JP5687287B2 - 改善された保存性及び溶解特性を有する3−ベータ−ヒドロキシ−5−アルファ−プレグナン−20−オンを含有する薬学的組成物 - Google Patents
改善された保存性及び溶解特性を有する3−ベータ−ヒドロキシ−5−アルファ−プレグナン−20−オンを含有する薬学的組成物 Download PDFInfo
- Publication number
- JP5687287B2 JP5687287B2 JP2012548918A JP2012548918A JP5687287B2 JP 5687287 B2 JP5687287 B2 JP 5687287B2 JP 2012548918 A JP2012548918 A JP 2012548918A JP 2012548918 A JP2012548918 A JP 2012548918A JP 5687287 B2 JP5687287 B2 JP 5687287B2
- Authority
- JP
- Japan
- Prior art keywords
- beta
- pharmaceutical composition
- hydroxy
- alpha
- pregnan
- 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.)
- Active
Links
- AURFZBICLPNKBZ-FZCSVUEKSA-N 3beta-hydroxy-5alpha-pregnan-20-one Chemical compound C([C@@H]1CC2)[C@@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](C(=O)C)[C@@]2(C)CC1 AURFZBICLPNKBZ-FZCSVUEKSA-N 0.000 title claims description 82
- 239000008194 pharmaceutical composition Substances 0.000 title claims description 38
- 239000000203 mixture Substances 0.000 claims description 65
- HVYWMOMLDIMFJA-DPAQBDIFSA-N cholesterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 HVYWMOMLDIMFJA-DPAQBDIFSA-N 0.000 claims description 45
- 229930182558 Sterol Natural products 0.000 claims description 39
- 235000003702 sterols Nutrition 0.000 claims description 39
- 150000003432 sterols Chemical class 0.000 claims description 36
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 24
- 235000012000 cholesterol Nutrition 0.000 claims description 21
- 239000000725 suspension Substances 0.000 claims description 20
- 150000002148 esters Chemical class 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 17
- 239000007788 liquid Substances 0.000 claims description 14
- 239000007787 solid Substances 0.000 claims description 14
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerol Natural products OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 8
- 239000008159 sesame oil Substances 0.000 claims description 8
- 235000011803 sesame oil Nutrition 0.000 claims description 8
- 239000004359 castor oil Substances 0.000 claims description 7
- 235000019438 castor oil Nutrition 0.000 claims description 7
- ZEMPKEQAKRGZGQ-XOQCFJPHSA-N glycerol triricinoleate Natural products CCCCCC[C@@H](O)CC=CCCCCCCCC(=O)OC[C@@H](COC(=O)CCCCCCCC=CC[C@@H](O)CCCCCC)OC(=O)CCCCCCCC=CC[C@H](O)CCCCCC ZEMPKEQAKRGZGQ-XOQCFJPHSA-N 0.000 claims description 7
- 235000015112 vegetable and seed oil Nutrition 0.000 claims description 7
- 239000008158 vegetable oil Substances 0.000 claims description 7
- 235000019483 Peanut oil Nutrition 0.000 claims description 5
- 238000002156 mixing Methods 0.000 claims description 5
- 239000000312 peanut oil Substances 0.000 claims description 5
- OILXMJHPFNGGTO-UHFFFAOYSA-N (22E)-(24xi)-24-methylcholesta-5,22-dien-3beta-ol Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)C=CC(C)C(C)C)C1(C)CC2 OILXMJHPFNGGTO-UHFFFAOYSA-N 0.000 claims description 4
- -1 acyl glycerols Chemical class 0.000 claims description 4
- LGJMUZUPVCAVPU-UHFFFAOYSA-N beta-Sitostanol Natural products C1CC2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(CC)C(C)C)C1(C)CC2 LGJMUZUPVCAVPU-UHFFFAOYSA-N 0.000 claims description 4
- 238000001704 evaporation Methods 0.000 claims description 3
- 239000004006 olive oil Substances 0.000 claims description 3
- 235000008390 olive oil Nutrition 0.000 claims description 3
- OSELKOCHBMDKEJ-UHFFFAOYSA-N (10R)-3c-Hydroxy-10r.13c-dimethyl-17c-((R)-1-methyl-4-isopropyl-hexen-(4c)-yl)-(8cH.9tH.14tH)-Delta5-tetradecahydro-1H-cyclopenta[a]phenanthren Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)CCC(=CC)C(C)C)C1(C)CC2 OSELKOCHBMDKEJ-UHFFFAOYSA-N 0.000 claims description 2
- MCWVPSBQQXUCTB-UHFFFAOYSA-N (24Z)-5alpha-Stigmasta-7,24(28)-dien-3beta-ol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)CCC(=CC)C(C)C)CCC33)C)C3=CCC21 MCWVPSBQQXUCTB-UHFFFAOYSA-N 0.000 claims description 2
- OQMZNAMGEHIHNN-UHFFFAOYSA-N 7-Dehydrostigmasterol Natural products C1C(O)CCC2(C)C(CCC3(C(C(C)C=CC(CC)C(C)C)CCC33)C)C3=CC=C21 OQMZNAMGEHIHNN-UHFFFAOYSA-N 0.000 claims description 2
- OILXMJHPFNGGTO-NRHJOKMGSA-N Brassicasterol Natural products O[C@@H]1CC=2[C@@](C)([C@@H]3[C@H]([C@H]4[C@](C)([C@H]([C@@H](/C=C/[C@H](C(C)C)C)C)CC4)CC3)CC=2)CC1 OILXMJHPFNGGTO-NRHJOKMGSA-N 0.000 claims description 2
- OILXMJHPFNGGTO-ZRUUVFCLSA-N UNPD197407 Natural products C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)C=C[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZRUUVFCLSA-N 0.000 claims description 2
- HZYXFRGVBOPPNZ-UHFFFAOYSA-N UNPD88870 Natural products C1C=C2CC(O)CCC2(C)C2C1C1CCC(C(C)=CCC(CC)C(C)C)C1(C)CC2 HZYXFRGVBOPPNZ-UHFFFAOYSA-N 0.000 claims description 2
- MCWVPSBQQXUCTB-OQTIOYDCSA-N avenasterol Chemical compound C1[C@@H](O)CC[C@]2(C)[C@@H](CC[C@@]3([C@@H]([C@H](C)CC/C(=C/C)C(C)C)CC[C@H]33)C)C3=CC[C@H]21 MCWVPSBQQXUCTB-OQTIOYDCSA-N 0.000 claims description 2
- 229940076810 beta sitosterol Drugs 0.000 claims description 2
- NJKOMDUNNDKEAI-UHFFFAOYSA-N beta-sitosterol Natural products CCC(CCC(C)C1CCC2(C)C3CC=C4CC(O)CCC4C3CCC12C)C(C)C NJKOMDUNNDKEAI-UHFFFAOYSA-N 0.000 claims description 2
- OILXMJHPFNGGTO-ZAUYPBDWSA-N brassicasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@H](C)C(C)C)[C@@]1(C)CC2 OILXMJHPFNGGTO-ZAUYPBDWSA-N 0.000 claims description 2
- 235000004420 brassicasterol Nutrition 0.000 claims description 2
- KZJWDPNRJALLNS-VJSFXXLFSA-N sitosterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CC[C@@H](CC)C(C)C)[C@@]1(C)CC2 KZJWDPNRJALLNS-VJSFXXLFSA-N 0.000 claims description 2
- 229950005143 sitosterol Drugs 0.000 claims description 2
- NLQLSVXGSXCXFE-UHFFFAOYSA-N sitosterol Natural products CC=C(/CCC(C)C1CC2C3=CCC4C(C)C(O)CCC4(C)C3CCC2(C)C1)C(C)C NLQLSVXGSXCXFE-UHFFFAOYSA-N 0.000 claims description 2
- HCXVJBMSMIARIN-PHZDYDNGSA-N stigmasterol Chemical compound C1C=C2C[C@@H](O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)/C=C/[C@@H](CC)C(C)C)[C@@]1(C)CC2 HCXVJBMSMIARIN-PHZDYDNGSA-N 0.000 claims description 2
- 235000016831 stigmasterol Nutrition 0.000 claims description 2
- 229940032091 stigmasterol Drugs 0.000 claims description 2
- BFDNMXAIBMJLBB-UHFFFAOYSA-N stigmasterol Natural products CCC(C=CC(C)C1CCCC2C3CC=C4CC(O)CCC4(C)C3CCC12C)C(C)C BFDNMXAIBMJLBB-UHFFFAOYSA-N 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims 2
- 229940107161 cholesterol Drugs 0.000 claims 1
- 238000007911 parenteral administration Methods 0.000 claims 1
- 238000009472 formulation Methods 0.000 description 24
- 238000002360 preparation method Methods 0.000 description 11
- 238000001556 precipitation Methods 0.000 description 8
- 239000002245 particle Substances 0.000 description 7
- 150000003431 steroids Chemical class 0.000 description 7
- 125000004432 carbon atom Chemical group C* 0.000 description 5
- 150000001875 compounds Chemical class 0.000 description 5
- 230000027758 ovulation cycle Effects 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- 239000003981 vehicle Substances 0.000 description 5
- 239000013020 final formulation Substances 0.000 description 4
- 239000007791 liquid phase Substances 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 210000003169 central nervous system Anatomy 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000011156 evaluation Methods 0.000 description 3
- 239000011521 glass Substances 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 150000002632 lipids Chemical class 0.000 description 3
- 150000002759 monoacylglycerols Chemical class 0.000 description 3
- WWZKQHOCKIZLMA-UHFFFAOYSA-N octanoic acid Chemical compound CCCCCCCC(O)=O WWZKQHOCKIZLMA-UHFFFAOYSA-N 0.000 description 3
- 238000005191 phase separation Methods 0.000 description 3
- 238000004062 sedimentation Methods 0.000 description 3
- 150000003626 triacylglycerols Chemical class 0.000 description 3
- 229920000858 Cyclodextrin Polymers 0.000 description 2
- 241001465754 Metazoa Species 0.000 description 2
- 241000283973 Oryctolagus cuniculus Species 0.000 description 2
- 208000027030 Premenstrual dysphoric disease Diseases 0.000 description 2
- 150000001982 diacylglycerols Chemical class 0.000 description 2
- 235000014113 dietary fatty acids Nutrition 0.000 description 2
- 239000000839 emulsion Substances 0.000 description 2
- 206010015037 epilepsy Diseases 0.000 description 2
- 206010016256 fatigue Diseases 0.000 description 2
- 229930195729 fatty acid Natural products 0.000 description 2
- 239000000194 fatty acid Substances 0.000 description 2
- 150000004665 fatty acids Chemical class 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 210000002540 macrophage Anatomy 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 235000019198 oils Nutrition 0.000 description 2
- 230000036470 plasma concentration Effects 0.000 description 2
- 238000007920 subcutaneous administration Methods 0.000 description 2
- GYSCBCSGKXNZRH-UHFFFAOYSA-N 1-benzothiophene-2-carboxamide Chemical compound C1=CC=C2SC(C(=O)N)=CC2=C1 GYSCBCSGKXNZRH-UHFFFAOYSA-N 0.000 description 1
- XUGISPSHIFXEHZ-UHFFFAOYSA-N 3beta-acetoxy-cholest-5-ene Natural products C1C=C2CC(OC(C)=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 XUGISPSHIFXEHZ-UHFFFAOYSA-N 0.000 description 1
- YEYCQJVCAMFWCO-UHFFFAOYSA-N 3beta-cholesteryl formate Natural products C1C=C2CC(OC=O)CCC2(C)C2C1C1CCC(C(C)CCCC(C)C)C1(C)CC2 YEYCQJVCAMFWCO-UHFFFAOYSA-N 0.000 description 1
- JWMFYGXQPXQEEM-GCOKGBOCSA-N 5α-pregnane Chemical compound C([C@@H]1CC2)CCC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H](CC)[C@@]2(C)CC1 JWMFYGXQPXQEEM-GCOKGBOCSA-N 0.000 description 1
- 208000007848 Alcoholism Diseases 0.000 description 1
- 208000024827 Alzheimer disease Diseases 0.000 description 1
- 241000282693 Cercopithecidae Species 0.000 description 1
- GHVNFZFCNZKVNT-UHFFFAOYSA-N Decanoic acid Natural products CCCCCCCCCC(O)=O GHVNFZFCNZKVNT-UHFFFAOYSA-N 0.000 description 1
- 208000019695 Migraine disease Diseases 0.000 description 1
- 206010027940 Mood altered Diseases 0.000 description 1
- 208000019022 Mood disease Diseases 0.000 description 1
- 238000005481 NMR spectroscopy Methods 0.000 description 1
- RJECHNNFRHZQKU-UHFFFAOYSA-N Oelsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCC=CCCCCCCCC)C2 RJECHNNFRHZQKU-UHFFFAOYSA-N 0.000 description 1
- BBJQPKLGPMQWBU-UHFFFAOYSA-N Palmitinsaeurecholesterylester Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCC)C2 BBJQPKLGPMQWBU-UHFFFAOYSA-N 0.000 description 1
- 206010036618 Premenstrual syndrome Diseases 0.000 description 1
- 241000700159 Rattus Species 0.000 description 1
- 206010040030 Sensory loss Diseases 0.000 description 1
- 239000004809 Teflon Substances 0.000 description 1
- 229920006362 Teflon® Polymers 0.000 description 1
- LJGMGXXCKVFFIS-IATSNXCDSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] decanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCC)C1 LJGMGXXCKVFFIS-IATSNXCDSA-N 0.000 description 1
- SKLBBRQPVZDTNM-SJTWHRLHSA-N [(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] octanoate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC)C1 SKLBBRQPVZDTNM-SJTWHRLHSA-N 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 201000007930 alcohol dependence Diseases 0.000 description 1
- OBETXYAYXDNJHR-UHFFFAOYSA-N alpha-ethylcaproic acid Natural products CCCCC(CC)C(O)=O OBETXYAYXDNJHR-UHFFFAOYSA-N 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- OGBUMNBNEWYMNJ-UHFFFAOYSA-N batilol Chemical class CCCCCCCCCCCCCCCCCCOCC(O)CO OGBUMNBNEWYMNJ-UHFFFAOYSA-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
- 229910052799 carbon Inorganic materials 0.000 description 1
- XHRPOTDGOASDJS-UHFFFAOYSA-N cholesterol n-octadecanoate Natural products C12CCC3(C)C(C(C)CCCC(C)C)CCC3C2CC=C2C1(C)CCC(OC(=O)CCCCCCCCCCCCCCCCC)C2 XHRPOTDGOASDJS-UHFFFAOYSA-N 0.000 description 1
- XUGISPSHIFXEHZ-VEVYEIKRSA-N cholesteryl acetate Chemical compound C1C=C2C[C@@H](OC(C)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 XUGISPSHIFXEHZ-VEVYEIKRSA-N 0.000 description 1
- UVZUFUGNHDDLRQ-LLHZKFLPSA-N cholesteryl benzoate Chemical compound O([C@@H]1CC2=CC[C@H]3[C@@H]4CC[C@@H]([C@]4(CC[C@@H]3[C@@]2(C)CC1)C)[C@H](C)CCCC(C)C)C(=O)C1=CC=CC=C1 UVZUFUGNHDDLRQ-LLHZKFLPSA-N 0.000 description 1
- RJECHNNFRHZQKU-RMUVNZEASA-N cholesteryl oleate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCC\C=C/CCCCCCCC)C1 RJECHNNFRHZQKU-RMUVNZEASA-N 0.000 description 1
- BBJQPKLGPMQWBU-JADYGXMDSA-N cholesteryl palmitate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCC)C1 BBJQPKLGPMQWBU-JADYGXMDSA-N 0.000 description 1
- XHRPOTDGOASDJS-XNTGVSEISA-N cholesteryl stearate Chemical compound C([C@@H]12)C[C@]3(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@H]3[C@@H]1CC=C1[C@]2(C)CC[C@H](OC(=O)CCCCCCCCCCCCCCCCC)C1 XHRPOTDGOASDJS-XNTGVSEISA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 229940097362 cyclodextrins Drugs 0.000 description 1
- HABLENUWIZGESP-UHFFFAOYSA-N decanoic acid Chemical compound CCCCCCCCCC(O)=O.CCCCCCCCCC(O)=O HABLENUWIZGESP-UHFFFAOYSA-N 0.000 description 1
- 230000001419 dependent effect Effects 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 230000008020 evaporation Effects 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000706 filtrate Substances 0.000 description 1
- 239000003205 fragrance Substances 0.000 description 1
- 229960003692 gamma aminobutyric acid Drugs 0.000 description 1
- BTCSSZJGUNDROE-UHFFFAOYSA-N gamma-aminobutyric acid Chemical compound NCCCC(O)=O BTCSSZJGUNDROE-UHFFFAOYSA-N 0.000 description 1
- 125000005456 glyceride group Chemical group 0.000 description 1
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 1
- 229940057917 medium chain triglycerides Drugs 0.000 description 1
- 230000005906 menstruation Effects 0.000 description 1
- 206010027599 migraine Diseases 0.000 description 1
- 230000007510 mood change Effects 0.000 description 1
- 238000011587 new zealand white rabbit Methods 0.000 description 1
- 229960002446 octanoic acid Drugs 0.000 description 1
- 229940127234 oral contraceptive Drugs 0.000 description 1
- 239000003539 oral contraceptive agent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 description 1
- 239000013049 sediment Substances 0.000 description 1
- 208000019116 sleep disease Diseases 0.000 description 1
- 229940080274 sodium cholesteryl sulfate Drugs 0.000 description 1
- LMPVQXVJTZWENW-KPNWGBFJSA-M sodium;[(3s,8s,9s,10r,13r,14s,17r)-10,13-dimethyl-17-[(2r)-6-methylheptan-2-yl]-2,3,4,7,8,9,11,12,14,15,16,17-dodecahydro-1h-cyclopenta[a]phenanthren-3-yl] sulfate Chemical compound [Na+].C1C=C2C[C@@H](OS([O-])(=O)=O)CC[C@]2(C)[C@@H]2[C@@H]1[C@@H]1CC[C@H]([C@H](C)CCCC(C)C)[C@@]1(C)CC2 LMPVQXVJTZWENW-KPNWGBFJSA-M 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 125000002328 sterol group Chemical group 0.000 description 1
- 238000010254 subcutaneous injection Methods 0.000 description 1
- 239000007929 subcutaneous injection Substances 0.000 description 1
- 201000009032 substance abuse Diseases 0.000 description 1
- 231100000736 substance abuse Toxicity 0.000 description 1
- 208000011117 substance-related disease Diseases 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- ODLHGICHYURWBS-LKONHMLTSA-N trappsol cyclo Chemical compound CC(O)COC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](COCC(C)O)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)COCC(O)C)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1COCC(C)O ODLHGICHYURWBS-LKONHMLTSA-N 0.000 description 1
- DCXXMTOCNZCJGO-UHFFFAOYSA-N tristearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(OC(=O)CCCCCCCCCCCCCCCCC)COC(=O)CCCCCCCCCCCCCCCCC DCXXMTOCNZCJGO-UHFFFAOYSA-N 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
-
- 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
- A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
- A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol
-
- 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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- 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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
-
- 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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
-
- 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
- A61K9/10—Dispersions; Emulsions
-
- 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
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
-
- 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
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/06—Antimigraine agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
- A61P25/32—Alcohol-abuse
-
- 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
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0034—Urogenital system, e.g. vagina, uterus, cervix, penis, scrotum, urethra, bladder; Personal lubricants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Medicinal Chemistry (AREA)
- Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Dispersion Chemistry (AREA)
- Psychiatry (AREA)
- Endocrinology (AREA)
- Addiction (AREA)
- Pain & Pain Management (AREA)
- Reproductive Health (AREA)
- Hospice & Palliative Care (AREA)
- Gynecology & Obstetrics (AREA)
- Diabetes (AREA)
- Anesthesiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Description
本出願で使用される場合、以下の用語は、他に特定されないならば、以下に特定される意味を有する。
本発明者は、ステロールの添加により、驚くべきことに、アシルグリセロール類における3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの溶解度が増加し、薬物動態が改善されることを見出した。
一般的に、アシルグリセロール類の混合物は、25℃で約5%未満、37℃で約0%の固形脂肪含有量を有することを特徴とする。よって、固形脂肪含有量は、実際的な目的によっては、37℃で0%である。固形脂肪含有量は、37℃で最大0.01%である。
3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンを含有する薬学的組成物を見出すために、幾つかの異なったビヒクル及びビヒクルの組合せを評価した。3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンを様々なビヒクルに溶解させ、室温での経時的な物理的安定性を目視評価した。外観に如何なる可視的変化もなく、30日以内で、濁り(haziness)、沈殿、沈降、2以上の液状相への相分離、又は色調変化の兆候がなく、室温での保存で透明性を維持している製剤を、「安定」と考えた。
次の手順を、3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン-含有製剤の調製に適合させた。
3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン(UC1010)(5mg/g)及びピーナッツ油を、表1に示す濃度で、上述したようなエタノールを含有するエマルションに混合し、エタノールを蒸発させた。調製物の最終重量は20gであった。混合物は油性液体の形態をしていた。1日後、サンプルを評価した時に、沈殿の兆候があった。30日後、沈殿物が、底部沈降物を形成した。よって、製剤は安定しなかった。
実施例2は、コレステロール(5.5mg/g)を添加した以外は、本質的に実施例1のように実施した。1日後、サンプルを評価したところ、サンプルの外観は変化していなかった。30日後、4ヶ月後までは、変化はなかった。5ヶ月後、わずかな沈殿があった。実施例1と比較して、実施例2では、ピーナッツ油中の5mg/gの3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの溶液への5.5mg/gのコレステロールの添加が、沈殿の代わりに、実質的溶解度を増加させ、沈殿が生じることなく、サンプルは4ヶ月安定していたことが示された。しかしながら、5ヶ月後には、わずかな沈降が生じた。
実施例3から49を、3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン濃度に関して変動させて、本質的に上述したようにして実施し、使用したアシルグリセロール混合物、使用したステロール及びステロール濃度を表1に示す。
実施例50から75を、実施例1−49と本質的に同様にして実施した。Akoline中鎖モノグリセリド(MCM)(バッチ8192270及び8218940)及びアコメッドR中鎖トリグリセリド(MCT)(バッチ4765)を、AarhusKarlshamns Sweden AB, Karlshamn, Swedenから得た。無水エタノール(>99%)をVWR Internationalから得た。
該研究の目的は、ニュージーランドホワイトウサギに皮下投与した後の、ゴマ油とコレステロールを含有する3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン製剤の、血漿中における相対的薬物動態を調査することである。3匹のメスウサギの2つのグループは、それぞれ1mg/kg(実施例7の製剤)又は5mg/kg(実施例10の製剤)の単一投与を受けた。動物の背部頸部領域に皮下注射した後、投与の0.25、0.5、1、2、4、6、8、12及び24時間後に、血液サンプルを取り出した。血漿中の3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン濃度を、有効LC-MS/MS法により測定した。データを図1に提示し、2つの投与量:1mg/kg(矩形)及び5mg/kg(丸)についての3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの平均血漿中濃度(ng/mL)を示す。
3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの懸濁液を、以下のようにして、溶解度の研究のために調製した:まず、コレステロールを室温で、ゴマ油にそれぞれ10及び20mg/ml溶解させた。異なるコレステロール量を有するゴマ油に、3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンが入った懸濁液を、室温で、数日間、2−8℃の偶発的サイクルにて、一般的なテフロンコーティング攪拌棒を使用し、約500rpmで、磁石式攪拌器において調製した。この時点で、粒子はかなり小さくなった。その後、それぞれの懸濁液のサンプルを0.2μmのフィルターで濾過し、3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン濃度に関して分析した。結果を表3と図2に提示するが、コレステロールの量を増加させると、3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの可溶性画分も増加することが分かった。図2には、10mg/gの3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン濃度についてのデータが示されている。図3a及び3bには、10mg/gの3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン濃度、1:1のコレステロール:3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン比率を有する懸濁液の、混合してすぐ(3a)及び攪拌して数日後(3b)の、5×拡大で撮られた顕微鏡写真が示されている。
平均粒子経6マイクロメーターを有する微細化された3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン(10mg/g)を、コレステロール(20mg/g) を含有するゴマ油に懸濁させ、実施例77のようにして攪拌した。懸濁してすぐ(図4a)及び攪拌して19時間後(図4b)の写真を撮った。
ステロール、例えばコレステロールが存在することで、油性溶液又は油性懸濁液のいずれにおいても、アシルグリセロール類を含有する薬学的組成物に3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンを処方する可能性が改善されることが分かった。
Claims (14)
- 3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オン、少なくとも一のステロール又はそのエステルと、25℃で25%未満、37℃で0%の固形脂肪含有量を有するアシルグリセロール類の混合物を含有する薬学的組成物であって、アシルグリセロール類の混合物が植物性油、中鎖アシルグリセロール、又はその組み合わせである、薬学的組成物。
- ステロールが、コレステロール、ベータ-シトステロール、スチグマステロール、ブラシカステロール及びアベナステロールからなる群から選択される、請求項1に記載の薬学的組成物。
- ステロールがコレステロールである、請求項2に記載の薬学的組成物。
- アシルグリセロール類の混合物が植物性油である、請求項1から3のいずれか一項に記載の薬学的組成物。
- 植物性油が、ゴマ油、ピーナッツ油、オリーブ油、及びヒマシ油からなる群から選択される、請求項4に記載の薬学的組成物。
- アシルグリセロール類の混合物が中鎖アシルグリセロールである、請求項1から3のいずれか一項に記載の薬学的組成物。
- 3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンが本質的に溶解している、請求項1から6のいずれか一項に記載の薬学的組成物。
- 3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンの懸濁液を含む、請求項1から6のいずれか一項に記載の薬学的組成物。
- 非経口投与のための、請求項1から8のいずれか一項に記載の薬学的組成物。
- 経口投与のための、請求項1から8のいずれか一項に記載の薬学的組成物。
- 経膣投与のための、請求項1から8のいずれか一項に記載の薬学的組成物。
- 経鼻投与のための、請求項1から8のいずれか一項に記載の薬学的組成物。
- a)エタノールに3-ベータ-ヒドロキシ-5-アルファ-プレグナン-20-オンを溶解させ、
b)25℃で25%未満、37℃で0%の固形脂肪含有量を有するアシルグリセロール類の混合物と、ステロール又はそのエステルを添加し、
c)均質な液体が得られるまで混合し、
d)エタノールを蒸発させることを含み、
アシルグリセロール類の混合物が植物性油、中鎖アシルグリセロール、又はその組み合わせである、請求項7に記載の薬学的組成物を調製する方法。 - 請求項13に記載の方法により得ることができる薬学的組成物。
Applications Claiming Priority (5)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US29502710P | 2010-01-14 | 2010-01-14 | |
SE1050029 | 2010-01-14 | ||
SE1050029-6 | 2010-01-14 | ||
US61/295,027 | 2010-01-14 | ||
PCT/SE2011/050036 WO2011087441A1 (en) | 2010-01-14 | 2011-01-14 | A pharmaceutical composition comprising 3-beta-hydroxy-5-alpha-pregnan-20-one with improved storage and solubility properties |
Publications (2)
Publication Number | Publication Date |
---|---|
JP2013517269A JP2013517269A (ja) | 2013-05-16 |
JP5687287B2 true JP5687287B2 (ja) | 2015-03-18 |
Family
ID=44304503
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP2012548918A Active JP5687287B2 (ja) | 2010-01-14 | 2011-01-14 | 改善された保存性及び溶解特性を有する3−ベータ−ヒドロキシ−5−アルファ−プレグナン−20−オンを含有する薬学的組成物 |
Country Status (15)
Country | Link |
---|---|
US (4) | US20120322781A1 (ja) |
EP (1) | EP2523666B8 (ja) |
JP (1) | JP5687287B2 (ja) |
CN (1) | CN102753181B (ja) |
AU (1) | AU2011205821B2 (ja) |
BR (1) | BR112012017136B1 (ja) |
CA (1) | CA2786330C (ja) |
DK (1) | DK2523666T3 (ja) |
ES (1) | ES2566765T3 (ja) |
HU (1) | HUE027298T2 (ja) |
MX (1) | MX2012008257A (ja) |
PL (1) | PL2523666T3 (ja) |
RU (1) | RU2012133627A (ja) |
WO (1) | WO2011087441A1 (ja) |
ZA (1) | ZA201204574B (ja) |
Families Citing this family (12)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10478505B2 (en) * | 2011-09-23 | 2019-11-19 | The Regents Of The University Of California | Edible oils to enhance delivery of orally administered steroids |
CN106146597A (zh) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | 一种马尾藻甾醇化合物及其提取方法、应用 |
CN106146596A (zh) * | 2016-07-05 | 2016-11-23 | 浙江海洋大学 | 一种铜藻β‑谷甾醇化合物及其提取方法、应用 |
JP6767583B2 (ja) * | 2016-09-27 | 2020-10-14 | グアンシー ジュフー バイオテクノロジー カンパニー リミテッド | 麻薬依存を治療する薬効のあるエキストラクト及びその調製方法 |
AU2018206222B2 (en) * | 2017-01-09 | 2023-04-13 | Asarina Pharma Ab | Injectable suspensions |
BR112019015362A2 (pt) | 2017-02-10 | 2020-10-20 | Asarina Pharma Ab | 3-beta-hidroxi-5-alfa-pregnan-20-ona para uso em tratamento médico |
WO2019102040A1 (en) | 2017-11-27 | 2019-05-31 | Umecrine Cognition Ab | PHARMACEUTICAL FORMULATION OF 3α-ETHYNYL-3β-HYDROXYANDROSTAN-17-ONE OXIME |
WO2020011789A1 (en) | 2018-07-09 | 2020-01-16 | Asarina Pharma Ab | Injectable suspensions |
EP3593789A1 (fr) * | 2018-07-11 | 2020-01-15 | Beta Innov | Composition contenant un dérivé de 7beta-hydroxycholestérol et un véhicule lipidique, et son utilisation dans le traitement de pathologies néoplasiques |
US20220202832A1 (en) * | 2019-04-05 | 2022-06-30 | The Regents Of The University Of California | Allopregnanolone compositions and uses thereof |
CN112341511A (zh) * | 2019-08-09 | 2021-02-09 | 南京诺瑞特医药科技有限公司 | 3-羟基-5-孕烷-20-酮衍生物及其用途 |
CN114907436A (zh) * | 2021-02-08 | 2022-08-16 | 南京诺瑞特医药科技有限公司 | 3-羟基-5-孕烷-20-酮衍生物的晶型及其制备方法和用途 |
Family Cites Families (29)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
JPS54122719A (en) * | 1978-03-16 | 1979-09-22 | Sankyo Co Ltd | Carcinostatic agent for oral administration |
US5232917A (en) | 1987-08-25 | 1993-08-03 | University Of Southern California | Methods, compositions, and compounds for allosteric modulation of the GABA receptor by members of the androstane and pregnane series |
US5120723A (en) | 1987-08-25 | 1992-06-09 | University Of Southern California | Method, compositions, and compounds for modulating brain excitability |
US5364632A (en) * | 1989-04-05 | 1994-11-15 | Yissum Research Development Company Of The Hebrew University Of Jerusalem | Medicinal emulsions |
JPH02286625A (ja) * | 1989-04-27 | 1990-11-26 | Dainippon Pharmaceut Co Ltd | 注射用持続性製剤 |
FR2663224B1 (fr) * | 1990-06-14 | 1995-01-20 | Applicationes Farmaceuticas Sa | Forme galenique parenterale. |
US5449474A (en) | 1992-02-21 | 1995-09-12 | Inland Technology, Inc. | Low toxicity solvent composition |
SE9302295D0 (sv) | 1993-07-02 | 1993-07-02 | Kabi Pharmacia Ab | New pharmaceutical composition |
WO1995005826A1 (en) | 1993-08-20 | 1995-03-02 | Jackson Meyer B | Method for regulating neuropeptide hormone secretion |
US5763431A (en) | 1993-08-20 | 1998-06-09 | Jackson; Meyer B. | Method for regulating neuropeptide hormone secretion |
GB9405304D0 (en) * | 1994-03-16 | 1994-04-27 | Scherer Ltd R P | Delivery systems for hydrophobic drugs |
CA2205919A1 (en) | 1994-11-23 | 1996-05-30 | Cocensys, Inc. | Androstane and pregnane series for allosteric modulation of gaba receptor |
FR2734418A1 (fr) * | 1995-05-16 | 1996-11-22 | Amp France | Connecteur, notamment du type jack modulaire |
PT981349E (pt) * | 1997-05-02 | 2003-01-31 | Wyeth Corp | Pregnan-3-ol-20-onas |
AU756001B2 (en) * | 1998-03-11 | 2003-01-02 | Umecrine Mood Ab | Epiallopregnanolone in the treatment of CNS disorders |
US6075058A (en) | 1998-12-12 | 2000-06-13 | Tufts University | Compositions for increased bioavailability of carotenoids |
WO2000059945A1 (en) | 1999-04-06 | 2000-10-12 | The Horticulture And Food Research Institute Of New Zealand Limited | Improvements in or relating to immunoassays for anaesthetics |
US20030236236A1 (en) * | 1999-06-30 | 2003-12-25 | Feng-Jing Chen | Pharmaceutical compositions and dosage forms for administration of hydrophobic drugs |
AU6381000A (en) | 1999-07-29 | 2001-02-19 | Interneuron Pharmaceuticals, Inc. | Methods and compositions for alleviating stuttering |
US20040204490A1 (en) | 1999-08-31 | 2004-10-14 | Farb David H. | Effect of steroids on NMDA receptors depends on subunit composition |
ATE425459T1 (de) | 1999-08-31 | 2009-03-15 | Univ Boston | Der effekt von steroiden auf ndma-rezeptoren beruht auf der zusammensetzung der untereinheiten |
US6855721B1 (en) | 2000-07-28 | 2005-02-15 | Indevus Pharmaceuticals, Inc. | Methods and compositions for alleviating stuttering |
SE0104423D0 (sv) | 2001-12-27 | 2001-12-27 | Umecrine Ab | Pregnane steroids and their use in the treatment of CNS disorders |
US6888721B1 (en) | 2002-10-18 | 2005-05-03 | Atec Corporation | Electrohydrodynamic (EHD) thin film evaporator with splayed electrodes |
US20050096365A1 (en) | 2003-11-03 | 2005-05-05 | David Fikstad | Pharmaceutical compositions with synchronized solubilizer release |
US20060003002A1 (en) | 2003-11-03 | 2006-01-05 | Lipocine, Inc. | Pharmaceutical compositions with synchronized solubilizer release |
US8604011B2 (en) | 2004-09-27 | 2013-12-10 | The Regents Of The University Of California | Therapy for treatment of chronic degenerative brain diseases and nervous system injury |
MX2007006032A (es) | 2004-11-18 | 2007-10-17 | Umecrine Ab | Antagonistas de gaba-esteroide y su uso para el tratamiento de trastornos del sistema nervioso central. |
HUE033037T2 (hu) | 2006-11-21 | 2017-11-28 | Umecrine Cognition Ab | Pregnán és androsztán szteroidok alkalmazása központi idegrendszerbeli rendellenességek kezelésére szolgáló gyógyszerészeti készítmények elõállítására |
-
2011
- 2011-01-14 ES ES11733156.1T patent/ES2566765T3/es active Active
- 2011-01-14 JP JP2012548918A patent/JP5687287B2/ja active Active
- 2011-01-14 CN CN201180005620.9A patent/CN102753181B/zh active Active
- 2011-01-14 BR BR112012017136-4A patent/BR112012017136B1/pt active IP Right Grant
- 2011-01-14 MX MX2012008257A patent/MX2012008257A/es active IP Right Grant
- 2011-01-14 EP EP11733156.1A patent/EP2523666B8/en active Active
- 2011-01-14 AU AU2011205821A patent/AU2011205821B2/en active Active
- 2011-01-14 RU RU2012133627/15A patent/RU2012133627A/ru not_active Application Discontinuation
- 2011-01-14 WO PCT/SE2011/050036 patent/WO2011087441A1/en active Application Filing
- 2011-01-14 CA CA2786330A patent/CA2786330C/en active Active
- 2011-01-14 HU HUE11733156A patent/HUE027298T2/en unknown
- 2011-01-14 US US13/522,081 patent/US20120322781A1/en not_active Abandoned
- 2011-01-14 DK DK11733156.1T patent/DK2523666T3/en active
- 2011-01-14 PL PL11733156T patent/PL2523666T3/pl unknown
-
2012
- 2012-06-20 ZA ZA2012/04574A patent/ZA201204574B/en unknown
-
2015
- 2015-02-19 US US14/626,490 patent/US9687496B2/en active Active
-
2017
- 2017-05-22 US US15/601,214 patent/US11534446B2/en active Active
-
2022
- 2022-11-17 US US18/056,475 patent/US20230117905A1/en active Pending
Also Published As
Publication number | Publication date |
---|---|
EP2523666A1 (en) | 2012-11-21 |
CN102753181B (zh) | 2014-09-17 |
BR112012017136A2 (pt) | 2018-06-12 |
JP2013517269A (ja) | 2013-05-16 |
US20120322781A1 (en) | 2012-12-20 |
US20150164914A1 (en) | 2015-06-18 |
AU2011205821B2 (en) | 2013-07-25 |
DK2523666T3 (en) | 2016-04-04 |
EP2523666A4 (en) | 2013-07-03 |
EP2523666B1 (en) | 2016-01-13 |
ZA201204574B (en) | 2013-08-28 |
CA2786330C (en) | 2013-11-19 |
CA2786330A1 (en) | 2011-07-21 |
US20230117905A1 (en) | 2023-04-20 |
BR112012017136B1 (pt) | 2021-05-25 |
PL2523666T3 (pl) | 2016-06-30 |
CN102753181A (zh) | 2012-10-24 |
WO2011087441A1 (en) | 2011-07-21 |
US9687496B2 (en) | 2017-06-27 |
EP2523666B8 (en) | 2016-04-06 |
ES2566765T3 (es) | 2016-04-15 |
MX2012008257A (es) | 2012-11-21 |
US11534446B2 (en) | 2022-12-27 |
RU2012133627A (ru) | 2014-04-20 |
AU2011205821A1 (en) | 2012-07-12 |
HUE027298T2 (en) | 2016-10-28 |
US20170258809A1 (en) | 2017-09-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
JP5687287B2 (ja) | 改善された保存性及び溶解特性を有する3−ベータ−ヒドロキシ−5−アルファ−プレグナン−20−オンを含有する薬学的組成物 | |
WO2009012718A1 (fr) | Émulsifiant composite, émulsion préparée à partir de celui-ci et procédé de préparation de celle-ci | |
JP6605047B2 (ja) | 疼痛治療のためのセレコキシブの経口用組成物 | |
JPH10511959A (ja) | フェノフィブレートおよびポリグリコール化グリセリドを含有する薬学的組成物 | |
OA12726A (en) | Pharmaceutical composition based on micronized progesterone, preparaion method and uses thereof. | |
TW200817046A (en) | An effective pharmaceutical carrier for poorly bioavailable drugs | |
CA2698513A1 (fr) | Composition pharmaceutique a base de progesterone micronisee et ses utilisations | |
WO2010146606A1 (en) | Nanodispersion of a drug and process for its preparation | |
DK175504B1 (da) | Farmaceutisk præparat indeholdende 3alfa-hydroxy-5beta-pregnan-20-on og fremstilling deraf | |
CN101496787A (zh) | 一种荷电性的前列腺素e1脂微球注射液及其制备方法 | |
US10500226B2 (en) | Alginate compositions and uses thereof | |
CN111012745A (zh) | 一种阿比特龙口服乳剂及其制备方法 | |
WO2014205226A1 (en) | Self-nanoemulsion of poorly soluble drugs | |
JPH09512794A (ja) | マラリアの治療用のハロファントリン遊離塩基および組成物 | |
JP2930242B2 (ja) | 非経口投与用エマルジヨン | |
KR100343272B1 (ko) | 생활성스테로이드를함유한약제학적에멀션 | |
CN114425038A (zh) | 一种20(s)-ppd脂质体乳剂复合体口服给药制剂及其制备方法和应用 | |
JP2022514991A (ja) | 安定な麻酔薬製剤および関連する剤形 | |
WO2024012361A1 (zh) | 阿法沙龙脂肪乳注射液及其制备方法 | |
JP5295771B2 (ja) | エタノールとx線不透過性の脂溶性化合物とを含む注入用粘稠医薬製剤 | |
CN105796552A (zh) | 一种辛伐他汀依折麦布复方纳米溶液和冻干粉及其制备方法 | |
WO2024086629A2 (en) | Anhydrous oral pharmaceutical suspensions | |
WO2017184436A1 (en) | Systems and methods for steroidal gels | |
DE3411910A1 (de) | Galenische zubereitung | |
TW200522940A (en) | Pharmaceutical compositions containing taxanes and methods for preparing the pharmaceutical compositions |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20131126 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140225 |
|
A131 | Notification of reasons for refusal |
Free format text: JAPANESE INTERMEDIATE CODE: A131 Effective date: 20140520 |
|
A521 | Request for written amendment filed |
Free format text: JAPANESE INTERMEDIATE CODE: A523 Effective date: 20140805 |
|
TRDD | Decision of grant or rejection written | ||
A01 | Written decision to grant a patent or to grant a registration (utility model) |
Free format text: JAPANESE INTERMEDIATE CODE: A01 Effective date: 20150106 |
|
A61 | First payment of annual fees (during grant procedure) |
Free format text: JAPANESE INTERMEDIATE CODE: A61 Effective date: 20150121 |
|
R150 | Certificate of patent or registration of utility model |
Ref document number: 5687287 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 |
|
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 |
|
R250 | Receipt of annual fees |
Free format text: JAPANESE INTERMEDIATE CODE: R250 |