferably 0.11-0.85, more preferably 0.12-0.6, and most preferably 0.12-0.58.
- the composition further comprises a disintegrant.
- the disintegrant is selected from the group consisting of crospovidone, pregelatinized starch, cross-linked modified starch, crospovidone, croscarmellose sodium, or its combination.
- the disintegrant is crospovidone.
- the content of the disintegrant is 20-80 parts by weight, preferably 25-70 parts by weight, more preferably 30-60 parts by weight.
- the composition further comprises: a lubricant, and the lubricant is magnesium stearate.
- the content of the lubricant is 3-20 parts by weight, preferably 5-15 parts by weight, more preferably 6-12 parts by weight.
- the composition further comprises: a glidant, which is colloidal silica.
- the content of the glidant is 5-15 parts by weight, preferably 6-12 parts by weight.
- the composition is a tablet.
- the dissolution rate of the composition at the 45min sampling point is greater than 75%, preferably greater than 80%, more preferably greater than 85%.
- the initial total amount of impurities in the composition is ⁇ 0.15%, preferably ⁇ 0.13%.
- the total amount of impurities in the composition is ⁇ 0.35%, preferably ⁇ 0.3%.
- the initial impurity C of the composition is less than or equal to 0.05%, preferably less than or equal to 0.03%.
- the initial impurity H of the composition is less than or equal to 0.05%, preferably less than or equal to 0.03%.
- the impurity C of the composition is less than or equal to 0.1%, preferably less than or equal to 0.08%.
- the impurity H of the composition is less than or equal to 0.03%, preferably less than or equal to 0.01%.
- the second aspect of the present invention provides a preparation method of the composition described in the first aspect of the present invention, comprising the following steps:
- the method further comprises the steps of:
- step 5 Dry-compress the homogeneous mixture obtained in the aforementioned step 2) into granules, and then add additional disintegrants, alkalizers, and lubricants to mix uniformly, and then press into tablets and film-coating.
- the third aspect of the present invention provides a use of the composition according to the first aspect of the present invention for preparing a medicament for treating uterine fibroids and/or endometriosis.
- Fig. 1 is a schematic diagram of the dissolution curves of Example 5-1, Example 5-2 of the present invention and Abbvie original research company's products on the market.
- the present invention has the following main advantages:
- any equipment that meets relevant standards can be used in the preparation process, such as dry granulators, tablet presses, coating machines, and the like.
- the preparation method can also selectively adopt the preparation method commonly used in the art.
- the following equipment is used:
- Dry granulator Mini-DC dry granulator (produced by Shenzhen Xinyite Technology Co., Ltd.)
- Tablet press ZP10A rotary tablet press (produced by Beijing Sinopharm Longli Technology Co., Ltd.)
- Coating machine Labcoating II coating machine (produced by Shenzhen Xinyite Technology Co., Ltd.)
- Elagolix Sodium Tablets the manufacturer is AbbVie Inc., USA.
- the prescription of Elagolix Sodium Tablets with a specification of 200mg consists of Elagolix Sodium, Mannitol, Sodium Carbonate Monohydrate, Pregelatinized starch, povidone, magnesium stearate and film coating (containing polyvinyl alcohol, titanium dioxide, polyethylene glycol, talc, red iron oxide).
- Elagolix sodium tablets were prepared with reference to the content disclosed in CN201880067969.7.
- step 2) Using a dry granulator, the mixture in step 2) will be dry pressed.
- step 5 After sieving the extra magnesium stearate, add it to the mixture obtained in step 4) and mix it uniformly.
- Example 1 Formulation containing water-soluble alkalizing agent
- Table 2 provides formulations containing water-soluble alkalizing agents in examples of the present invention.
- step 2) Dry pressing the mixture in step 2) using a dry granulator.
- step 5 After sieving magnesium stearate, add it to the mixture obtained in step 4), and mix uniformly.
- step 5 After sieving magnesium stearate, add it to the mixture obtained in step 4) and mix by hand.
- the dissolution test method is as follows:
- the preparation method of the dissolution medium is as follows:
- pH1.2 hydrochloric acid solution take 7.65ml of hydrochloric acid, add water and dilute to 1000ml.
- pH4.5 acetate buffer take 18g of sodium acetate, add 9.8ml of glacial acetic acid, and add water to dilute to 1000ml.
- Example compositions containing one of these water-soluble alkalizing agents can reduce the degree of drug gelation to some extent, but with the alkalizing agent containing monohydrate
- the dissolution rate of formulations containing one of these water-soluble alkalizing agents was also low compared to the sodium carbonate control.
- Table 4 provides formulations containing water-soluble alkalizing agents in examples of the present invention.
- the reagents in this example were prepared according to the following steps:
- step 2) Mix the sieved materials in step 1) evenly to obtain a mixture.
- step 2) Add a solution of sodium hydroxide to the mixture of step 2) for granulation.
- Table 6 provides the formulations of the aqueous insoluble alkalizing agents in the examples of the present invention.
- the reagents in this example were prepared according to the following steps:
- step 2) Manually mix the sieved raw and auxiliary materials in step 1) to obtain a mixture.
- the prescription contains a water-insoluble alkalizing agent or antigelling agent (calcium phosphate, calcium carbonate, magnesium carbonate or oxidizing agent). Magnesium), which can reduce the degree of drug gelation to a certain extent.
- a water-insoluble alkalizing agent or antigelling agent calcium carbonate, magnesium carbonate or oxidizing agent. Magnesium
- Embodiment 4 contains magnesium oxide and water-soluble alkalizer combination prescription
- Table 8 provides the formulations of the water-insoluble alkalizing agent magnesium oxide in combination with the water-soluble alkalizing agent (meglumine or arginine) in examples of the present invention.
- step 2) Put the sieved material in step 1) into a mixing container and mix evenly to obtain a mixture.
- step 4) The mixture obtained in step 3) is subjected to dry compression granulation using a dry granulator.
- step 6) Put the sieved material in step 5) and the particles in step 4) into a mixing container and mix evenly.
- Example 4-1 Example 4-2 5 5 7 12 10 twenty one twenty two 29 15 37 37 45 20 51 50 59 30 74 74 81 45 94 93 96 60 98 98 100
- Table 10 provides formulations containing the combination of meglumine and magnesium oxide in examples of the present invention.
- Example 5-1 and 5-2 of the present invention compared with Example 4-1, the dosage of each tablet of the alkalizing agent meglumine in the prescription was increased to 48 mg and 60 mg respectively, which was at pH 4.
- the dissolution rate in .5 acetate buffer was significantly faster than that of Comparative Example 1. Therefore, the formulation containing the combination of magnesium oxide and meglumine can achieve a faster dissolution rate than the comparative example 1 containing sodium carbonate. From the perspective of in vitro dissolution, the combined formulation of the alkalizing agent is a better formulation than that of Comparative Example 1.
- Table 12 provides formulations containing meglumine and magnesium oxide in combination with crospovidone in examples of the present invention.
- step 2) Put the sieved material in step 1) into a mixing container and mix evenly to obtain a mixture.
- step 4) The mixture obtained in step 3) is subjected to dry compression granulation using a dry granulator.
- step 6) Put the sieved material in step 5) and the particles in step 4) into a mixing container and mix evenly.
- Example 6-1 Example 6-2 5 0 5 3 10 7 30 18 15 twenty one 52 38 20 35 71 56 30 57 93 85 45 84 106 98 60 97 107 105
- Example 1-1 and Example 4-1 were packaged with aluminum-plastic, they were placed under the conditions of 40°C and RH75% with Comparative Example 1 (original packaging of the marketed product, namely aluminum-plastic packaging).
- An accelerated stability study was carried out. Samples were taken at 0 days and 3 months to detect the related substances of elagolix sodium tablets. The related substance levels of the stability samples were determined by high performance liquid chromatography.
- octadecylsilane-bonded silica gel (Inertsil ODS-3V C18) chromatographic column, 10mM KH2PO4 aqueous solution as mobile phase A, acetonitrile as mobile phase B gradient elution, the flow rate is 1.0ml/min, the column temperature is 40 °C, The detection wavelength is 274 nm.
- Example 1-1 and Example 4-1 of the present invention are placed 3M under accelerated conditions, and the impurity C, impurity H and total impurities are lower, and their stability is better.
- Example 1-1 and Example 4-1 of the present invention have lower impurity growth rates after 3 months of accelerated stability investigation and better stability.
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Diabetes (AREA)
- Endocrinology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Organic Chemistry (AREA)
- Inorganic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明涉及一种噁拉戈利钠组合物。具体地,本发明公开了一种噁拉戈利钠组合物,所述组合物包括:如式(I)所示的噁拉戈利钠,以及药学上可接受的碱化剂、填充剂、粘合剂;其中,所述碱化剂包括选自下组的物质:碱金属氢氧化物、碱金属盐、有机碱、氨基酸、碱土金属盐、碱土金属氧化物。所述组合物在与原研制剂具有相近或更优的溶出性能的同时,避免了碳酸盐的使用,从而减少了在胃部的二氧化碳气体的产生。此外,本发明的制剂/组合物在放置过程中产生的杂质更少,稳定性更高。
Description
本发明涉及药物制剂领域,具体地涉及一种噁拉戈利钠组合物。
噁拉戈利钠(分子结构如式I所示)是一种口服GnRH拮抗剂,由Abbvie与Neurocrine Biosciences共同研发。它通过抑制脑垂体促性腺释放激素受体,降低血液循环中性腺激素水平。依拉戈利作为新型的GnRH拮抗剂,对子宫肌瘤、子宫内膜异位具有较好的疗效,极具市场前景。
噁拉戈利钠药物在水性介质中容易形成凝胶状,影响制剂的崩解和药物的溶出速度,从而影响药物在体内的吸收。另外,噁拉戈利钠在制剂中稳定性较差,有效期较短。
专利CN201880067969.7公开了一种噁拉戈利钠的组合物,该组合物中采用抗凝胶剂(碱化剂)解决以上噁拉戈利钠片剂存在的问题。在该申请专利中,处方中加入一水合碳酸钠作为抗凝胶剂和稳定剂,采用干法或湿法制粒工艺。在该专利技术中,规格200mg片剂处方中加入了高达104mg一水合碳酸钠,在口服后该片剂中一水合碳酸钠与胃酸中和反应,会产生二氧化碳,可能会引起嗳气及继发性胃酸分泌增加。
因此,有必要对噁拉戈利钠的组合物/制剂进行进一步优化,以解决上述问题。
发明内容
本发明的目的在于提供一种含噁拉戈利钠的新型组合物。
本发明的第一方面,提供了一种噁拉戈利钠组合物,所述组合物包括:如式(I) 所示的噁拉戈利钠,以及药学上可接受的碱化剂、填充剂、粘合剂;
其中,所述碱化剂选自下组:碱金属氢氧化物、碱金属盐、有机碱、氨基酸、碱土金属盐、碱土金属氧化物;
所述碱化剂包括第一碱化剂和第二碱化剂,且所述第一碱化剂和所述第二碱化剂中的至少一种为氧化镁。
在另一优选例中,所述碱化剂不包含碳酸盐,如碳酸钠。
在另一优选例中,所述碱化剂选自下组:精氨酸、磷酸钠、碳酸氢钠、氢氧化钠、碳酸钙、葡甲胺、磷酸钙、碳酸镁、氧化镁。
在另一优选例中,所述第一碱化剂为氧化镁,且所述第二碱化剂选自下组中的一种或多种:精氨酸、磷酸钠、氢氧化钠、葡甲胺和磷酸钙。
在另一优选例中,所述第一碱化剂为氧化镁,第二碱化剂为葡甲胺和/或精氨酸。
在另一优选例中,所述填充剂选自下组:甘露醇、预胶化淀粉。
在另一优选例中,所述粘合剂选自下组:聚维酮、聚乙二醇、羟丙基纤维素。
在另一优选例中,所述组合物包含如下组分:
在另一优选例中,所述组合物包含如下组分:
在另一优选例中,所述碱化剂与所述噁拉戈利钠的重量比为0.1-0.9,较佳地 0.11-0.85,更佳地0.12-0.6,最佳地0.12-0.58。
在另一优选例中,所述组合物还包含崩解剂。
在另一优选例中,所述崩解剂选自下组:交联聚维酮、预胶化淀粉、交联改性淀粉、交联聚乙烯吡咯烷酮、交联羧甲基纤维素钠、或其组合。
在另一优选例中,所述崩解剂为交联聚维酮。
在另一优选例中,所述崩解剂的含量为20-80重量份,较佳地25-70重量份,更佳地30-60重量份。
在另一优选例中,所述组合物还包括:润滑剂,所述润滑剂为硬脂酸镁。
在另一优选例中,所述润滑剂的含量为3-20重量份,较佳地5-15重量份,更佳地6-12重量份。
在另一优选例中,所述组合物还包括:助流剂,所述助流剂为胶态二氧化硅。
在另一优选例中,所述助流剂的含量为5-15重量份,较佳地6-12重量份。
在另一优选例中,所述组合物为片剂。
在另一优选例中,以pH 4.5醋酸盐缓冲液作为溶出介质时,45min取样点所述组合物的溶出度大于75%,较佳地大于80%,更佳地大于85%。
在另一优选例中,所述组合物的初始杂质总量≤0.15%,较佳地≤0.13%。
在另一优选例中,放置3个月后,所述组合物的杂质总量≤0.35%,较佳地≤0.3%。
在另一优选例中,所述组合物的初始杂质C≤0.05%,较佳地≤0.03%。
在另一优选例中,所述组合物的初始杂质H≤0.05%,较佳地≤0.03%。
在另一优选例中,放置3个月后,所述组合物的杂质C≤0.1%,较佳地≤0.08%。
在另一优选例中,放置3个月后,所述组合物的杂质H≤0.03%,较佳地≤0.01%。
本发明的第二方面,提供了一种本发明第一方面所述的组合物的制备方法,包括如下步骤:
1)称取噁拉戈利钠、碱化剂、填充剂、粘合剂和任选的润滑剂;
2)将上述各组分混合均匀;
3)压片;
4)包衣,得到本发明第一方面所述的组合物。
在另一优选例中,所述方法还包括步骤:
5)将前述步骤2)所得均匀混合物干压制粒,然后加入外加部分的崩解剂、碱化剂、润滑剂混合均匀后压片和包薄膜衣。
本发明的第三方面,提供了一种如本发明第一方面所述的组合物的用途,用于制备用于治疗子宫肌瘤和/或子宫内膜异位的药物。
应理解,在本发明范围内中,本发明的上述各技术特征和在下文(如实施例)中具体描述的各技术特征之间都可以互相组合,从而构成新的或优选的技术方案。限于篇幅,在此不再一一累述。
图1为本发明实施例5-1、实施例5-2和Abbvie原研公司生产上市产品的溶出曲线示意图。
本发明人经过长期而深入的研究,对噁拉戈利钠片处方中抗凝剂和/或稳定剂和/或碱化剂和/或崩解剂的种类和用量进行了筛选研究,在此过程中意外地发现了一类稳定性和溶出曲线非常好的式(I)化合物的组合物。在此基础上,发明人完成了本发明。
与现有技术相比,本发明具有以下主要优点:
(1)在与原研制剂具有相近或更优的溶出性能的同时,避免了碳酸盐的使用,从而减少了在胃部的二氧化碳气体的产生。
(2)本发明的制剂/组合物在放置过程中产生的杂质更少,稳定性更高。
下面结合具体实施例,进一步阐述本发明。应理解,这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法,通常按照常规条件或按照制造厂商所建议的条件。除非另外说明,否则百分比和份数按重量计算。
除非另行定义,文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意 义相同。此外,任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
制剂制备使用的设备
本申请中的制剂,其制备过程中可以使用任何符合相关标准的设备,如干法制粒机、压片机、包衣机等。制备方法也可以选择性地采用本领域内通用的制备方法。优选地,采用如下设备:
干法制粒机:Mini-DC干法制粒机(深圳信宜特科技有限公司生产)
压片机:ZP10A型旋转式压片机(北京国药龙立科技有限公司生产)
包衣机:Labcoating II包衣机(深圳信宜特科技有限公司生产)
对比例1
规格200mg噁拉戈利钠片(生产厂家为美国AbbVie Inc.)。根据噁拉戈利(即依拉戈利)钠片原研产品的药品说明书,规格为200mg的噁拉戈利钠片的处方组成为噁拉戈利钠、甘露醇、一水合碳酸钠、预胶化淀粉、聚维酮、硬脂酸镁和薄膜衣(含聚乙烯醇、二氧化钛、聚乙二醇、滑石粉、氧化铁红)。
对比例2
参照CN201880067969.7公开的内容,制备噁拉戈利钠片。
表1
根据下述方法制备该对比例中的制剂:
1)将噁拉戈利钠、甘露醇、一水合碳酸钠、预胶化淀粉、聚维酮K30和内加硬脂酸镁分别过筛。
2)将第1步已过筛的各物料置于混合容器内混合均匀,得到混合物。
3)使用干法制粒机,将对步骤2)中的混合物进行干压。
4)过筛整粒,得到整粒后的混合物。
5)将外加硬脂酸镁过筛之后,加入第4)步所得的混合物中,混合均匀。
6)采用旋转式压片机进行压片。
7)将薄膜包衣预混粉(欧巴代II)加入纯水中配成包衣液。
8)将素片置高效包衣机包衣锅内,进行包衣,包衣层相对于片芯增重3.0%。
实施例1含水溶性碱化剂的制剂
表2提供了本发明实施例中含水溶性碱化剂的制剂。
表2
按照表中所示的配比,根据下述方法制备该实施例中的制剂:
方法一、干法制粒(实施例1-1.实施例1-2):
1)将噁拉戈利钠、甘露醇、碳酸氢钠或精氨酸、预胶化淀粉和聚维酮K30分 别过筛;
2)将第1步已过筛的各物料置于混合容器内混合均匀,得到混合物。
3)使用干法制粒机将步骤2)中的混合物进行干压。
4)过筛整粒,得到整粒后的混合物。
5)将硬脂酸镁过筛之后,加入第4)步所得的混合物中,混合均匀。
6)采用旋转式压片机进行压片。
方法二、粉末直压(实施例1-3)
1)将噁拉戈利钠、甘露醇、磷酸钠、预胶化淀粉和聚维酮分别过30目筛。
2)将第1步已过筛的各物料手动混合均匀。
3)将硬脂酸镁过筛,加入第2)步所得混合物中,混合均匀。
4)采用旋转式压片机进行压片。
方法三、湿法制粒(实施例1-4)
1)将噁拉戈利钠、甘露醇、预胶化淀粉和聚维酮分别过筛。
2)将第1步已过筛的各物料手动混合均匀,得到混合物。
3)将氢氧化钠溶液加入混合物中手动制粒。
4)对步骤3)中的混合物进行过筛整粒。
5)将硬脂酸镁过筛之后,加入第4)步所得的混合物中手动混合均匀。
6)采用旋转式压片机进行压片。
测试例1
按照溶出度与释放度测定法(中国药典2015年版四部通则0931第二法),对各实施例中制得的制剂进行溶出度测定。溶出度测定方法如下:
分别量取900ml溶出介质(pH1.2盐酸溶液或pH4.5醋酸盐缓冲液),置于不同的溶出杯中,恒温于37.0℃±0.5℃后,取上述制剂,分别投入装有溶出介质的不同溶出杯内,在转速为50rpm下搅拌,于制剂接触溶出介质时开始计时,每间隔一固定时间分别取样一次,过滤,采用HPLC测定滤液中药物浓度,并计算溶出度。
其中溶出介质的配制方法如下:
pH1.2盐酸溶液:取7.65ml盐酸,加水稀释至1000ml即得。
pH4.5醋酸盐缓冲液:取醋酸钠18g,加冰醋酸9.8ml,再加水稀释至1000ml即得。
按照上述方法,使用900mL,pH 1.2盐酸溶液作为溶出介质,分别测定对比例1、对比例2和实施例1-1~实施例1-4所得制剂的溶出度,结果列于表3。
表3
由上述结果可以得出,与对比例相比,本发明实施例1-1至实施例1-4的制剂在pH 1.2盐酸溶液中的溶出较慢,并且可以在观察了活性药物有凝胶化趋势。药物凝胶化会降低制剂中活性药物的溶出速度,从而降低在体内药物的吸收。含一种这些水溶性碱化剂(精氨酸、磷酸钠、碳酸氢钠或氢氧化钠)的实施例组合物可以在一定程度上减少药物凝胶化程度,但与含碱化剂一水合碳酸钠对比例相比,含一种这些水溶性碱化剂(精氨酸、磷酸钠、碳酸氢钠或氢氧化钠)的制剂的溶出度还偏低。
实施例2含组合水溶性碱化剂制剂
表4提供了本发明实施例中含水溶性碱化剂的制剂。
表4
按照表中所示的配比,根据下述步骤制备该实施例中的试剂:
1)将噁拉戈利钠、甘露醇、碱化剂(精氨酸、碳酸氢钠或葡甲胺)、预胶化淀粉和聚维酮分别过筛。
2)将第1)步已过筛的物料混合均匀,得到混合物。
3)将氢氧化钠的溶液加入步骤2)的混合物中制粒。
4)对步骤3)中的混合物进行过筛整粒。
5)将硬脂酸镁过筛,加入步骤4)的混合物中,混合均匀。
6)采用旋转式压片机进行压片。
测试例2
按照测试例1中所述的方法,使用900mL,pH 1.2盐酸溶液作为溶出介质,分别测定对比例1和实施例2-1~实施例2-4所得制剂的溶出度,结果列于表5。
表5
可见,以上分别含碱化剂氢氧化钠或者水溶性碱化剂(精氨酸、碳酸氢钠或葡甲胺)与氢氧化钠组合的处方,可以在一定程度上减少药物凝胶化程度,但与对比例1相比,溶出速度均较慢。
实施例3
表6提供了本发明实施例中含水不溶性碱化剂的制剂。
表6
按照表中所示的配比,根据下述步骤制备该实施例中的试剂:
1)将噁拉戈利钠、甘露醇、碱化剂(碳酸镁、磷酸钙、氧化镁或碳酸钙)、预胶化淀粉和聚维酮分别过筛。
2)将第1)步已过筛的原辅料手动混合均匀,得到混合物。
3)将硬脂酸镁过筛,之后与步骤2)中的混合物混合均匀。
4)采用旋转式压片机进行压片。
测试例3
按照测试例1中所述的方法,使用900mL pH 1.2盐酸溶液作为溶出介质,分别测定对比例1和实施例3-1至实施例3-4所得制剂的溶出度,结果列于表7。
表7
可见,与以一水合碳酸钠为碱化剂或抗凝胶剂的对比例1相比,处方中含一种水不溶性碱化剂或抗凝胶剂(磷酸钙、碳酸钙、碳酸镁或氧化镁)的处方,可以在一定程度上减少药物凝胶化程度。但与对比例1相比,溶出速度均较慢。
实施例4含氧化镁和水溶性碱化剂组合处方
表8提供了本发明实施例中含水不溶性碱化剂氧化镁和水溶性碱化剂(葡甲胺或精胺酸)组合的制剂。
表8
按照表中所示的配比,根据下述方法制备该实施例中的制剂:
1)将噁拉戈利钠、甘露醇、氧化镁、聚维酮K30、内加部分的预胶化淀粉、内加部分的胶态二氧化硅分别过筛。
2)将第1)步已过筛的物料置混合容器内混合均匀,得到混合物。
3)将内加部分硬脂酸镁过筛,加入第2)步混合物中,继续混合均匀。
4)将步骤3)中得到的混合物使用干法制粒机进行干压制粒。
5)将外加部分的葡甲胺或精氨酸、预胶化淀粉、胶态二氧化硅分别过筛。
6)将已过筛的第5)步物料与第4)步颗粒置混合容器内混合均匀。
7)将外加部分硬脂酸镁过筛,加入第6)步所得混合物中,混合均匀。
8)采用旋转式压片机进行压片。
测试例4
按照测试例1中所述的方法,使用900mL,pH4.5醋酸盐缓冲液作为溶出介质,分别测定对比例1、实施例4-1和实施例4-2所得制剂的溶出度,结果列于表9。
表9
时间(min) | 对比例1 | 实施例4-1 | 实施例4-2 |
5 | 5 | 7 | 12 |
10 | 21 | 22 | 29 |
15 | 37 | 37 | 45 |
20 | 51 | 50 | 59 |
30 | 74 | 74 | 81 |
45 | 94 | 93 | 96 |
60 | 98 | 98 | 100 |
由上述结果可以得出,当处方中含有不溶性碱化剂(氧化镁)和水溶性碱化剂(葡甲胺)时,在pH 4.5醋酸盐缓冲液溶出度较好,60min内释药率超过85%。可见,含有不溶性碱化剂(氧化镁)和水溶性碱化剂(葡甲胺或精氨酸)组合的处方与含一水合碳酸钠作为碱化剂的对比例1相比,其溶出速度能够达到相同的效果。
实施例5
表10提供了本发明实施例中含葡甲胺和氧化镁组合的制剂。
表10
按照表10中所示的配比,根据下述方法制备该实施例中的试剂:
1)将噁拉戈利钠、甘露醇、预胶化淀粉、聚维酮、氧化镁和葡甲胺、胶态二氧化硅分别过筛。
2)将第1步已过筛的物料混合均匀,得到混合物。
3)将硬脂酸镁过筛,加入第2)步所得混合物中,混合均匀。
4)采用旋转式压片机进行压片。
测试例5
按照测试例1中所述的方法,使用900mL pH4.5醋酸盐缓冲液作为溶出介质,分别测定对比例1和实施例5-1和实施例5-2所得制剂的溶出度,结果列于表11,溶出曲线如图1所示。
表11
由上述结果可以得出,本发明实施例5-1和5-2中,相比于实施例4-1,处方中碱化剂葡甲胺每片用量分别增加至48mg和60mg,其在pH4.5醋酸盐缓冲液中溶出度明显快于对比例1。因此,含有氧化镁和葡甲胺组合的处方,相比于含碳酸钠的对比例1,能够达到更快的溶出速度。从体外溶出角度,该碱化剂组合处方相比于对比例1是更优的处方。
实施例6
表12提供了本发明实施例中含葡甲胺和氧化镁,以及交联聚维酮组合的制剂。
表12
按照表12中所示的配比,根据下述方法制备该实施例中的试剂:
1)将噁拉戈利钠、甘露醇、聚维酮K30、氧化镁和内加部分的葡甲胺分别过筛。
2)将第1)步已过筛的物料置混合容器内混合均匀,得到混合物。
3)将内加部分硬脂酸镁过筛,加入第2)步混合物中,继续混合均匀。
4)将步骤3)中得到的混合物使用干法制粒机进行干压制粒。
5)将外加部分的葡甲胺、交联聚维酮分别过筛。
6)将已过筛的第5)步物料与第4)步颗粒置混合容器内混合均匀。
7)将外加部分硬脂酸镁过筛,加入第6)步所得混合物中,混合均匀。
8)采用旋转式压片机进行压片。
9)将欧巴代II加入纯水中配成包衣液。
10)将素片置高效包衣机包衣锅内,进行包衣,包衣层相对于片芯增重3.0%。
测试例6
按照测试例1中所述的方法,使用900mL pH1.2盐酸溶液作为溶出介质,分别测定对比例1和实施例6-1和实施例6-2所得制剂的溶出度,结果列于表13。
表13
时间(min) | 对比例1 | 实施例6-1 | 实施例6-2 |
5 | 0 | 5 | 3 |
10 | 7 | 30 | 18 |
15 | 21 | 52 | 38 |
20 | 35 | 71 | 56 |
30 | 57 | 93 | 85 |
45 | 84 | 106 | 98 |
60 | 97 | 107 | 105 |
由上述结果可以得出,本发明实施例6-1和6-2在pH1.2盐酸溶液中溶出度明显快于对比例1。因此,含有氧化镁和葡甲胺碱化剂,以及崩解剂交联聚维酮组合的处方,相比于含碳酸钠的对比例1,能够达到更快的溶出速度。从体外溶出角度,该组合处方相比于对比例1是更优的处方。
测试例7
将对比例2、实施例1-1和实施例4-1所得的制剂采用铝塑包装后,与对比例 1(上市产品原包装,即铝塑包装)分别置于40℃,RH75%条件下进行加速稳定性考察。分别于0天和3个月取样检测噁拉戈利钠片样品的有关物质。稳定性样品的有关物质水平采用高效液相色谱法测定。采用十八烷基硅烷键合硅胶(Inertsil ODS-3V C18)色谱柱,以10mM KH2PO4水溶液为流动相A,乙腈为流动相B的梯度洗脱,流速为1.0ml/min,柱温40℃,检测波长为274nm。
按照上述方法进行测试,所得结果见表14。
其中,杂质C和杂质H的化学名称和结构式如下:
杂质C:
化学名:(R)-4-((3-羧丙基)-{2-[5-(2-氟-3-甲氧基-苯基)-3-(2-氟-6-三氟甲基-苄基)-4-甲基-2,6-二氧代-3,6-二氢-2H-嘧啶-1-基]-1-苯基-乙基}-氨基)-丁酸
杂质H:
化学名:(R)-3-(2-氨基-2-苯基-乙基)-5-(2-氟-3-甲氧基-苯基)-1-(2-氟-6-三氟甲基-苄基)-6-甲基-1H-嘧啶-2,4-二酮;硫酸氢盐
表14
“--”表示未检出。
可见,本发明实施例1-1和实施例4-1与对比例1或对比例2相比,在加速条件下放置3M,杂质C、杂质H以及总杂更低,其稳定性更优。本发明实施例1-1和实施例4-1与对比例2相比,其加速稳定性考察3个月的杂质增长幅度均较低,稳定性更好。
在本发明提及的所有文献都在本申请中引用作为参考,就如同每一篇文献被单独引用作为参考那样。此外应理解,在阅读了本发明的上述讲授内容之后,本领域技术人员可以对本发明作各种改动或修改,这些等价形式同样落于本申请所附权利要求书所限定的范围。
Claims (10)
- 如权利要求1所述的组合物,其特征在于,所述碱化剂选自下组:精氨酸、磷酸钠、碳酸氢钠、氢氧化钠、碳酸钙、葡甲胺、磷酸钙、碳酸镁、氧化镁。
- 如权利要求1所述的组合物,其特征在于,所述第一碱化剂为氧化镁,且所述第二碱化剂选自下组中的一种或多种:精氨酸、磷酸钠、氢氧化钠、葡甲胺和磷酸钙。
- 如权利要求1所述的组合物,其特征在于,所述第一碱化剂为氧化镁,第二碱化剂为葡甲胺和/或精氨酸。
- 如权利要求1所述的组合物,其特征在于,所述填充剂选自下组:甘露醇、预胶化淀粉。
- 如权利要求1所述的组合物,其特征在于,所述粘合剂选自下组:聚维酮、聚乙二醇、羟丙基纤维素。
- 如权利要求1所述的组合物,其特征在于,所述组合物还包含崩解剂。
- 一种权利要求1所述的组合物的制备方法,其特征在于,包括如下步骤:1)称取噁拉戈利钠、碱化剂、填充剂、粘合剂和任选的润滑剂;2)将上述各组分混合均匀;3)压片;4)包衣,得到权利要求1所述的组合物。
- 一种如权利要求1-8任一所述的组合物的用途,其特征在于,用于制备用于治疗子宫肌瘤和/或子宫内膜异位的药物。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202280026950.4A CN117545484A (zh) | 2021-04-21 | 2022-04-18 | 一种噁拉戈利钠组合物 |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202110431087 | 2021-04-21 | ||
CN202110431087.8 | 2021-04-21 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO2022222886A1 true WO2022222886A1 (zh) | 2022-10-27 |
Family
ID=83721955
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/CN2022/087432 WO2022222886A1 (zh) | 2021-04-21 | 2022-04-18 | 一种噁拉戈利钠组合物 |
Country Status (2)
Country | Link |
---|---|
CN (1) | CN117545484A (zh) |
WO (1) | WO2022222886A1 (zh) |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115856138A (zh) * | 2022-12-13 | 2023-03-28 | 安徽联创生物医药股份有限公司 | 一种用hplc分离测定噁拉戈利钠中有关物质的方法 |
Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018189213A1 (en) * | 2017-04-13 | 2018-10-18 | Sandoz Ag | Amorphous solid dispersion of an orally available gonadotropin-releasing hormone receptor antagonist |
CN111246850A (zh) * | 2017-08-18 | 2020-06-05 | 艾伯维公司 | 用于治疗子宫内膜异位症、子宫肌瘤、多囊卵巢综合症以及子宫腺肌症的固体药物配制物 |
CN111698992A (zh) * | 2017-08-18 | 2020-09-22 | 艾伯维公司 | 用于治疗子宫内膜异位症、子宫肌瘤、多囊卵巢综合症或子宫腺肌症的药物配制物 |
CN113384581A (zh) * | 2020-03-12 | 2021-09-14 | 成都倍特药业股份有限公司 | 一种包含促性腺激素释放激素拮抗剂的药物组合物 |
WO2021180862A1 (en) * | 2020-03-12 | 2021-09-16 | Synthon B.V. | Pharmaceutical compositions comprising elagolix sodium |
US11273128B1 (en) * | 2021-04-15 | 2022-03-15 | Sandoz Ag | Elagolix formulation |
-
2022
- 2022-04-18 CN CN202280026950.4A patent/CN117545484A/zh active Pending
- 2022-04-18 WO PCT/CN2022/087432 patent/WO2022222886A1/zh active Application Filing
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2018189213A1 (en) * | 2017-04-13 | 2018-10-18 | Sandoz Ag | Amorphous solid dispersion of an orally available gonadotropin-releasing hormone receptor antagonist |
CN111246850A (zh) * | 2017-08-18 | 2020-06-05 | 艾伯维公司 | 用于治疗子宫内膜异位症、子宫肌瘤、多囊卵巢综合症以及子宫腺肌症的固体药物配制物 |
CN111698992A (zh) * | 2017-08-18 | 2020-09-22 | 艾伯维公司 | 用于治疗子宫内膜异位症、子宫肌瘤、多囊卵巢综合症或子宫腺肌症的药物配制物 |
CN113384581A (zh) * | 2020-03-12 | 2021-09-14 | 成都倍特药业股份有限公司 | 一种包含促性腺激素释放激素拮抗剂的药物组合物 |
WO2021180862A1 (en) * | 2020-03-12 | 2021-09-16 | Synthon B.V. | Pharmaceutical compositions comprising elagolix sodium |
US11273128B1 (en) * | 2021-04-15 | 2022-03-15 | Sandoz Ag | Elagolix formulation |
Non-Patent Citations (1)
Title |
---|
LAMB YVETTE N.: "Elagolix: First Global Approval", DRUGS, ADIS INTERNATIONAL LTD., NZ, vol. 78, no. 14, 1 September 2018 (2018-09-01), NZ , pages 1501 - 1508, XP055806347, ISSN: 0012-6667, DOI: 10.1007/s40265-018-0977-4 * |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN115856138A (zh) * | 2022-12-13 | 2023-03-28 | 安徽联创生物医药股份有限公司 | 一种用hplc分离测定噁拉戈利钠中有关物质的方法 |
CN115856138B (zh) * | 2022-12-13 | 2024-06-04 | 安徽联创生物医药股份有限公司 | 一种用hplc分离测定噁拉戈利钠中有关物质的方法 |
Also Published As
Publication number | Publication date |
---|---|
CN117545484A (zh) | 2024-02-09 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
KR101406767B1 (ko) | 프라미펙솔 또는 약제학적으로 허용되는 이의 염을함유하는 연장 방출성 정제 제형, 이의 제조방법 및 이의용도 | |
US6531153B2 (en) | Composition with sustained release of levodopa and carbidopa | |
US11413295B2 (en) | Oral preparation of obeticholic acid | |
EP1574215B1 (en) | Solid drug for oral use | |
US20090324718A1 (en) | Imatinib compositions | |
WO2020249001A1 (zh) | 一种含有布鲁顿氏酪氨酸激酶抑制剂的口服固体片剂及其制备方法 | |
JP2010047612A (ja) | ナテグリニド含有製剤 | |
CN105056246A (zh) | 一种卡谷氨酸固体组合物及其制备方法 | |
WO2022222886A1 (zh) | 一种噁拉戈利钠组合物 | |
JP7428356B2 (ja) | 高いバイオアベイラビリティを有するソラフェニブの医薬組成物、ソラフェニブ経口固形製剤、及びその使用 | |
JP6680297B2 (ja) | 経口投与用医薬組成物 | |
CN112294773B (zh) | 一种富马酸丙酚替诺福韦的药物组合物 | |
JP2000026292A (ja) | 速放性経口医薬品組成物 | |
WO2000071117A1 (fr) | Compositions medicinales a liberation immediate pour administration orale | |
US20160193162A1 (en) | Stable crystal i-form agomelatine tablet and preparation method thereof | |
CN108078945B (zh) | 卡格列净药物组合物 | |
WO2011079764A1 (zh) | 一种右旋佐匹克隆固体制剂及其制备方法 | |
US20160120825A1 (en) | Stable crystal x-form agomelatine tablet and preparation method thereof | |
KR101428149B1 (ko) | 이매티닙메실산염 함유 과립, 이를 포함하는 경구용 속방성 정제 조성물 및 그것의 제조방법 | |
CN111035619B (zh) | 一种吉非替尼片及其制备方法 | |
WO2022042646A1 (zh) | 盐酸鲁拉西酮组合物及其制备方法 | |
CN116440089A (zh) | 含噁拉戈利的药物组合物及其制备方法 | |
WO2021136089A1 (zh) | 一种抗肿瘤药物组合物以及提高化合物的溶解度的方法 | |
WO2021226738A1 (zh) | 包含仑伐替尼的分子水平的药物组合物及其制备方法和应用 | |
CN115804774A (zh) | 一种噁拉戈利的药物组合物,包含其的药物制剂,及其应用 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
121 | Ep: the epo has been informed by wipo that ep was designated in this application |
Ref document number: 22790994 Country of ref document: EP Kind code of ref document: A1 |
|
NENP | Non-entry into the national phase |
Ref country code: DE |
|
WWE | Wipo information: entry into national phase |
Ref document number: 202280026950.4 Country of ref document: CN |
|
122 | Ep: pct application non-entry in european phase |
Ref document number: 22790994 Country of ref document: EP Kind code of ref document: A1 |