JP2015531340A - ウリプリスタール酢酸エステルの結晶多形 - Google Patents
ウリプリスタール酢酸エステルの結晶多形 Download PDFInfo
- Publication number
- JP2015531340A JP2015531340A JP2015515333A JP2015515333A JP2015531340A JP 2015531340 A JP2015531340 A JP 2015531340A JP 2015515333 A JP2015515333 A JP 2015515333A JP 2015515333 A JP2015515333 A JP 2015515333A JP 2015531340 A JP2015531340 A JP 2015531340A
- Authority
- JP
- Japan
- Prior art keywords
- ulipristal acetate
- acetate
- crystal
- polymorph
- ulipristal
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
- 229960000499 ulipristal acetate Drugs 0.000 title claims abstract description 118
- OOLLAFOLCSJHRE-ZHAKMVSLSA-N ulipristal acetate Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(OC(C)=O)C(C)=O)[C@]2(C)C1 OOLLAFOLCSJHRE-ZHAKMVSLSA-N 0.000 title claims abstract description 110
- 239000013078 crystal Substances 0.000 claims abstract description 151
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims abstract description 61
- -1 ulipristal acetate ester Chemical class 0.000 claims abstract description 26
- 239000003433 contraceptive agent Substances 0.000 claims abstract description 23
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 22
- 239000012046 mixed solvent Substances 0.000 claims abstract description 16
- 239000003814 drug Substances 0.000 claims abstract description 13
- 201000010260 leiomyoma Diseases 0.000 claims abstract description 13
- 206010046798 Uterine leiomyoma Diseases 0.000 claims abstract description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 claims description 46
- 238000001228 spectrum Methods 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 37
- 239000000126 substance Substances 0.000 claims description 36
- 238000000634 powder X-ray diffraction Methods 0.000 claims description 29
- 239000000463 material Substances 0.000 claims description 28
- 230000002254 contraceptive effect Effects 0.000 claims description 22
- 238000000113 differential scanning calorimetry Methods 0.000 claims description 19
- 239000008194 pharmaceutical composition Substances 0.000 claims description 19
- 239000000546 pharmaceutical excipient Substances 0.000 claims description 13
- 229940079593 drug Drugs 0.000 claims description 3
- 239000012453 solvate Substances 0.000 claims description 2
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims 1
- 230000002265 prevention Effects 0.000 claims 1
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 abstract description 53
- 238000004519 manufacturing process Methods 0.000 abstract description 14
- 229940124597 therapeutic agent Drugs 0.000 abstract description 5
- 229940124558 contraceptive agent Drugs 0.000 abstract description 2
- 230000003449 preventive effect Effects 0.000 abstract description 2
- 238000002360 preparation method Methods 0.000 description 23
- 239000002904 solvent Substances 0.000 description 22
- 239000000203 mixture Substances 0.000 description 21
- 239000000243 solution Substances 0.000 description 18
- 238000002425 crystallisation Methods 0.000 description 13
- 230000008025 crystallization Effects 0.000 description 13
- 239000002775 capsule Substances 0.000 description 11
- 238000002844 melting Methods 0.000 description 11
- 230000008018 melting Effects 0.000 description 11
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 10
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 9
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- 230000000052 comparative effect Effects 0.000 description 9
- 238000001816 cooling Methods 0.000 description 9
- 201000010099 disease Diseases 0.000 description 9
- 238000009472 formulation Methods 0.000 description 9
- 239000000725 suspension Substances 0.000 description 8
- 239000008187 granular material Substances 0.000 description 7
- 238000010438 heat treatment Methods 0.000 description 7
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 7
- ZWEHNKRNPOVVGH-UHFFFAOYSA-N 2-Butanone Chemical compound CCC(C)=O ZWEHNKRNPOVVGH-UHFFFAOYSA-N 0.000 description 6
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 239000003795 chemical substances by application Substances 0.000 description 6
- 239000011248 coating agent Substances 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 6
- 239000003826 tablet Substances 0.000 description 6
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 5
- 235000010980 cellulose Nutrition 0.000 description 5
- 229920002678 cellulose Polymers 0.000 description 5
- 239000001913 cellulose Substances 0.000 description 5
- 239000002552 dosage form Substances 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 239000000843 powder Substances 0.000 description 5
- 239000002994 raw material Substances 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 4
- 241000282472 Canis lupus familiaris Species 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- 229920002472 Starch Polymers 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 4
- 239000000654 additive Substances 0.000 description 4
- 150000001875 compounds Chemical class 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 150000002170 ethers Chemical class 0.000 description 4
- 238000001914 filtration Methods 0.000 description 4
- 230000000069 prophylactic effect Effects 0.000 description 4
- 239000011541 reaction mixture Substances 0.000 description 4
- 239000008107 starch Substances 0.000 description 4
- 235000019698 starch Nutrition 0.000 description 4
- 229920002126 Acrylic acid copolymer Polymers 0.000 description 3
- 229920002134 Carboxymethyl cellulose Polymers 0.000 description 3
- 201000009273 Endometriosis Diseases 0.000 description 3
- 239000001856 Ethyl cellulose Substances 0.000 description 3
- ZZSNKZQZMQGXPY-UHFFFAOYSA-N Ethyl cellulose Chemical compound CCOCC1OC(OC)C(OCC)C(OCC)C1OC1C(O)C(O)C(OC)C(CO)O1 ZZSNKZQZMQGXPY-UHFFFAOYSA-N 0.000 description 3
- LRHPLDYGYMQRHN-UHFFFAOYSA-N N-Butanol Chemical compound CCCCO LRHPLDYGYMQRHN-UHFFFAOYSA-N 0.000 description 3
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 description 3
- 206010046788 Uterine haemorrhage Diseases 0.000 description 3
- 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 3
- 150000001338 aliphatic hydrocarbons Chemical class 0.000 description 3
- 239000011230 binding agent Substances 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000008367 deionised water Substances 0.000 description 3
- 229910021641 deionized water Inorganic materials 0.000 description 3
- 239000003085 diluting agent Substances 0.000 description 3
- 239000007884 disintegrant Substances 0.000 description 3
- 150000002148 esters Chemical class 0.000 description 3
- 235000019325 ethyl cellulose Nutrition 0.000 description 3
- 229920001249 ethyl cellulose Polymers 0.000 description 3
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 description 3
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 239000002245 particle Substances 0.000 description 3
- 230000036470 plasma concentration Effects 0.000 description 3
- 239000002244 precipitate Substances 0.000 description 3
- 239000006188 syrup Substances 0.000 description 3
- 235000020357 syrup Nutrition 0.000 description 3
- 238000012360 testing method Methods 0.000 description 3
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- DLFVBJFMPXGRIB-UHFFFAOYSA-N Acetamide Chemical compound CC(N)=O DLFVBJFMPXGRIB-UHFFFAOYSA-N 0.000 description 2
- 208000008035 Back Pain Diseases 0.000 description 2
- 206010010774 Constipation Diseases 0.000 description 2
- 208000005171 Dysmenorrhea Diseases 0.000 description 2
- 206010013935 Dysmenorrhoea Diseases 0.000 description 2
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 description 2
- 229920003134 Eudragit® polymer Polymers 0.000 description 2
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 description 2
- 241000282412 Homo Species 0.000 description 2
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 2
- 229920000663 Hydroxyethyl cellulose Polymers 0.000 description 2
- 239000004354 Hydroxyethyl cellulose Substances 0.000 description 2
- 229920002153 Hydroxypropyl cellulose Polymers 0.000 description 2
- 208000008930 Low Back Pain Diseases 0.000 description 2
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 2
- 229920000881 Modified starch Polymers 0.000 description 2
- 208000002193 Pain Diseases 0.000 description 2
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 description 2
- 239000004372 Polyvinyl alcohol Substances 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 229920002125 Sokalan® Polymers 0.000 description 2
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 2
- 208000016599 Uterine disease Diseases 0.000 description 2
- VJHCJDRQFCCTHL-UHFFFAOYSA-N acetic acid 2,3,4,5,6-pentahydroxyhexanal Chemical compound CC(O)=O.OCC(O)C(O)C(O)C(O)C=O VJHCJDRQFCCTHL-UHFFFAOYSA-N 0.000 description 2
- 150000001298 alcohols Chemical class 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 208000007502 anemia Diseases 0.000 description 2
- 239000003963 antioxidant agent Substances 0.000 description 2
- 239000003418 antiprogestin Substances 0.000 description 2
- 239000008346 aqueous phase Substances 0.000 description 2
- 150000004945 aromatic hydrocarbons Chemical class 0.000 description 2
- 235000010948 carboxy methyl cellulose Nutrition 0.000 description 2
- 229950008138 carmellose Drugs 0.000 description 2
- 238000005119 centrifugation Methods 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- RKTYLMNFRDHKIL-UHFFFAOYSA-N copper;5,10,15,20-tetraphenylporphyrin-22,24-diide Chemical compound [Cu+2].C1=CC(C(=C2C=CC([N-]2)=C(C=2C=CC=CC=2)C=2C=CC(N=2)=C(C=2C=CC=CC=2)C2=CC=C3[N-]2)C=2C=CC=CC=2)=NC1=C3C1=CC=CC=C1 RKTYLMNFRDHKIL-UHFFFAOYSA-N 0.000 description 2
- 150000004292 cyclic ethers Chemical class 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 230000002357 endometrial effect Effects 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 238000011049 filling Methods 0.000 description 2
- 239000000796 flavoring agent Substances 0.000 description 2
- 235000013355 food flavoring agent Nutrition 0.000 description 2
- 230000002496 gastric effect Effects 0.000 description 2
- 150000004676 glycans Chemical class 0.000 description 2
- 235000011187 glycerol Nutrition 0.000 description 2
- 235000019447 hydroxyethyl cellulose Nutrition 0.000 description 2
- 235000010977 hydroxypropyl cellulose Nutrition 0.000 description 2
- 239000001863 hydroxypropyl cellulose Substances 0.000 description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 description 2
- 229920003132 hydroxypropyl methylcellulose phthalate Polymers 0.000 description 2
- 229940031704 hydroxypropyl methylcellulose phthalate Drugs 0.000 description 2
- 208000000509 infertility Diseases 0.000 description 2
- 230000036512 infertility Effects 0.000 description 2
- 231100000535 infertility Toxicity 0.000 description 2
- 238000002347 injection Methods 0.000 description 2
- 239000007924 injection Substances 0.000 description 2
- 150000002576 ketones Chemical class 0.000 description 2
- 238000001294 liquid chromatography-tandem mass spectrometry Methods 0.000 description 2
- 239000000314 lubricant Substances 0.000 description 2
- 230000001394 metastastic effect Effects 0.000 description 2
- 206010061289 metastatic neoplasm Diseases 0.000 description 2
- CMIAIUZBKPLIOP-YZLZLFLDSA-N methyl (1r,4ar,4br,10ar)-7-(2-hydroperoxypropan-2-yl)-4a-methyl-2,3,4,4b,5,6,10,10a-octahydro-1h-phenanthrene-1-carboxylate Chemical compound C1=C(C(C)(C)OO)CC[C@@H]2[C@]3(C)CCC[C@@H](C(=O)OC)[C@H]3CC=C21 CMIAIUZBKPLIOP-YZLZLFLDSA-N 0.000 description 2
- 229920000609 methyl cellulose Polymers 0.000 description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 2
- 239000001923 methylcellulose Substances 0.000 description 2
- 230000027939 micturition Effects 0.000 description 2
- 239000002674 ointment Substances 0.000 description 2
- 239000012074 organic phase Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 239000006187 pill Substances 0.000 description 2
- 229920000642 polymer Polymers 0.000 description 2
- 229920001282 polysaccharide Polymers 0.000 description 2
- 239000005017 polysaccharide Substances 0.000 description 2
- 229920002451 polyvinyl alcohol Polymers 0.000 description 2
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 2
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 2
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 2
- CHKVPAROMQMJNQ-UHFFFAOYSA-M potassium bisulfate Chemical compound [K+].OS([O-])(=O)=O CHKVPAROMQMJNQ-UHFFFAOYSA-M 0.000 description 2
- 230000001376 precipitating effect Effects 0.000 description 2
- 239000003755 preservative agent Substances 0.000 description 2
- 239000002379 progesterone receptor modulator Substances 0.000 description 2
- 230000003623 progesteronic effect Effects 0.000 description 2
- 238000000746 purification Methods 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- 238000010583 slow cooling Methods 0.000 description 2
- 235000015424 sodium Nutrition 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 229910052708 sodium Inorganic materials 0.000 description 2
- 241000894007 species Species 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 150000003462 sulfoxides Chemical class 0.000 description 2
- 239000000454 talc Substances 0.000 description 2
- 229910052623 talc Inorganic materials 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- 230000001225 therapeutic effect Effects 0.000 description 2
- 238000004809 thin layer chromatography Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- IXPNQXFRVYWDDI-UHFFFAOYSA-N 1-methyl-2,4-dioxo-1,3-diazinane-5-carboximidamide Chemical compound CN1CC(C(N)=N)C(=O)NC1=O IXPNQXFRVYWDDI-UHFFFAOYSA-N 0.000 description 1
- 244000215068 Acacia senegal Species 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 1
- 229910018072 Al 2 O 3 Inorganic materials 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
- 241000283690 Bos taurus Species 0.000 description 1
- OYPRJOBELJOOCE-UHFFFAOYSA-N Calcium Chemical compound [Ca] OYPRJOBELJOOCE-UHFFFAOYSA-N 0.000 description 1
- 229920000623 Cellulose acetate phthalate Polymers 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- 229920002261 Corn starch Polymers 0.000 description 1
- 229920002785 Croscarmellose sodium Polymers 0.000 description 1
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 description 1
- FBPFZTCFMRRESA-FSIIMWSLSA-N D-Glucitol Natural products OC[C@H](O)[C@H](O)[C@@H](O)[C@H](O)CO FBPFZTCFMRRESA-FSIIMWSLSA-N 0.000 description 1
- FBPFZTCFMRRESA-KVTDHHQDSA-N D-Mannitol Chemical compound OC[C@@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-KVTDHHQDSA-N 0.000 description 1
- FBPFZTCFMRRESA-JGWLITMVSA-N D-glucitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO FBPFZTCFMRRESA-JGWLITMVSA-N 0.000 description 1
- 239000004375 Dextrin Substances 0.000 description 1
- 229920001353 Dextrin Polymers 0.000 description 1
- 241000283086 Equidae Species 0.000 description 1
- DNXHEGUUPJUMQT-CBZIJGRNSA-N Estrone Chemical compound OC1=CC=C2[C@H]3CC[C@](C)(C(CC4)=O)[C@@H]4[C@@H]3CCC2=C1 DNXHEGUUPJUMQT-CBZIJGRNSA-N 0.000 description 1
- 241000282326 Felis catus Species 0.000 description 1
- BDAGIHXWWSANSR-UHFFFAOYSA-N Formic acid Chemical class OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 229920000084 Gum arabic Polymers 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
- 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
- 241000124008 Mammalia Species 0.000 description 1
- 229930195725 Mannitol Natural products 0.000 description 1
- 208000037093 Menstruation Disturbances Diseases 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- 229920000168 Microcrystalline cellulose Polymers 0.000 description 1
- 241000699670 Mus sp. Species 0.000 description 1
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 1
- WHNWPMSKXPGLAX-UHFFFAOYSA-N N-Vinyl-2-pyrrolidone Chemical compound C=CN1CCCC1=O WHNWPMSKXPGLAX-UHFFFAOYSA-N 0.000 description 1
- BPQQTUXANYXVAA-UHFFFAOYSA-N Orthosilicate Chemical compound [O-][Si]([O-])([O-])[O-] BPQQTUXANYXVAA-UHFFFAOYSA-N 0.000 description 1
- 241000283973 Oryctolagus cuniculus Species 0.000 description 1
- 229920003171 Poly (ethylene oxide) Polymers 0.000 description 1
- 239000002202 Polyethylene glycol Substances 0.000 description 1
- 206010036086 Polymenorrhoea Diseases 0.000 description 1
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- 241000282887 Suidae Species 0.000 description 1
- GWEVSGVZZGPLCZ-UHFFFAOYSA-N Titan oxide Chemical compound O=[Ti]=O GWEVSGVZZGPLCZ-UHFFFAOYSA-N 0.000 description 1
- HKDLNTKNLJPAIY-WKWWZUSTSA-N Ulipristal Chemical compound C1=CC(N(C)C)=CC=C1[C@@H]1C2=C3CCC(=O)C=C3CC[C@H]2[C@H](CC[C@]2(O)C(C)=O)[C@]2(C)C1 HKDLNTKNLJPAIY-WKWWZUSTSA-N 0.000 description 1
- 238000002441 X-ray diffraction Methods 0.000 description 1
- TVXBFESIOXBWNM-UHFFFAOYSA-N Xylitol Natural products OCCC(O)C(O)C(O)CCO TVXBFESIOXBWNM-UHFFFAOYSA-N 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 235000010489 acacia gum Nutrition 0.000 description 1
- 239000000205 acacia gum Substances 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 230000000996 additive effect Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 229910000147 aluminium phosphate Inorganic materials 0.000 description 1
- 239000003242 anti bacterial agent Substances 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 239000002518 antifoaming agent Substances 0.000 description 1
- 239000002216 antistatic agent Substances 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 239000003899 bactericide agent Substances 0.000 description 1
- WQZGKKKJIJFFOK-VFUOTHLCSA-N beta-D-glucose Chemical compound OC[C@H]1O[C@@H](O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-VFUOTHLCSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 239000011575 calcium Substances 0.000 description 1
- 229910052791 calcium Inorganic materials 0.000 description 1
- 229960005069 calcium Drugs 0.000 description 1
- 235000001465 calcium Nutrition 0.000 description 1
- 150000001720 carbohydrates Chemical class 0.000 description 1
- 239000001768 carboxy methyl cellulose Substances 0.000 description 1
- 125000002057 carboxymethyl group Chemical group [H]OC(=O)C([H])([H])[*] 0.000 description 1
- 229940081734 cellulose acetate phthalate Drugs 0.000 description 1
- 229920003086 cellulose ether Polymers 0.000 description 1
- 238000004587 chromatography analysis Methods 0.000 description 1
- 238000000576 coating method Methods 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000013267 controlled drug release Methods 0.000 description 1
- 239000002826 coolant Substances 0.000 description 1
- 239000008120 corn starch Substances 0.000 description 1
- 239000006071 cream Substances 0.000 description 1
- 229960001681 croscarmellose sodium Drugs 0.000 description 1
- 229960000913 crospovidone Drugs 0.000 description 1
- 235000010947 crosslinked sodium carboxy methyl cellulose Nutrition 0.000 description 1
- 239000012043 crude product Substances 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 238000001514 detection method Methods 0.000 description 1
- 235000019425 dextrin Nutrition 0.000 description 1
- 125000004985 dialkyl amino alkyl group Chemical group 0.000 description 1
- 208000035475 disorder Diseases 0.000 description 1
- 239000002270 dispersing agent Substances 0.000 description 1
- 239000002612 dispersion medium Substances 0.000 description 1
- 238000007908 dry granulation Methods 0.000 description 1
- 230000008030 elimination Effects 0.000 description 1
- 238000003379 elimination reaction Methods 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000003995 emulsifying agent Substances 0.000 description 1
- 210000004696 endometrium Anatomy 0.000 description 1
- 150000002168 ethanoic acid esters Chemical class 0.000 description 1
- 238000001704 evaporation Methods 0.000 description 1
- 239000007941 film coated tablet Substances 0.000 description 1
- 239000012065 filter cake Substances 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000004503 fine granule Substances 0.000 description 1
- WBJINCZRORDGAQ-UHFFFAOYSA-N formic acid ethyl ester Natural products CCOC=O WBJINCZRORDGAQ-UHFFFAOYSA-N 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 239000000499 gel Substances 0.000 description 1
- 239000007903 gelatin capsule Substances 0.000 description 1
- 239000003862 glucocorticoid Substances 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 229930195733 hydrocarbon Natural products 0.000 description 1
- WGCNASOHLSPBMP-UHFFFAOYSA-N hydroxyacetaldehyde Natural products OCC=O WGCNASOHLSPBMP-UHFFFAOYSA-N 0.000 description 1
- 229920003063 hydroxymethyl cellulose Polymers 0.000 description 1
- 229940031574 hydroxymethyl cellulose Drugs 0.000 description 1
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 description 1
- 208000022168 hypermenorrhea Diseases 0.000 description 1
- 229960003943 hypromellose Drugs 0.000 description 1
- 239000005457 ice water Substances 0.000 description 1
- 239000012729 immediate-release (IR) formulation Substances 0.000 description 1
- 238000007918 intramuscular administration Methods 0.000 description 1
- 238000010255 intramuscular injection Methods 0.000 description 1
- 239000007927 intramuscular injection Substances 0.000 description 1
- 239000007928 intraperitoneal injection Substances 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 238000010253 intravenous injection Methods 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
- YOBAEOGBNPPUQV-UHFFFAOYSA-N iron;trihydrate Chemical compound O.O.O.[Fe].[Fe] YOBAEOGBNPPUQV-UHFFFAOYSA-N 0.000 description 1
- GJRQTCIYDGXPES-UHFFFAOYSA-N iso-butyl acetate Natural products CC(C)COC(C)=O GJRQTCIYDGXPES-UHFFFAOYSA-N 0.000 description 1
- FGKJLKRYENPLQH-UHFFFAOYSA-M isocaproate Chemical compound CC(C)CCC([O-])=O FGKJLKRYENPLQH-UHFFFAOYSA-M 0.000 description 1
- JMMWKPVZQRWMSS-UHFFFAOYSA-N isopropanol acetate Natural products CC(C)OC(C)=O JMMWKPVZQRWMSS-UHFFFAOYSA-N 0.000 description 1
- 229940011051 isopropyl acetate Drugs 0.000 description 1
- GWYFCOCPABKNJV-UHFFFAOYSA-N isovaleric acid Chemical compound CC(C)CC(O)=O GWYFCOCPABKNJV-UHFFFAOYSA-N 0.000 description 1
- OQAGVSWESNCJJT-UHFFFAOYSA-N isovaleric acid methyl ester Natural products COC(=O)CC(C)C OQAGVSWESNCJJT-UHFFFAOYSA-N 0.000 description 1
- 235000015110 jellies Nutrition 0.000 description 1
- 239000008101 lactose Substances 0.000 description 1
- 238000007561 laser diffraction method Methods 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 229940031703 low substituted hydroxypropyl cellulose Drugs 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000000873 masking effect Effects 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 208000007106 menorrhagia Diseases 0.000 description 1
- HEBKCHPVOIAQTA-UHFFFAOYSA-N meso ribitol Natural products OCC(O)C(O)C(O)CO HEBKCHPVOIAQTA-UHFFFAOYSA-N 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 150000002825 nitriles Chemical class 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- 239000006191 orally-disintegrating tablet Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 230000027758 ovulation cycle Effects 0.000 description 1
- 238000007911 parenteral administration Methods 0.000 description 1
- 239000013618 particulate matter Substances 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- XNGIFLGASWRNHJ-UHFFFAOYSA-L phthalate(2-) Chemical compound [O-]C(=O)C1=CC=CC=C1C([O-])=O XNGIFLGASWRNHJ-UHFFFAOYSA-L 0.000 description 1
- 229920000747 poly(lactic acid) Polymers 0.000 description 1
- 239000004584 polyacrylic acid Substances 0.000 description 1
- 229920001223 polyethylene glycol Polymers 0.000 description 1
- 239000004626 polylactic acid Substances 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229910000343 potassium bisulfate Inorganic materials 0.000 description 1
- 238000001556 precipitation Methods 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000012264 purified product Substances 0.000 description 1
- 238000010791 quenching Methods 0.000 description 1
- 230000000171 quenching effect Effects 0.000 description 1
- 230000005855 radiation Effects 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 230000001568 sexual effect Effects 0.000 description 1
- RMAQACBXLXPBSY-UHFFFAOYSA-N silicic acid Chemical compound O[Si](O)(O)O RMAQACBXLXPBSY-UHFFFAOYSA-N 0.000 description 1
- 235000012239 silicon dioxide Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 210000002460 smooth muscle Anatomy 0.000 description 1
- 229940083542 sodium Drugs 0.000 description 1
- 235000010413 sodium alginate Nutrition 0.000 description 1
- 239000000661 sodium alginate Substances 0.000 description 1
- 229940005550 sodium alginate Drugs 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 235000019812 sodium carboxymethyl cellulose Nutrition 0.000 description 1
- 229920001027 sodium carboxymethylcellulose Polymers 0.000 description 1
- 239000007901 soft capsule Substances 0.000 description 1
- 239000012265 solid product Substances 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000010356 sorbitol Nutrition 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 238000007920 subcutaneous administration Methods 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 235000000346 sugar Nutrition 0.000 description 1
- 150000005846 sugar alcohols Chemical class 0.000 description 1
- 150000008163 sugars Chemical class 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000375 suspending agent Substances 0.000 description 1
- 229920001059 synthetic polymer Polymers 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- OGIDPMRJRNCKJF-UHFFFAOYSA-N titanium oxide Inorganic materials [Ti]=O OGIDPMRJRNCKJF-UHFFFAOYSA-N 0.000 description 1
- 230000000699 topical effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
- 238000009423 ventilation Methods 0.000 description 1
- 239000000811 xylitol Substances 0.000 description 1
- HEBKCHPVOIAQTA-SCDXWVJYSA-N xylitol Chemical compound OC[C@H](O)[C@@H](O)[C@H](O)CO HEBKCHPVOIAQTA-SCDXWVJYSA-N 0.000 description 1
- 235000010447 xylitol Nutrition 0.000 description 1
- 229960002675 xylitol Drugs 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07J—STEROIDS
- C07J41/00—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring
- C07J41/0033—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005
- C07J41/0077—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom
- C07J41/0083—Normal steroids containing one or more nitrogen atoms not belonging to a hetero ring not covered by C07J41/0005 substituted in position 11-beta by a carbon atom, further substituted by a group comprising at least one further carbon atom substituted in position 11-beta by an optionally substituted phenyl group not further condensed with other rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/18—Feminine contraceptives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
-
- 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
- A61P5/24—Drugs for disorders of the endocrine system of the sex hormones
- A61P5/36—Antigestagens
-
- 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
- A61P5/38—Drugs for disorders of the endocrine system of the suprarenal hormones
- A61P5/46—Drugs for disorders of the endocrine system of the suprarenal hormones for decreasing, blocking or antagonising the activity of glucocorticosteroids
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B29/00—Single crystals or homogeneous polycrystalline material with defined structure characterised by the material or by their shape
- C30B29/54—Organic compounds
-
- C—CHEMISTRY; METALLURGY
- C30—CRYSTAL GROWTH
- C30B—SINGLE-CRYSTAL GROWTH; UNIDIRECTIONAL SOLIDIFICATION OF EUTECTIC MATERIAL OR UNIDIRECTIONAL DEMIXING OF EUTECTOID MATERIAL; REFINING BY ZONE-MELTING OF MATERIAL; PRODUCTION OF A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; SINGLE CRYSTALS OR HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; AFTER-TREATMENT OF SINGLE CRYSTALS OR A HOMOGENEOUS POLYCRYSTALLINE MATERIAL WITH DEFINED STRUCTURE; APPARATUS THEREFOR
- C30B7/00—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions
- C30B7/08—Single-crystal growth from solutions using solvents which are liquid at normal temperature, e.g. aqueous solutions by cooling of the solution
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Engineering & Computer Science (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Endocrinology (AREA)
- Diabetes (AREA)
- Metallurgy (AREA)
- Crystallography & Structural Chemistry (AREA)
- Materials Engineering (AREA)
- Reproductive Health (AREA)
- Gynecology & Obstetrics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Steroid Compounds (AREA)
- Epidemiology (AREA)
Abstract
Description
本明細書では、ウリプリスタール酢酸エステル物質とは、多形の混合物又は組成物の形態のウリプリスタール酢酸エステルをいう。本発明によるウリプリスタール酢酸エステル物質は、結晶多形Cを少なくとも含む。いくつかの実施形態において、本発明によるウリプリスタール酢酸エステル物質は、結晶多形Cを少なくとも5重量%含む。重量割合は、ウリプリスタール酢酸エステル物質の総重量に対する割合である。
(1)以下の回折角度2θ:9.2±0.2°、11.4±0.2°、11.7±0.2°、12.0±0.2°、15.2±0.2°、17.0±0.2°、17.2±0.2°及び24.4±0.2°に回折ピークを含む粉末X線回折スペクトルを有する結晶多形A(A形結晶)、
(2)以下の回折角度2θ:6.4±0.2°、8.4±0.2°、9.4±0.2°、9.6±0.2°、11.8±0.2°、12.8±0.2°、15.3±0.2°、16.7±0.2°、17.5±0.2°、18.6±0.2°、19.3±0.2°、21.0±0.2°及び25.5±0.2°に回折ピークを含む粉末X線回折スペクトルを有する結晶多形B(B形結晶)などが例示できる。
本発明のウリプリスタール酢酸エステル物質又は結晶多形Cの製造方法は、上記粉末X線回折スペクトル又は示差走査熱量スペクトルで特徴付けられる結晶を得ることができる限り、特に制限されず、例えば、ウリプリスタール酢酸エステルのイソプロパノール溶媒和結晶を、エタノールと水との混合溶媒に溶解し、この溶液(又は晶析系)からウリプリスタール酢酸エステルを結晶化(析出又は沈殿)する工程を含んでいる。
(a)本発明の結晶多形Cを準備する工程、
(b)1又はいくつかのウリプリスタール酢酸エステル結晶多形を準備する工程、及び
(c)結晶多形Cと工程(b)において提供された結晶多形とを混合する工程
を含んでいてもよい。
本発明のウリプリスタール酢酸エステル結晶多形C又はウリプリスタール酢酸エステル物質は、抗プロゲステロン活性に加えて、抗グルココルチコイド活性を有するため、選択的プロゲステロン受容体調節剤として好適に用いられる。具体的には、本発明のウリプリスタール酢酸エステル結晶多形C又はウリプリスタール酢酸エステル物質は、婦人科疾患[例えば、子宮筋腫又は子宮筋腫に起因する疾患(転移性平滑筋腫、月経困難症、過多月経、貧血、不妊症、便秘、頻尿、腰痛など)など]の予防及び/又は治療に有用である。また、本発明のウリプリスタール酢酸エステル結晶多形C又はウリプリスタール酢酸エステル物質は、避妊剤(例えば、緊急避妊剤)としても有用である。
粉末X線回折スペクトルは、線源:Cu K(α1)、管電圧:40kV、管電流:40mA、サンプリング間隔:0.1°、スキャン速度10°/分の条件で測定した。なお、粉末X線回折チャートにおいて、回折ピークは、ピーク幅の閾値を0.1°として、二次微分法によりサーチした。
示差走査熱量スペクトルは、示差走査熱量計(型式:DSC8230L)を用いて、昇温速度2℃/分の条件で測定した。
37℃のエタノールと水との混合溶媒[エタノール/水(体積比)=10/90]40mLに、比較例及び実施例のウリプリスタール酢酸エステルの各試料を40mg加えて試験サンプルを作製し、試験サンプルをマグネティックスターラーで5分間撹拌した後、その一部をとり、固形分を濾別し、ウリプリスタール酢酸エステル含量を高性能液体クロマトグラフィー(カラム:ODS、カラム温度:40℃、溶離液:0.1%トリフルオロ酢酸水溶液/アセトニトリル混液(体積比3:2)、流量:1.0mL/分、検出:UV302nm)により定量し、溶解度を算出した。
比較例及び実施例のウリプリスタール酢酸エステルを、それぞれ、ゼラチンカプセル(製造元:クオリカプス(株)、サイズ:00号、ロット:C0079A)に充填してカプセル剤を作製した。6頭の雌性イヌにカプセル剤を25mg/kg(ウリプリスタール酢酸エステル換算)の用量で経口投与し、経口投与後0.5、1、2、4、6、24及び48時間に血液を採取し、遠心分離により血漿を得た。LC−MS/MS(液体クロマトグラフィー−タンデム質量分析)法により、上記血漿中のウリプリスタール酢酸エステル濃度を測定し、血漿中濃度消失半減期(T1/2)、最高血漿中濃度到達時間(Tmax)、最高血漿中濃度(Cmax)、血漿中濃度−時間曲線下面積(AUC:Area Under the Plasma Concentration−time Curve)及び平均滞留時間(MRT)を算出した。なお、雌性イヌには、クロスオーバー法により、カプセル剤を1週間の投与間隔(休薬期間)をおいて2回投与した。
3,3−(1,2−エタンジオキシ)−5α−ヒドロキシ−11β−(4−N,N−ジメチルアミノフェニル)−17α−アセトキシ−19−ノルプレグナ−9−エン−20−オン[カルビノールアセテート]38.5gを、窒素雰囲気下、20〜22℃の温度でフラスコに入れ、脱イオン水385mLと硫酸水素カリウム17.91gを加えた。得られた懸濁液を、完全に溶解するまで約4時間攪拌した。反応の終了は、薄層クロマトグラフィー(TLC)によって確認した。
比較例で得られたウリプリスタール酢酸エステル結晶1.761gをイソプロパノール10mLに加熱溶解し、溶媒を減圧留去した。得られた残渣にイソプロパノール9mLを加えて加熱溶解し、溶媒を減圧留去した。得られた残渣にイソプロパノール9mLを加えて加熱溶解し、この溶液を氷水浴中で1時間放置した。得られた析出物をろ取し、ウリプリスタール酢酸エステルイソプロパノールヘミソルベートの湿結晶1.782gを得た。この湿結晶1.782gをエタノールと水との混合溶媒[エタノール/水(体積比)=80/20]17.8mLに加熱溶解し、1時間程度かけて室温に冷却し、室温で17時間攪拌した。得られた析出物をろ取し、温度100℃及び圧力15hPa以下で19時間減圧乾燥し、C形結晶(結晶多形C)1.0gを得た。なお、結晶多形Cの粉末X線回折スペクトルを図1に示し、示差走査熱量スペクトルを図2に示す。また、結晶多形Cの各回折角度(格子間隔d値)における回折ピーク強度及び相対強度を表1に示す。
比較例で得られたウリプリスタール酢酸エステル結晶0.1gと、実施例1で得られたC形結晶0.1gとを混合することにより、ウリプリスタール酢酸エステル物質を得た。なお、結晶多形Aの粉末X線回折スペクトルを図3に示し、示差走査熱量スペクトルを図4に示す。また、結晶多形Aの各回折角度(格子間隔d値)における回折ピーク強度及び相対強度を表2に示す。
比較例で得られたウリプリスタール酢酸エステル結晶1.3gを、エタノール6.5mLに加熱溶解し、26℃で1時間、次いで4℃で16時間放置した。得られた析出物をろ取し、恒量に達するまで減圧乾燥し、B形結晶(結晶多形B)1.0gを得た。このB形結晶0.1gと、実施例1で得られたC形結晶0.1gとを混合することにより、ウリプリスタール酢酸エステル物質を得た。なお、結晶多形Bの粉末X線回折スペクトルを図5に示し、示差走査熱量スペクトルを図6に示す。また、結晶多形Bの各回折角度(格子間隔d値)における回折ピーク強度及び相対強度を表3に示す。
実施例1で得られたC形結晶を0号カプセルに充填して、カプセル剤を得た。
次の処方に従って、実施例1で得られたC形結晶と担体成分とを混合し、この混合物を乾式造粒法により造粒し、この造粒物を整粒することにより、顆粒剤を得た。
実施例1で得られたC形結晶 300mg
結晶セルロース 590mg
カルボキシメチルスターチナトリウム 50mg
グリセリン脂肪酸エステル 50mg
タルク 10mg
全量 1000mg
次の処方に従って、製剤例2で得られた顆粒剤と担体成分を混合して打錠することにより錠剤を得た。
製剤例2で得られた顆粒剤 100mg
結晶セルロース 174mg
グリセリン脂肪酸エステル 20mg
タルク 4mg
軽質無水ケイ酸 2mg
全量 300mg
次の処方のコーティング剤を用いて、製剤例3で得られた錠剤をコーティングすることによりフィルムコーティング錠を得た。
ヒプロメロース 70.5重量%
酸化チタン 20.5重量%
プロピレングリコール 6.9重量%
三二酸化鉄 2.1重量%
Claims (12)
- 以下の回折角度2θに回折ピークを含む粉末X線回折パターンを有するウリプリスタール酢酸エステルの結晶多形C。
回折角度2θ:9.0±0.2°、9.3±0.2°、10.8±0.2°、11.5±0.2°、12.2±0.2°、13.1±0.2°、14.3±0.2°、15.6±0.2°、15.7±0.2°、15.9±0.2°、16.6±0.2°、17.6±0.2°、17.9±0.2°、18.9±0.2°、19.3±0.2°、23.8±0.2° - 示差走査熱量スペクトルにおいて、135〜145℃に吸熱ピークを有する請求項1記載のウリプリスタール酢酸エステルの結晶多形C。
- 請求項1又は2記載のウリプリスタール酢酸エステルの結晶多形Cを含むウリプリスタール酢酸エステル物質。
- さらに、以下の回折角度2θに回折ピークを含む粉末X線回折パターンを有するウリプリスタール酢酸エステルの結晶多形Aを含む請求項3記載のウリプリスタール酢酸エステル物質。
回折角度2θ:9.2±0.2°、11.4±0.2°、11.7±0.2°、12.0±0.2°、15.2±0.2°、17.0±0.2°、17.2±0.2°、24.4±0.2° - 結晶多形Cと結晶多形Aとの割合(重量比)が、前者/後者=0.5/99.5〜99.5/0.5である請求項4記載のウリプリスタール酢酸エステル物質。
- さらに、以下の回折角度2θに回折ピークを含む粉末X線回折パターンを有するウリプリスタール酢酸エステルの結晶多形Bを含む請求項3〜5のいずれかに記載のウリプリスタール酢酸エステル物質。
回折角度2θ:6.4±0.2°、8.4±0.2°、9.4±0.2°、9.6±0.2°、11.8±0.2°、12.8±0.2°、15.3±0.2°、16.7±0.2°、17.5±0.2°、18.6±0.2°、19.3±0.2°、21.0±0.2°、25.5±0.2° - 結晶多形Cと結晶多形Bとの割合(重量比)が、前者/後者=0.5/99.5〜99.5/0.5である請求項6記載のウリプリスタール酢酸エステル物質。
- 請求項1又は2記載のウリプリスタール酢酸エステルの結晶多形C、若しくは請求項3〜7のいずれかに記載のウリプリスタール酢酸エステル物質と、薬学的に許容可能な賦形剤とを含む医薬組成物。
- 請求項1又は2記載のウリプリスタール酢酸エステルの結晶多形C、若しくは請求項3〜7のいずれかに記載のウリプリスタール酢酸エステル物質を含む子宮筋腫の予防及び/又は治療に使用若しくは避妊のための薬剤。
- ウリプリスタール酢酸エステルのイソプロパノール溶媒和結晶を、エタノールと水との混合溶媒に溶解し、この溶液からウリプリスタール酢酸エステルを結晶化する工程を含む請求項1又は2記載のウリプリスタール酢酸エステルの結晶多形C、若しくは請求項3〜7のいずれかに記載のウリプリスタール酢酸エステル物質を製造する方法。
- 溶液に種結晶を添加することなくウリプリスタール酢酸エステルを結晶化する請求項10記載の方法。
- 請求項1又は2記載のウリプリスタール酢酸エステルの結晶多形C、若しくは請求項3〜7のいずれかに記載のウリプリスタール酢酸エステル物質の避妊に有効な量を投与する工程を含む、避妊を必要とする女性を避妊させる方法。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2015515333A JP6474722B2 (ja) | 2012-09-28 | 2013-09-26 | ウリプリスタール酢酸エステルの結晶多形 |
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
JP2012215436 | 2012-09-28 | ||
JP2012215436 | 2012-09-28 | ||
JP2015515333A JP6474722B2 (ja) | 2012-09-28 | 2013-09-26 | ウリプリスタール酢酸エステルの結晶多形 |
PCT/JP2013/005709 WO2014050106A1 (en) | 2012-09-28 | 2013-09-26 | Crystalline polymorphic form of ulipristal acetate |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2015531340A true JP2015531340A (ja) | 2015-11-02 |
JP6474722B2 JP6474722B2 (ja) | 2019-02-27 |
Family
ID=49585551
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2015515333A Active JP6474722B2 (ja) | 2012-09-28 | 2013-09-26 | ウリプリスタール酢酸エステルの結晶多形 |
Country Status (9)
Country | Link |
---|---|
US (1) | US9643993B2 (ja) |
EP (1) | EP2900683B1 (ja) |
JP (1) | JP6474722B2 (ja) |
KR (1) | KR20150063486A (ja) |
AU (1) | AU2013321890B2 (ja) |
CA (1) | CA2885795A1 (ja) |
ES (1) | ES2672509T3 (ja) |
IL (1) | IL237824B (ja) |
WO (1) | WO2014050106A1 (ja) |
Families Citing this family (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
TN2017000482A1 (en) | 2015-05-18 | 2019-04-12 | Bayer Pharma AG | Selective progesterone receptor modulator (sprm) regimen. |
Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1753905A (zh) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | 获得17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的方法 |
Family Cites Families (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4954490A (en) | 1988-06-23 | 1990-09-04 | Research Triangle Institute | 11 β-substituted progesterone analogs |
US5929262A (en) | 1995-03-30 | 1999-07-27 | The United States Of America As Represented By The Department Of Health And Human Services | Method for preparing 17α-acetoxy-11β-(4-N, N-dimethylaminophyl)-19-Norpregna-4,9-diene-3, 20-dione, intermediates useful in the method, and methods for the preparation of such intermediates |
EP1613640A4 (en) | 2003-02-28 | 2010-05-19 | Us Gov Health & Human Serv | PROCESS FOR PREPARING 17 ALPHA-ACETOXY-11 BETA- (4-N, N-DIMETHYLAMINOPHENYL) -19-NORPREGNA-4,9-DIENE-3,20-DION, INTERMEDIATE PRODUCTS AND METHOD OF MANUFACTURING THESE INTERMEDIATE PRODUCTS |
HU227112B1 (hu) * | 2006-06-14 | 2010-07-28 | Richter Gedeon Nyrt | Ipari eljárás 17-alfa-acetoxi-11-béta-[4-(N,N-dimetil-amino)-fenil]-19-norpregna-4,9-dién-3,20-dion elõállítására és új intermedierek az eljáráshoz |
ME02548B (me) | 2009-04-14 | 2017-02-20 | Hra Pharma Lab | Postupak za kontracepciju po potrebi |
CN103193850A (zh) * | 2012-01-04 | 2013-07-10 | 北京紫竹药业有限公司 | 甾体化合物的新晶型及其制备方法 |
CN102675395B (zh) * | 2012-04-17 | 2014-04-30 | 常州市第四制药厂有限公司 | 醋酸乌利司他的多晶型及其制备方法 |
CN102887931B (zh) | 2012-07-07 | 2015-04-15 | 山东诚创医药技术开发有限公司 | 一种醋酸乌利司他的结晶体及其制备方法 |
JP2015532263A (ja) * | 2012-09-28 | 2015-11-09 | あすか製薬株式会社 | ウリプリスタール酢酸エステルの結晶多形 |
WO2014050105A1 (en) * | 2012-09-28 | 2014-04-03 | Aska Pharmaceutical Co., Ltd. | Amorphous ulipristal acetate |
-
2013
- 2013-09-26 JP JP2015515333A patent/JP6474722B2/ja active Active
- 2013-09-26 ES ES13792105.2T patent/ES2672509T3/es active Active
- 2013-09-26 US US14/431,351 patent/US9643993B2/en not_active Expired - Fee Related
- 2013-09-26 KR KR1020157010893A patent/KR20150063486A/ko active IP Right Grant
- 2013-09-26 AU AU2013321890A patent/AU2013321890B2/en not_active Ceased
- 2013-09-26 EP EP13792105.2A patent/EP2900683B1/en not_active Not-in-force
- 2013-09-26 CA CA2885795A patent/CA2885795A1/en not_active Abandoned
- 2013-09-26 WO PCT/JP2013/005709 patent/WO2014050106A1/en active Application Filing
-
2015
- 2015-03-19 IL IL237824A patent/IL237824B/en unknown
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN1753905A (zh) * | 2003-01-22 | 2006-03-29 | 克利斯托制药股份有限公司 | 获得17α-乙酰氧基-11β-(4-N,N-二甲氨基苯基)-19-去甲孕甾-4,9-二烯-3,20-二酮的方法 |
JP2006515869A (ja) * | 2003-01-22 | 2006-06-08 | クリスタル、ファーマ、ソシエダッド、アノニマ | 17α−アセトキシ−11β−(4−N,N−ジメチルアミノフェニル)−19−ノルプレグナ−4,9−ジエン−3,20−ジオンを得る方法 |
Non-Patent Citations (5)
Title |
---|
厚生労働省医薬局審査管理課長: "新医薬品の規格及び試験方法の設定について", 医薬審発第568号, JPN6015027393, 1 May 2001 (2001-05-01), ISSN: 0003706275 * |
大島寛: "結晶多形・擬多形の析出挙動と制御", PHARM STAGE, vol. 6, no. 10, JPN6011001457, 15 January 2007 (2007-01-15), pages 48 - 53, ISSN: 0003706276 * |
山野光久: "医薬品のプロセス研究における結晶多形現象への取り組み", 有機合成化学協会誌, vol. 65, no. 9, JPN6010003277, 1 September 2007 (2007-09-01), pages 907 - 69, ISSN: 0003706278 * |
川口洋子ら: "医薬品と結晶多形", 生活工学研究, vol. Voo.4, No.2, JPN6015027394, 2002, pages 310 - 7, ISSN: 0003706274 * |
高田則幸: "創薬段階における原薬Formスクリーニングと選択", PHARM STAGE, vol. 6, no. 10, JPN6009053755, 15 January 2007 (2007-01-15), pages 20 - 25, ISSN: 0003706277 * |
Also Published As
Publication number | Publication date |
---|---|
IL237824B (en) | 2019-03-31 |
US9643993B2 (en) | 2017-05-09 |
KR20150063486A (ko) | 2015-06-09 |
EP2900683B1 (en) | 2018-03-14 |
AU2013321890B2 (en) | 2017-05-18 |
ES2672509T3 (es) | 2018-06-14 |
WO2014050106A1 (en) | 2014-04-03 |
US20150239927A1 (en) | 2015-08-27 |
AU2013321890A1 (en) | 2015-04-09 |
JP6474722B2 (ja) | 2019-02-27 |
CA2885795A1 (en) | 2014-04-03 |
EP2900683A1 (en) | 2015-08-05 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
US20070105828A1 (en) | Novel polymorph form M of mifepristone and process for its preparation | |
CN110078780B (zh) | 黄体酮共晶的制备方法及其用途 | |
JP2008539243A (ja) | スクアラミンジラクテートの多形塩形態および無定形塩形態 | |
JP7241807B2 (ja) | 15β-ヒドロキシ-酢酸オサテロンの結晶多形 | |
WO2015176591A1 (zh) | 贝曲西班盐及其制备方法和用途 | |
JP6474722B2 (ja) | ウリプリスタール酢酸エステルの結晶多形 | |
JP2015532263A (ja) | ウリプリスタール酢酸エステルの結晶多形 | |
JP5809367B2 (ja) | レボノルゲストレルの結晶多形α及びその製造方法 | |
CN113214337B (zh) | 黄体酮与吡啶及其衍生物的药物共晶 | |
JP6200493B2 (ja) | 無定形ウリプリスタール酢酸エステル | |
JP5809368B2 (ja) | レボノルゲストレルの結晶多形β及びその製造方法 | |
TW201522360A (zh) | 烏普司他醋酸之結晶多晶型 | |
TW201522362A (zh) | 烏普司他醋酸之結晶多晶型 | |
TW201522361A (zh) | 非晶形烏普司他醋酸 | |
JP6433910B2 (ja) | レボノルゲストレルの新規結晶混合物及びその製造方法 | |
WO2014175302A1 (ja) | 無定形レボノルゲストレル、固体分散体及びそれらの製造方法 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A621 | Written request for application examination |
Free format text: JAPANESE INTERMEDIATE CODE: A621 Effective date: 20160902 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20170530 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20170727 |
|
A02 | Decision of refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A02 Effective date: 20170822 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20171121 |
|
A911 | Transfer to examiner for re-examination before appeal (zenchi) |
Free format text: JAPANESE INTERMEDIATE CODE: A911 Effective date: 20171128 |
|
A912 | Re-examination (zenchi) completed and case transferred to appeal board |
Free format text: JAPANESE INTERMEDIATE CODE: A912 Effective date: 20171222 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20180726 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20190130 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 6474722 Country of ref document: JP Free format text: JAPANESE INTERMEDIATE CODE: R150 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |