JPH02210A - Aqueous recipe containing pyperidinylcyclopentylpentenic acid derivative - Google Patents
Aqueous recipe containing pyperidinylcyclopentylpentenic acid derivativeInfo
- Publication number
- JPH02210A JPH02210A JP63320759A JP32075988A JPH02210A JP H02210 A JPH02210 A JP H02210A JP 63320759 A JP63320759 A JP 63320759A JP 32075988 A JP32075988 A JP 32075988A JP H02210 A JPH02210 A JP H02210A
- Authority
- JP
- Japan
- Prior art keywords
- cyclodextrin
- compound
- hydrochloride
- aqueous
- water
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- 239000002253 acid Substances 0.000 title description 3
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 77
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 35
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims abstract description 32
- 229960004853 betadex Drugs 0.000 claims abstract description 28
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims abstract description 27
- 238000002347 injection Methods 0.000 claims abstract description 23
- 239000007924 injection Substances 0.000 claims abstract description 23
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 claims abstract description 11
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims abstract description 11
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 6
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 6
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims abstract description 6
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 5
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims abstract 4
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 claims abstract 4
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims abstract 4
- 229940126062 Compound A Drugs 0.000 claims description 57
- NLDMNSXOCDLTTB-UHFFFAOYSA-N Heterophylliin A Natural products O1C2COC(=O)C3=CC(O)=C(O)C(O)=C3C3=C(O)C(O)=C(O)C=C3C(=O)OC2C(OC(=O)C=2C=C(O)C(O)=C(O)C=2)C(O)C1OC(=O)C1=CC(O)=C(O)C(O)=C1 NLDMNSXOCDLTTB-UHFFFAOYSA-N 0.000 claims description 57
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 42
- 239000000203 mixture Substances 0.000 claims description 28
- 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 claims description 27
- 239000013011 aqueous formulation Substances 0.000 claims description 24
- 239000001116 FEMA 4028 Substances 0.000 claims description 23
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 23
- 238000009472 formulation Methods 0.000 claims description 17
- QCQCHGYLTSGIGX-GHXANHINSA-N 4-[[(3ar,5ar,5br,7ar,9s,11ar,11br,13as)-5a,5b,8,8,11a-pentamethyl-3a-[(5-methylpyridine-3-carbonyl)amino]-2-oxo-1-propan-2-yl-4,5,6,7,7a,9,10,11,11b,12,13,13a-dodecahydro-3h-cyclopenta[a]chrysen-9-yl]oxy]-2,2-dimethyl-4-oxobutanoic acid Chemical compound N([C@@]12CC[C@@]3(C)[C@]4(C)CC[C@H]5C(C)(C)[C@@H](OC(=O)CC(C)(C)C(O)=O)CC[C@]5(C)[C@H]4CC[C@@H]3C1=C(C(C2)=O)C(C)C)C(=O)C1=CN=CC(C)=C1 QCQCHGYLTSGIGX-GHXANHINSA-N 0.000 claims description 12
- 239000012458 free base Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 238000001802 infusion Methods 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims 1
- 238000002360 preparation method Methods 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 7
- 239000004480 active ingredient Substances 0.000 abstract description 5
- 208000019553 vascular disease Diseases 0.000 abstract description 3
- 230000003073 embolic effect Effects 0.000 abstract description 2
- 229920001353 Dextrin Polymers 0.000 abstract 1
- 239000004375 Dextrin Substances 0.000 abstract 1
- 235000019425 dextrin Nutrition 0.000 abstract 1
- 239000000243 solution Substances 0.000 description 44
- 229940097362 cyclodextrins Drugs 0.000 description 11
- 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 9
- 229930195725 Mannitol Natural products 0.000 description 9
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 9
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 9
- 239000000594 mannitol Substances 0.000 description 9
- 235000010355 mannitol Nutrition 0.000 description 9
- 238000010253 intravenous injection Methods 0.000 description 7
- 238000007911 parenteral administration Methods 0.000 description 7
- 235000002639 sodium chloride Nutrition 0.000 description 7
- 239000003814 drug Substances 0.000 description 6
- 239000008363 phosphate buffer Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 238000011282 treatment Methods 0.000 description 6
- 239000002585 base Substances 0.000 description 5
- 238000000034 method Methods 0.000 description 5
- 239000011521 glass Substances 0.000 description 4
- 230000002265 prevention Effects 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 3
- 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 3
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 3
- 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 3
- 230000000747 cardiac effect Effects 0.000 description 3
- 238000006243 chemical reaction Methods 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- 230000000694 effects Effects 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 150000004677 hydrates Chemical class 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 3
- 230000001404 mediated effect Effects 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 0.000 description 3
- 229910052698 phosphorus Inorganic materials 0.000 description 3
- 239000011574 phosphorus Substances 0.000 description 3
- 150000003839 salts Chemical class 0.000 description 3
- 239000001488 sodium phosphate Substances 0.000 description 3
- 239000002904 solvent Substances 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- DSNBHJFQCNUKMA-SCKDECHMSA-N thromboxane A2 Chemical compound OC(=O)CCC\C=C/C[C@@H]1[C@@H](/C=C/[C@@H](O)CCCCC)O[C@@H]2O[C@H]1C2 DSNBHJFQCNUKMA-SCKDECHMSA-N 0.000 description 3
- 208000008469 Peptic Ulcer Diseases 0.000 description 2
- 229930006000 Sucrose Natural products 0.000 description 2
- 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 2
- 238000004458 analytical method Methods 0.000 description 2
- 239000011230 binding agent Substances 0.000 description 2
- 239000003795 chemical substances by application Substances 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 239000000706 filtrate Substances 0.000 description 2
- 238000007429 general method Methods 0.000 description 2
- -1 hydroxypropyl Chemical group 0.000 description 2
- 239000004615 ingredient Substances 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000007788 liquid Substances 0.000 description 2
- 238000002844 melting Methods 0.000 description 2
- 230000008018 melting Effects 0.000 description 2
- 230000002093 peripheral effect Effects 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 229960004793 sucrose Drugs 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 238000012360 testing method Methods 0.000 description 2
- 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 2
- YURNCBVQZBJDAJ-UHFFFAOYSA-N 2-heptenoic acid Chemical compound CCCCC=CC(O)=O YURNCBVQZBJDAJ-UHFFFAOYSA-N 0.000 description 1
- 206010002388 Angina unstable Diseases 0.000 description 1
- 241000282472 Canis lupus familiaris Species 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 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
- 241000406668 Loxodonta cyclotis Species 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000035965 Postoperative Complications Diseases 0.000 description 1
- 206010050902 Postoperative thrombosis Diseases 0.000 description 1
- 208000010378 Pulmonary Embolism Diseases 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 238000004220 aggregation Methods 0.000 description 1
- 230000002776 aggregation Effects 0.000 description 1
- 230000029936 alkylation Effects 0.000 description 1
- 238000005804 alkylation reaction Methods 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000008280 blood Substances 0.000 description 1
- 210000004369 blood Anatomy 0.000 description 1
- 239000000872 buffer Substances 0.000 description 1
- 239000008364 bulk solution Substances 0.000 description 1
- 239000002775 capsule Substances 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 201000002676 cerebral atherosclerosis Diseases 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 238000005352 clarification Methods 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 239000000356 contaminant Substances 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 239000002178 crystalline material Substances 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical class NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 238000010790 dilution Methods 0.000 description 1
- 239000012895 dilution Substances 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 238000005516 engineering process Methods 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 239000000796 flavoring agent Substances 0.000 description 1
- 235000019634 flavors Nutrition 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 150000003840 hydrochlorides Chemical class 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 239000007972 injectable composition Substances 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- XMGQYMWWDOXHJM-UHFFFAOYSA-N limonene Chemical compound CC(=C)C1CCC(C)=CC1 XMGQYMWWDOXHJM-UHFFFAOYSA-N 0.000 description 1
- 230000011987 methylation Effects 0.000 description 1
- 238000007069 methylation reaction Methods 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- 238000002663 nebulization Methods 0.000 description 1
- 239000006199 nebulizer Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 239000008014 pharmaceutical binder Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000003755 preservative agent Substances 0.000 description 1
- 230000002335 preservative effect Effects 0.000 description 1
- 230000000328 pro-aggregatory effect Effects 0.000 description 1
- 238000009877 rendering Methods 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 235000019980 sodium acid phosphate Nutrition 0.000 description 1
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 1
- 229910000162 sodium phosphate Inorganic materials 0.000 description 1
- PESXGULMKCKJCC-UHFFFAOYSA-M sodium;4-methoxycarbonylphenolate Chemical compound [Na+].COC(=O)C1=CC=C([O-])C=C1 PESXGULMKCKJCC-UHFFFAOYSA-M 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 208000010110 spontaneous platelet aggregation Diseases 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000011550 stock solution Substances 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 201000010875 transient cerebral ischemia Diseases 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
- C07F9/02—Phosphorus compounds
- C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
- C07F9/6564—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms
- C07F9/6581—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms
- C07F9/6584—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having phosphorus atoms, with or without nitrogen, oxygen, sulfur, selenium or tellurium atoms, as ring hetero atoms having phosphorus and nitrogen atoms with or without oxygen or sulfur atoms, as ring hetero atoms having one phosphorus atom as ring hetero atom
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/445—Non condensed piperidines, e.g. piperocaine
-
- 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
- A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P11/00—Drugs for disorders of the respiratory system
- A61P11/08—Bronchodilators
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
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Abstract
Description
【発明の詳細な説明】
〔産業上の利用分野〕
本発明は、活性成分として〔1R−〔lα(Z)、2β
、3β、5α))−(+)−7−(5−[((1,1’
−ビフェニル)−4−イル〕メi−キシ〕−3−ヒドロ
キシ−2−(1−ピペリジニル)シクロペンチル〕−4
−ヘプテン酸(以下、「化合物A」という)を含有する
水性処方物、その製法およびその医薬における使用に関
する。DETAILED DESCRIPTION OF THE INVENTION [Industrial Application Field] The present invention provides active ingredients [1R-[lα(Z), 2β
, 3β, 5α))-(+)-7-(5-[((1,1'
-biphenyl)-4-yl]mei-xy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4
- Concerning an aqueous formulation containing heptenoic acid (hereinafter referred to as "compound A"), its preparation and its use in medicine.
化合物Aは、エンドペルオキシドおよびトロンボキサン
拮抗活性を有する一群のアミノシクロペンタン誘導体の
一つとして、本出願人の英国特許第2097397号に
記載されており、この中で、こうした化合物は、喘息お
よび心臓血管疾患の治療において重要であると報告され
ている。さらに最近になって、化合物への塩酸塩は、そ
の製法および医薬における使用の両面で、化合物A並び
にその異種の塩および溶媒和物よりも有利であることを
本発明者らは見出した。この塩酸塩は英国特許第212
7406号に記載されている。Compound A is described in the Applicant's UK Patent No. 2097397 as one of a family of aminocyclopentane derivatives with endoperoxide and thromboxane antagonist activity, in which such compounds are shown to be effective against asthma and cardiac It has been reported to be important in the treatment of vascular diseases. More recently, the inventors have discovered that the hydrochloride salt of the compound has advantages over Compound A and its heterogeneous salts and solvates, both in terms of its preparation and use in medicine. This hydrochloride is known as British Patent No. 212.
No. 7406.
残念なことに、化合物Aは水にわずかしか溶けない。ま
た、化合物Aの塩酸塩を標準的な結合剤および/または
担体とともに含有する水系処方物は、静脈を通しての投
与に不向きであることがわかっている。これは、生理的
pl+近くでは、化合物Aの塩酸塩は実質的に不溶性の
化合物Aに転化するためである。Unfortunately, Compound A is only sparingly soluble in water. It has also been found that aqueous formulations containing the hydrochloride salt of Compound A with standard binders and/or carriers are unsuitable for intravenous administration. This is because, near physiological pl+, the hydrochloride salt of Compound A is converted to Compound A, which is substantially insoluble.
生理的p)I付近での化合物Aおよびその塩酸塩の水に
対する溶解度が、非置換または置換α−1β−もしくは
γ−シクロデキス(〜リン(またはその水和物)の存在
下、顕著に改良されることがあらたに見出された。また
、化合物Aまたはその塩酸塩および非置換または置換α
−1β−もしくはγ−シクロデキストリン(またはその
水和物)からなる水性処方物が、医薬における使用、よ
り特定すれば、トロンボキサンA2の介在により起こる
諸症状の治療または予防におけろ使用に、経口的方法、
吸入あるいは非経口的方法のいずれか、特に注射(たと
えば静脈注射)により投与される場合、好適であること
も見出された。The aqueous solubility of Compound A and its hydrochloride near physiological p)I is significantly improved in the presence of unsubstituted or substituted α-1β- or γ-cyclodex(~phosphorus (or its hydrate)). It was newly discovered that compound A or its hydrochloride and unsubstituted or substituted α
- Aqueous formulations consisting of 1β- or γ-cyclodextrins (or hydrates thereof) for use in medicine, more particularly in the treatment or prevention of conditions mediated by thromboxane A2, oral method,
It has also been found suitable when administered either by inhalation or parenterally, especially by injection (eg intravenous injection).
本発明は非置換または置換α−β−もしくはγ−シクロ
デキストリン(またはその水和物)とともに化合物Aま
たはその塩酸塩からなる水性処方物を提供する。The present invention provides an aqueous formulation consisting of Compound A or its hydrochloride salt with an unsubstituted or substituted α-β- or γ-cyclodextrin (or hydrate thereof).
また、本発明は、医療において使用する。より特定すれ
ば、トロンボキサンA2の介在により起こる諸症状の治
療または予防において使用する、ここで定義する水性処
方物を提供する。The invention also has use in medicine. More particularly, aqueous formulations as defined herein are provided for use in the treatment or prevention of conditions mediated by thromboxane A2.
また、本発明は、人間または動物の患者に、ここで定義
する水性処方物によって化合物Aを有効量投与すること
からなる、トロンボキサンA2の介在により起こる諸症
状の治療方法を提供する。The present invention also provides a method for treating conditions mediated by thromboxane A2, comprising administering to a human or animal patient an effective amount of Compound A by an aqueous formulation as defined herein.
本発明の水性処方物による治療が適合する症状には、英
国特許第2097397号および第2127406号に
記載のものがある。そこでは、それぞれ、化合物Aの異
種の(たとえば経口的)処方物、および、化合物Aの塩
酸塩を用いての治療が施されていた。Conditions amenable to treatment with the aqueous formulations of the invention include those described in GB 2097397 and GB 2127406. There, treatments were administered with different (eg, oral) formulations of Compound A and the hydrochloride salt of Compound A, respectively.
本発明の水性処方物は特に、塞栓性血管疾患の治療また
は予防に使用できる。具体的には、心筋便塞、心臓性致
死症、不安定狭心症、一過性虚血発作および脳梗塞、ア
テローム硬化症および血管壁疾患、末梢血管症患、網膜
症、術後血栓症および肺塞栓を含む。本水性処方物はま
た。臓器移植(特に心臓および’Ff Pm )、冠状
動脈バイパス、末梢動脈バイパスおよび血栓溶解後の術
崩術中(perioρerative)および術後合併
症の予防にも使用できる。本水性処方物は、消化性潰瘍
に関した使用、より特定すれば、治癒した消化性潰瘍の
再発防止に使用できる可能性もある。The aqueous formulations of the invention can be used in particular for the treatment or prevention of embolic vascular disease. Specifically, myocardial infarction, cardiac fatality, unstable angina, transient ischemic attack and cerebral infarction, atherosclerosis and vascular wall disease, peripheral vasculopathy, retinopathy, and postoperative thrombosis. and pulmonary embolism. This aqueous formulation also contains: It can also be used in the prevention of perioρerative and post-operative complications after organ transplantation (particularly cardiac and 'Ff Pm), coronary artery bypass, peripheral artery bypass and thrombolysis. The aqueous formulations also have potential for use in connection with peptic ulcers, more particularly in preventing recurrence of healed peptic ulcers.
好ましくは、本発明の水性処方物において、化合物Aは
その塩酸塩として用いる。Preferably, in the aqueous formulations of the invention, Compound A is used as its hydrochloride salt.
−収約には、単一のシクロデキストリンの使用が好まし
いが、本発明の効果が二種類以上のシクロデキストリン
を用いて達成しうろことも当業者には了解されるであろ
う。- Although the use of a single cyclodextrin is preferred for aggregation, those skilled in the art will appreciate that the effects of the invention may be achieved using more than one cyclodextrin.
置換シクロデキストリンを用いる場合、本発明によれば
、当業者に既知のシクロデキストリンは、適すればいず
れも使用できる。本発明による使用に適する置換シクロ
デキストリンは、当業者には容易に予解されるであろう
が、含硫黄シクロデキストリン、含窒素シクロデキスト
リン、シクロデキストリンのモノ−、ジーまたはトリメ
チル化誘導体のようなアルキル化(たとえばメチル化)
したシクロデキストリン並びにヒドロキシプロピルβ−
シクロデキストリンのようなヒドロキシアルキル化(た
とえばヒドロキシプロピル化した)シクロデキストリン
およびそのアシル化誘導体を含む。ヒドロキシプロピル
β−シクロデキストリンのようなヒドロキシアルキル(
たとえばヒドロキシプロピル)シクロデキストリンは、
本発明による使用に特に適することがわかっている。When using substituted cyclodextrins, according to the invention any suitable cyclodextrins known to the person skilled in the art can be used. Substituted cyclodextrins suitable for use in accordance with the present invention will be readily appreciated by those skilled in the art, such as sulfur-containing cyclodextrins, nitrogen-containing cyclodextrins, mono-, di- or trimethylated derivatives of cyclodextrins. Alkylation (e.g. methylation)
cyclodextrin and hydroxypropyl β-
Includes hydroxyalkylated (eg hydroxypropylated) cyclodextrins such as cyclodextrins and acylated derivatives thereof. Hydroxyalkyl (such as hydroxypropyl β-cyclodextrin)
For example, hydroxypropyl) cyclodextrin
It has been found to be particularly suitable for use according to the invention.
本発呻によれば、単一の非置換シクロデキストリンが便
宜に用いられる。特に好ましいのはβ−シクロデキスト
リンで、便宜にはその水和物のかたちで使用する。According to the present disclosure, a single unsubstituted cyclodextrin is conveniently used. Particularly preferred is β-cyclodextrin, conveniently used in the form of its hydrate.
水性処方物が望みとする特性を示すようにするためには
、化合物Aまたはその塩酸塩をシクロデキストリンに対
し正確なモル比で用いることが重要である。化合物Aま
たはその塩酸塩のシクロデキストリンに対するモル比は
1:1ないし1:4の範囲内が適当であることが見出さ
れた。In order for the aqueous formulation to exhibit the desired properties, it is important to use the correct molar ratio of Compound A or its hydrochloride to cyclodextrin. It has been found that the molar ratio of Compound A or its hydrochloride to cyclodextrin is suitably within the range of 1:1 to 1:4.
本発明の水性処方物が、所望ならば、一種以上の薬剤用
担体または結合剤を含んでもよいことは、当業者には了
解されるであろう。本水性処方物に組入れうる適当な結
合剤は、調製品を血漿と等張にする剤(たとえば、塩化
ナトリウム、デキストロースあるいは好ましくはマンニ
トール)および緩衝剤(たとえば、リン酸塩緩衝液ある
いは酸性リン酸ナトリウムとリン酸二ナトリウムの混合
物)を含む。It will be appreciated by those skilled in the art that the aqueous formulations of the present invention may, if desired, contain one or more pharmaceutical carriers or binders. Suitable binders that may be incorporated into the aqueous formulations include agents rendering the preparation isotonic with plasma (e.g. sodium chloride, dextrose or preferably mannitol) and buffers (e.g. phosphate buffer or acid phosphate). (a mixture of sodium and disodium phosphate).
本発明の水性処方物は特に、非経口投与、特に注射(た
とえば静脈注射)に適している。非経口投与に供する場
合には、処方物は大体生理的pHであることが望ましい
。したがって、従来からある手段、たとえば水酸化物(
たとえば水酸化ナトリウム溶液のようなアルカリ全屈水
酸化物)のような適当な塩基を使用して、pHを生理的
pi近くに調整するのもよい。便宜には、pHは約6.
0に調整する。The aqueous formulations of the invention are particularly suitable for parenteral administration, especially injection (eg intravenous injection). When intended for parenteral administration, it is desirable that the formulation be at about physiological pH. Therefore, conventional means such as hydroxide (
The pH may be adjusted to near physiological pi using a suitable base, such as an alkaline total hydroxide such as sodium hydroxide solution. Conveniently, the pH is about 6.
Adjust to 0.
非経口投与、特に注射(たとえば静脈注射)による投与
のためには、処方物を清澄な溶液上して供することが高
度に望ましい。乾燥粉末等と異なり清澄溶液では余計な
手順が必要とされず、直ちに投与できる。また、清澄溶
液の使用によって、確実に、製品中に粒子状または他の
目に見える混入物があるかどうか容易に検査できるよう
になる。For parenteral administration, particularly by injection (eg, intravenous), it is highly desirable to present the formulation as a clear solution. Unlike dry powders, clear solutions require no extra steps and can be administered immediately. The use of clarification solutions also ensures that the product can be easily tested for particulate or other visible contaminants.
しかも、薬剤水溶液の静脈注射では瞬時に生理的効果が
現われる。生理的pH付近、通常の保存温度で清澄溶液
を得るためには、化合物Aの塩化物各1モルに対し少な
くとも1モルのシフロブキス]・リンを使用すべきこと
、β−シクロデキストリンの場合は少なくとも約1.2
モルを使用すべきことが見出された。Furthermore, intravenous injection of an aqueous drug solution produces instant physiological effects. In order to obtain a clear solution at near physiological pH and at normal storage temperatures, at least 1 mole of sifurobukis] phosphorus should be used for each mole of chloride of compound A; in the case of β-cyclodextrin, at least Approximately 1.2
It was found that moles should be used.
したがって、本発明の好ましい実施態様において、化合
物Aの塩酸塩およびβ−シクロデキストリン(またはそ
の水和物)からなり、生理的pH付近で、化合物への塩
酸塩各1モルに対し少なくとも約1.2モルの(たとえ
ば、1.2ないし2モル)β−シクロデキストリンを含
有する清澄な水性処方物を提供する。好ましくは、この
モル比は約1 : 1.4である。Accordingly, in a preferred embodiment of the invention, the hydrochloride salt of Compound A and β-cyclodextrin (or its hydrate) are comprised, at about physiological pH, at least about 1. A clear aqueous formulation containing 2 moles (eg, 1.2 to 2 moles) of β-cyclodextrin is provided. Preferably, this molar ratio is about 1:1.4.
非経口投与、特に注射(たとえば静脈注射)による投与
に適した前記水性処方物中の化合物Aまたはその塩酸塩
の濃度は、自由塩基として換算して便宜には0.1〜1
0mg/+nI2の範囲、たとえば、0.1〜b
脈注射により投与する場合に、この濃度はis塩基換算
で1 mg/mQである。所望ならば、より高い濃度を
用い、使用に先立って、たとえば等張の食塩水またはデ
キストロースもしくはマンニト−ル溶液で処方物溶液を
稀釈してもよい。便宜には、注射に適する溶液は適当な
投与量(たとえば1〜100mfl)で供する。点滴に
適する稀釈液では、化合物Aまたはその塩酸塩の濃度は
、遊離塩基換算で0.01〜0.2mg/mlである。The concentration of Compound A or its hydrochloride in said aqueous formulation suitable for parenteral administration, in particular administration by injection (e.g. intravenous injection), is conveniently between 0.1 and 1, expressed as free base.
When administered by intravenous injection, this concentration is 1 mg/mQ in the range of 0 mg/+nI2, eg, 0.1 to b. If desired, higher concentrations may be used and the formulation solution may be diluted with, for example, isotonic saline or dextrose or mannitol solutions prior to use. Conveniently, solutions suitable for injection are presented in appropriate dosages (eg, 1-100 mfl). In a diluted solution suitable for infusion, the concentration of Compound A or its hydrochloride is 0.01 to 0.2 mg/ml in terms of free base.
連続注入用溶液は、このかたちで、たとえば、50〜1
00n+Qのパックにして供してもよいし、あるいはよ
り高い濃度のかたちにして使用前に稀釈するものとして
供してもよい。Solutions for continuous injection can be prepared in this form, e.g.
It may be provided in packs of 00n+Q, or it may be provided in a higher concentration form to be diluted before use.
稀釈には、たとえば等張の食塩水またはデキストロース
もしくはマンニトール溶液を用いる。あるいは、より高
い1度(たとえば0.1〜5 mg/mQ)の溶液をい
くらかの量、注入に、便宜には0.5ないし9.9mρ
/時の割合で投与することに用いてもよい。For dilution, for example, isotonic saline or dextrose or mannitol solutions are used. Alternatively, some amount of a higher 1 degree (e.g. 0.1-5 mg/mQ) solution can be injected, conveniently from 0.5 to 9.9 mρ.
It may also be used to administer at a rate of /hour.
ここに述べる水性処方物は、化合物A、または、より好
ましくはその塩酸塩を残りの構成成分と水中に混合する
ことにより便宜に調整できる。好ましくは、化合物Aま
たはその塩酸塩を水に溶解し。The aqueous formulations described herein can be conveniently prepared by mixing Compound A, or more preferably its hydrochloride salt, with the remaining components in water. Preferably, Compound A or its hydrochloride is dissolved in water.
これに残りの成分を加える。非経口投与、特に注射(た
とえば静脈注射)によるためには、好ましくは、小別は
前の液(bulk 5olution)を濾過して適当
な容器に充填し最後に、たとえば加熱により滅菌する。Add the remaining ingredients to this. For parenteral administration, especially by injection (eg intravenous injection), the bulk solution is preferably filtered, filled into suitable containers and finally sterilized, eg by heating.
あるいは、溶液を濾過により除菌し、ついで無菌状態で
適当な容器に充填する。Alternatively, the solution may be sterilized by filtration and then aseptically filled into suitable containers.
非経口投与処方物を静脈注射または点滴により投与すべ
き場合には、注射適合水が使用されることは了解される
であろう。It will be appreciated that if the parenterally administered formulation is to be administered by intravenous injection or infusion, water suitable for injection will be used.
注射用処方物は、アンプル、バイアルまたは事前充填注
射器のような容器に一回分ずつのかたちで、あるいは、
保存剤を加えた複数回投与用容器にいれて供することが
できる。Injectable formulations may be presented in single dose form in containers such as ampoules, vials or prefilled syringes;
It can be presented in multi-dose containers with an added preservative.
前に述べたように、本発明の水性処方物は。As previously mentioned, the aqueous formulations of the present invention.
経口役午(たとえば、カプセル、シロップまたは溶液)
にも吸入による投与(たとえばエアゾル・スプレーとし
て1便宜には噴霧器として供して)にも適している。英
国特許第2097397号および2127406号は、
本目的のため人がかりな実験法を用いなくても容易に適
用しうる経口および吸入処方物の調製のための適当な一
般的方法を提供する9
水性処方物はまた、上で定義した一種以上の他の成分と
ともに、化合物Δまたはその塩酸塩のシクロデキストリ
ン固形複合体を水に溶解して調製してもよい。Oral medicine (e.g. capsules, syrups or solutions)
It is also suitable for administration by inhalation (eg as an aerosol spray, conveniently as a nebulizer). British Patent Nos. 2097397 and 2127406 are
For this purpose, it provides a suitable general method for the preparation of oral and inhalation formulations that can be easily applied without resorting to unaided experimentation.9 Aqueous formulations may also be used for one or more of the above defined A cyclodextrin solid complex of Compound Δ or its hydrochloride salt may be dissolved in water, along with other ingredients.
このように1本発明は、化合物Aまたはその塩酸塩とシ
クロデキストリンとの複合体からなる水性処方物を提供
する。Thus, one invention provides an aqueous formulation comprising a complex of Compound A or its hydrochloride and cyclodextrin.
また、本発明は、化合物Aまたはその塩酸塩とシクロデ
キストリンの複合体を提供する。該複合体における化合
物Aまたは化合物Aの塩酸塩とシクロデキストリンとの
比は、使用するシクロデキストリンおよび複合体の製造
に用いる条件によって、もちろんかなり変化する。しか
し、化合物Aまたはその塩酸塩とシクロデキストリンと
のモル比は、1:工ないし1:3の範囲内が適すること
が見出された。The present invention also provides a complex of Compound A or its hydrochloride and cyclodextrin. The ratio of Compound A or the hydrochloride of Compound A to cyclodextrin in the complex will of course vary considerably depending on the cyclodextrin used and the conditions used to prepare the complex. However, it has been found that the molar ratio of Compound A or its hydrochloride to cyclodextrin is suitably within the range of 1:1 to 1:3.
固形複合体に用いるシクロデキストリンは、前に規定し
たような非直換または置換α−1β−もしくはγ−シク
ロデキストリンでもよいし、こうしたシフロブキス1−
リンの混合物(たとえば二種類のこうしたシクロデキス
トリンの混合物)でもよい。好ましくはγ−シクロデキ
ストリン、より好ましくはβ−シクロデキストリンを用
いる。The cyclodextrin used in the solid composite may be a non-converted or substituted α-1β- or γ-cyclodextrin as previously defined, or such a cyclodextrin
It may also be a mixture of phosphorus (eg a mixture of two such cyclodextrins). Preferably, γ-cyclodextrin is used, and β-cyclodextrin is more preferably used.
本発明は、化合物Aのβ−シクロデキストリンに対する
モル比が1:1ないし1:2の範囲内、好ましくは約1
=1である化合物Aとβ−シクロデキストリンの複合体
を提供する。The present invention provides that the molar ratio of Compound A to β-cyclodextrin is within the range of 1:1 to 1:2, preferably about 1
Provided is a complex of Compound A and β-cyclodextrin where =1.
また、本発明は特に化合物Aのγ−シクロデキストリン
に対するモル比が約1 : 1.5である化合物Aとγ
−シクロデキストリンとの複合体を提供する。Further, the present invention particularly provides compound A and γ-cyclodextrin in which the molar ratio of compound A to γ-cyclodextrin is about 1:1.5.
- providing a complex with cyclodextrin;
化合物Aまたはその塩酸塩とシクロデキストリンとの複
合体は、所望の複合体が形成される条件下、化合物Aま
たはその塩酸塩を一種類または複数のシクロデキストリ
ンまたはその水和物と適当な溶媒中に混合して製造する
ことができる。このように、たとえば、化合物Aまたは
その塩酸塩を、水または水と混和する有機溶媒(たとえ
ばメタノールのようなアルコール)に溶解し、この溶液
に。The complex of Compound A or its hydrochloride and cyclodextrin is prepared by combining Compound A or its hydrochloride with one or more cyclodextrins or hydrates thereof in a suitable solvent under conditions that form the desired complex. It can be manufactured by mixing with. Thus, for example, compound A or its hydrochloride is dissolved in water or a water-miscible organic solvent (e.g. an alcohol such as methanol) and in this solution.
一種類または複数の適当なシクロデキストリンまたはそ
の水和物を水および/または水と混和する有機溶媒に溶
かした溶液を加え、複合体を製造することができる。反
応は0℃ないし80℃の範囲の温度で行なえるが、好ま
しくは、混合物を室温付近に保ち、混合物を減圧下に濃
縮するか、あるいは混合物を冷却させて所望の複合体を
得る。有機溶媒の水との混合比は、出発原料および生成
物の溶解度により相当に変化する。好ましくは、シクロ
デキストリンまたはその塩酸塩1モルあたり。A complex can be prepared by adding a solution of one or more suitable cyclodextrins or hydrates thereof in water and/or a water-miscible organic solvent. The reaction can be carried out at temperatures ranging from 0°C to 80°C, but preferably the mixture is kept near room temperature and the mixture is concentrated under reduced pressure or allowed to cool to yield the desired conjugate. The mixing ratio of organic solvent to water varies considerably depending on the solubility of the starting materials and products. Preferably per mole of cyclodextrin or its hydrochloride.
工ないし4モルのシクロデキストリンを使用する。4 to 4 moles of cyclodextrin are used.
生成した複合体は、高い熱安定性および良好な水溶性を
備えた白色の固体として得られる。こうした物理的特徴
のため、医療用製剤に処方をするのには特に適してい°
る。化合物Aまたはその塩酸塩およびシクロデキストリ
ンからなる複合体の前記水性処方物は特に非経口投与に
適しているが、この複合体は、英国特許第209739
7号および2127406号記載の一般的方法に従い、
経口または非経口投与または吸入による投与にも処方で
きる。The resulting complex is obtained as a white solid with high thermal stability and good water solubility. These physical characteristics make it particularly suitable for formulation into medical preparations.
Ru. Said aqueous formulation of a complex consisting of compound A or its hydrochloride and cyclodextrin is particularly suitable for parenteral administration, but this complex is described in British Patent No. 209739.
According to the general method described in No. 7 and No. 2127406,
It can also be formulated for oral or parenteral administration or for administration by inhalation.
以下の実施例は本発明を例示するために述べるものであ
って1発明を限定するものではない。また、以下の例に
おいてモル比は”H−N、M、R,分析により測定し、
温度はすべて0℃である。The following examples are provided to illustrate the invention and are not intended to limit the invention. In addition, in the following examples, the molar ratio is determined by "H-N, M, R, analysis,
All temperatures were 0°C.
失庭史上
(6) 〔1R−(l α (Z)、2 β、3β、
5 a ))−(+)−7−(5−[((1,1’−ビ
フェニル)−4−イル]メトキシ〕−3−ヒドロキシ−
2−(1−ピペリジニル)シクロペンチル〕−4−へブ
テン酸:β−シクロデキストリン(1: L)複合体β
Sシクロデキストリン水和物(0,954g)を水(3
5mM)にほぼ完全に溶解した。この懸濁液を濾過し、
濾液を化合物A(0,2g)のメタノール(10mM)
溶液に加えた。反応溶液を21”Cで26時間かくはん
し、清澄溶液を得た。容積12+aDになるまで溶媒を
留去したところ微かに結晶化が起こり始めた。懸濁液を
5℃に冷却し1時間保つと濃厚な沈殿が生じた。Lost garden history (6) [1R-(l α (Z), 2 β, 3β,
5 a ))-(+)-7-(5-[((1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-
2-(1-piperidinyl)cyclopentyl]-4-hebutenoic acid: β-cyclodextrin (1: L) complex β
S cyclodextrin hydrate (0,954 g) was dissolved in water (3
5mM) was almost completely dissolved. Filter this suspension and
The filtrate was mixed with compound A (0.2g) in methanol (10mM).
added to the solution. The reaction solution was stirred at 21"C for 26 hours to obtain a clear solution. When the solvent was distilled off to a volume of 12+aD, slight crystallization began to occur. The suspension was cooled to 5°C and kept for 1 hour. A thick precipitate was formed.
これを濾別、乾燥し、標記の化合物(0,273g)を
得た。融点〉310℃、230℃以上で黒色化。This was filtered off and dried to obtain the title compound (0,273 g). Melting point: 310℃, turns black above 230℃.
(b)上の実験で得た濾液を静置するとさらに結晶状物
質が沈殿し始めた。そこで、溶媒を留去して残った白色
固体を熱?RI(3d)に溶かし、冷却(5℃)して、
白い結晶状の固体(121mg)を得た。(b) When the filtrate obtained in the above experiment was allowed to stand still, more crystalline material began to precipitate. So, when the solvent was distilled off, the remaining white solid was heated. Dissolve in RI (3d), cool (5°C),
A white crystalline solid (121 mg) was obtained.
’ +1−N、M、R,(DMSO)分析によれば、次
の物質を含む。' +1-N, M, R, (DMSO) According to analysis, it contains the following substances.
(a) 〔1R−[1a (Z)、2 β 、3β
、5 α))−(+)−7−(5−〔〔(1,1’−ビ
フェニル)−4−イル〕メトキシ〕−3−ヒドロキシ−
2−(1−ピペリジニル)シクロペンチル〕−4−ヘプ
テン酸:β−シクロデキストリン(1: 1.5)複合
体。(a) [1R-[1a (Z), 2β, 3β
, 5 α))-(+)-7-(5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-
2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid:β-cyclodextrin (1:1.5) complex.
去】01象
(a) (1計〔1α(ス)、2β、3β、5α〕〕−
(÷)−7−(5−〔〔(1,1’−ビフェニル)−4
−イル〕メトキシ〕−3−ヒドロキシ−2−(1−ピペ
リジニル)シクロペンチル〕−4−ヘプテン酸:γ−シ
クロデキストリン(1: 1,5)複合体。01 elephant (a) (1 total [1α (su), 2β, 3β, 5α]] -
(÷)-7-(5-[[(1,1'-biphenyl)-4
-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid:γ-cyclodextrin (1:1,5) complex.
γ−シクロデキストリン(1,09g)を水(25mM
)に漕力化だ溶液を、化合物A (0,20g)のメタ
ノール(10mM)溶液に加えた。反応溶液を21℃で
26時間かくはんすると濃厚な白色懸濁が生じた。沈殿
を濾別し真空乾燥すると、標記の化合物が白色固体(0
,612g) トL 1”残ツタ。融点>310’C1
250’C以Eで黒色化。γ-Cyclodextrin (1,09g) was dissolved in water (25mM
) was added to a solution of Compound A (0.20 g) in methanol (10 mM). The reaction solution was stirred at 21° C. for 26 hours, resulting in a thick white suspension. When the precipitate was filtered and dried under vacuum, the title compound was obtained as a white solid (0
, 612g) To L 1" remaining ivy. Melting point >310'C1
Turns black from 250'C to E.
塩
β−シクロデキストリン水和物 143mg 166m
g 238mg水酸化ナトリウム溶液 pH7
に調整する必要量注射適合水 全量
50mNにする必要量化合物A塩酸塩を35mflの注
射適合水に溶がし、β−シクロデキストリンを加えた。Salt β-cyclodextrin hydrate 143mg 166m
g 238mg sodium hydroxide solution pH7
Required amount of water suitable for injection to make a total volume of 50 mN Compound A hydrochloride was dissolved in 35 mfl of water suitable for injection, and β-cyclodextrin was added.
0.02M水酸化す1−リウム溶液を滴下して溶液をp
H7に調整し、注射適合水を加えて全量を調整した。Add 0.02M sodium hydroxide solution dropwise to reduce the solution to p.
The total volume was adjusted to H7 and injection compatible water was added.
溶液は、この後、濾過により除菌し、バイアルまたはア
ンプルに充填してもよい。The solution may then be sterilized by filtration and filled into vials or ampoules.
(M) 50naHの塩基と当量関係にある化合物A液
酸塩
β−シクロデキストリン水和物 166mg塩化ナトリ
ウム 450mgp)17.0リン酸塩
緩衝液 2.5m12水酸化すl・リウム溶
液 p117に調整する必要量注射適合水
全量50mQにする必要量化合物Aの
塩酸塩を約25mΩの注射適合水に溶解した。これにβ
−シクロデキストリンを溶解し、得られた溶液に0.0
2M水酸化ナトリウム溶液を滴下してp116とし、リ
ン酸塩緩衝液を加えた。注射適合水で全量を整えた。こ
の溶液の試料をガラス製バイアルに充填し、ゴム栓と金
属製オーバーシールで密封した。この後、これをオート
クレープで滅菌した。(M) Compound A liquid salt β-cyclodextrin hydrate having an equivalent relationship with a base of 50 naH 166 mg Sodium chloride 450 mg p) 17.0 Phosphate buffer 2.5 ml 12 Solutonium hydroxide solution Adjust to p117 Required amount of water suitable for injection
The required amount of Compound A hydrochloride to make a total volume of 50 mQ was dissolved in approximately 25 mΩ injection compatible water. β to this
-Dissolve the cyclodextrin and add 0.0
2M sodium hydroxide solution was added dropwise to p116 and phosphate buffer was added. The entire volume was made up with injection-compatible water. Samples of this solution were filled into glass vials and sealed with rubber stoppers and metal overseals. Thereafter, it was sterilized by autoclaving.
(ff) 50mgの塩基と当量関係にある化合物A塩
酸塩
ヒドロキシプロピル−β−ジシクロデキストリン1フ0
マンニトール 2.5gpH6、0リ
ン酸塩緩衝液 5.0mΩ水酸化ナトリウム溶
液 pH6.0に調整する必要量注射適合水
全量50mQにする必要量化合物A
の塩酸塩を約25社の注射適合水に溶解し、これにヒド
ロキシプロピル−β−シクロデキストリンを加えた。こ
の後マンニトールを加え、0、02M水酸化ナトリウム
溶液を滴下してP116とした。(ff) Compound A hydrochloride hydroxypropyl-β-dicyclodextrin 1 F0 in equivalent relationship with 50 mg of base
Mannitol 2.5 g pH 6,0 phosphate buffer 5.0 mΩ Sodium hydroxide solution Required amount to adjust to pH 6.0 Water suitable for injection
Required amount of compound A to make the total amount 50mQ
hydrochloride was dissolved in approximately 25 injection compatible water and hydroxypropyl-β-cyclodextrin was added thereto. After this, mannitol was added and 0.02M sodium hydroxide solution was added dropwise to obtain P116.
リン酸塩緩衝溶液を加え、注射適合水で全量を調整した
。ついで、この溶液を濾過し、ガラス製バイアルに充填
し、ゴム栓と金属製オーバーシールで密封した。ついで
、これをオートクレープで滅菌した。Phosphate buffer solution was added and the total volume was made up with injection compatible water. The solution was then filtered, filled into glass vials, and sealed with rubber stoppers and metal overseals. This was then sterilized using an autoclave.
(〜) 5 0 m gの塩基と当量関係にある化合物
Aの塩酸塩
β−シクロデキストリン水和物 1 66mgマンニト
ール 2 、 5mg酸性リン酸ナ
トリウム 46mgリン酸二ナトリウム無水塩
5mg水酸化ナトリウム溶液 pH6
に調整する必要量注射適合水 全量
50mQにする必要量化合物Aの塩酸塩を約25nnQ
の注射適合水に溶解した。これにβ−シクロデキストリ
ンおよびマンニトールを溶かし、0.02M水酸化ナト
リウム溶液を滴下してPl(6とした。酸性リン酸ナト
リウムおよびリン酸二ナトリウム無水塩を注射適合水に
溶解し、この溶液を先の原液に加え、注射適合水で全量
を整えた。この溶液を濾過し、ガラス製バイアルに充填
し、密封後、オートクレープで滅菌した。(~) 5 0 mg Hydrochloride of Compound A in equivalent relationship with the base β-cyclodextrin hydrate 1 66 mg Mannitol 2 , 5 mg Sodium acid phosphate 46 mg Disodium phosphate anhydrous 5 mg Sodium hydroxide solution pH 6
The required amount of water suitable for injection is adjusted to make the total volume 50 mQ.
injection-compatible water. β-Cyclodextrin and mannitol were dissolved in this, and 0.02M sodium hydroxide solution was added dropwise to give Pl (6). In addition to the above stock solution, the total volume was made up with water suitable for injection.The solution was filtered, filled into glass vials, sealed, and sterilized by autoclaving.
(1) シクロデキストリンα 工
1ムL蕗企立
L 、L
シクロデキストリン、mg
マンニトール、g
pH6、0リン酸塩緩衝液, mQ
143 190 119 13G2、5
2.5 2.5
5、0 5.0 5.0
水酸化ナトリウム溶液 pH6に調整する必要量注
射適合水 全量50dにする必要量化合
物A塩酸塩を約25mflの注射適合水に溶かし、シク
ロデキストリンを加えた。ついで、マンニトールを加え
、0.02M水酸化ナトリウム溶液を滴下しp)16に
調整した。リン酸塩緩衝溶液を加え、注射適合水で全量
を整えた。ついで溶液を濾過し、ガラス製バイアルに充
填し、ゴム栓と金属製オーバーシールで密封した。(1) Cyclodextrin α 1ml L Cyclodextrin, mg Mannitol, g pH 6, 0 phosphate buffer, mQ 143 190 119 13G2, 5
2.5 2.5 5,0 5.0 5.0 Sodium hydroxide solution Required amount of water suitable for injection to adjust pH to 6 Required amount to make a total volume of 50 d Dissolve Compound A hydrochloride in approximately 25 mfl of water suitable for injection, add cyclodextrin added. Then, mannitol was added, and 0.02M sodium hydroxide solution was added dropwise to adjust to p) 16. Phosphate buffer solution was added and made up to volume with injection compatible water. The solution was then filtered, filled into glass vials, and sealed with rubber stoppers and metal overseals.
経口 シロップ」 ■し乞凱
2、5mgの塩基と当量関係にある化合物A塩酸塩βー
シクロデキストリン水和物 91■クエン酸
pH4.5に調整する必
梨量メチルヒドロキシ安息香酸ナトリウム 5+ngプ
ロピルヒドロキシ安息香酸ナトリウ 2+ng液体オレ
ンジ香料 qsシヨ糖
3.25g純水
全量5.0成にする必要量ショ糖を必要最
低限の水に溶かす。化合物への塩酸塩を、ついでβ−シ
クロデキストリンをかくはんしながら加える。クエン酸
でUll4.5に調整する。かくはんを続けながらヒド
ロキシ安息香酸塩の溶液を、そして最後に香料を加える
。水を加えてほぼ全量5 、0+aQに調整し、さらに
がくはんする。Oral syrup" Compound A hydrochloride β-cyclodextrin hydrate 91 ■ Citric acid in equivalent relationship with 2.5 mg of base
Required amount to adjust to pH 4.5 Sodium methyl hydroxybenzoate 5 + ng Sodium propyl hydroxybenzoate 2 + ng Liquid orange flavor qs Cane sugar
3.25g pure water
Dissolve the required amount of sucrose in the minimum amount of water to make the total amount 5.0. The hydrochloride salt of the compound is then added with stirring to the β-cyclodextrin. Adjust to Ull4.5 with citric acid. While continuing to stir, add the hydroxybenzoate solution and finally the flavor. Add water to adjust almost the total volume to 5.0+aQ, and stir further.
pHを検査し、必要ならばクエン酸で4.5に調整する
。水で全量5.OmQにする。Check the pH and adjust to 4.5 with citric acid if necessary. Total amount 5. with water. Make it OmQ.
1人゛ の
2〜&の1回投薬分につき
β−シクロデキストリン水和物 7mg塩化ナトリウム
18B水酸化ナトリウム溶液
pH7,2に調整する必要量pH7,2リン酸塩緩衝液
0.2mM注射適合水 全
量を2mgにする必要量化合物Aの塩酸塩を注射適合水
に溶解する。Beta-Cyclodextrin Hydrate 7mg Sodium Chloride 18B Sodium Hydroxide Solution per 2 to 1 person dosage
Required amount to adjust pH to 7.2 pH 7.2 Phosphate buffer 0.2mM Injection-compatible water Required amount to bring total volume to 2 mg Dissolve Compound A hydrochloride in Injection-compatible water.
これにβ−シクロデキストリンを溶解し、水酸化ナトリ
ウム溶液で得られた溶液をPl(6に滴定する。リン酸
塩緩衝溶液を加える。食塩を加え、水酸化ナトリウム溶
液でpH7,2に調整する。溶液を注射適合水で全量に
整え、濾過により除菌する。Dissolve β-cyclodextrin in this and titrate the resulting solution with sodium hydroxide solution to PI (6). Add phosphate buffer solution. Add common salt and adjust the pH to 7.2 with sodium hydroxide solution. Make up the solution with injection-compatible water and sterilize by filtration.
噴霧による吸入に適する容器に無菌状態で充填する。Fill aseptically into containers suitable for inhalation by nebulization.
ム4焦」Ull
本発明組成物の血小板凝集限外性能を、ヒトの全血を用
い、Lum1eyとllumpheryの方法(J 、
Pharma−col、 Methods、 198
1.6.153−166)で実験・証明した。凝集促進
剤(pro−aggregatory agent)と
しては、 U−46619を使用した。ヒト全血の各試
料についてU−46619を濃度−効果曲線を求め、試
験組成物の存在下での該曲線の右方変位量を評定した。The ultra-platelet aggregation performance of the composition of the present invention was evaluated using the method of Lumley and Illumpery (J.
Pharma-col, Methods, 198
1.6.153-166) was experimented and proven. U-46619 was used as a pro-aggregation agent. A concentration-effect curve of U-46619 was determined for each sample of human whole blood, and the amount of rightward shift of the curve in the presence of the test composition was evaluated.
Arunlakshanaと5childの方法(Br
、J、Pharmacol、14゜48−58(195
9))によりこれらのデータを分析し、試験組成物の平
均PAz値を出した。実施例に述べた上記実験組成物で
は、8.0〜&、3の範囲のPAz値を有する。Arunlakshana and the 5child method (Br
, J. Pharmacol, 14°48-58 (195
These data were analyzed according to 9)) to give the average PAz value for the test compositions. The experimental compositions described in the Examples have PAz values ranging from 8.0 to &3.
産血
本発明の組成物は、治療有用投与量では無毒である。た
とえば、実施例の組成物を10mg/kgの投与量で犬
に処方した場合、いずれも、有意な悪影響は何ら生じな
かった。The compositions of the present invention are non-toxic at therapeutically useful doses. For example, when the compositions of the Examples were prescribed to dogs at a dose of 10 mg/kg, no significant adverse effects occurred.
Claims (1)
デキストリンまたはこれらの水和物と〔1¥R¥−〔1
α(¥Z¥),2β,3β,5α〕〕−(+)−7−〔
5−〔〔(1,1′−ビフェニル)−4−イル〕メトキ
シ〕−3−ヒドロキシ−2−(1−ピペリジニル)シク
ロペンチル〕−4−ヘプテン酸(化合物A)またはその
塩酸塩からなる水性処方物。 2、請求項第1項の処方物であって化合物Aの塩酸塩を
用いるもの。 3、請求項第1項または第2項の処方物であって、シク
ロデキストリンがβ−シクロデキストリンであるもの。 4、請求項1ないし3のいずれかの項の処方物であって
注射に適したかたちであるもの。5、請求項第4項の処
方物であって、ほぼ生理的pHにおいて、化合物Aの塩
酸塩およびβ−シクロデキストリンまたはその水和物か
らなり、化合物A1モルあたり少なくとも約1.2モル
のβ−シクロデキストリンを含む清澄な水性処方物。 6、請求項第5項の処方物であって、化合物Aの塩酸塩
のβ−シクロデキストリンに対するモル比が約1:1.
4であるもの。 7、請求項第4〜6項のいずれかの項の処方物であって
、pHが約6.0であるもの。 8、請求項第4〜7項のいずれかの項の処方物であって
、さらに水酸化ナトリウムからなるもの。 9、請求項第4〜8項のいずれかの項の処方物であって
、化合物Aまたはその塩酸塩の濃度が、遊離塩基換算で
0.1〜5mg/mlであるもの。 10、請求項第4〜8項のいずれかの項の処方物であっ
て、点滴に適したかたちをしており、化合物Aまたはそ
の塩酸塩の濃度が、遊離塩基換算で0.01〜0.2m
g/mlであるもの。 11、先行する請求項のいずれかの項の処方物の製法で
あって、化合物Aまたはその塩酸塩を残りの構成成分と
ともに水に混ぜることからなるもの。 12、化合物Aまたはその塩酸塩と非置換または置換α
−、β−、もしくはγ−シクロデキストリンとの複合体
。 13、化合物Aのβ−シクロデキストリンに対するモル
比が約1:1である化合物Aとβ−シクロデキストリン
との複合体。[Claims] 1. Unsubstituted or substituted α-, β- or γ-cyclodextrin or a hydrate thereof and [1\R\-[1
α(¥Z¥), 2β, 3β, 5α]]-(+)-7-[
Aqueous formulation consisting of 5-[[(1,1′-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (compound A) or its hydrochloride thing. 2. The formulation according to claim 1, which uses the hydrochloride of compound A. 3. The formulation according to claim 1 or 2, wherein the cyclodextrin is β-cyclodextrin. 4. The formulation according to any one of claims 1 to 3, which is in a form suitable for injection. 5. The formulation of claim 4, comprising the hydrochloride salt of Compound A and β-cyclodextrin or a hydrate thereof, at about physiological pH, at least about 1.2 moles of β per mole of Compound A. - A clear aqueous formulation containing cyclodextrin. 6. The formulation of claim 5, wherein the molar ratio of the hydrochloride of Compound A to β-cyclodextrin is about 1:1.
Something that is 4. 7. The formulation according to any one of claims 4 to 6, having a pH of about 6.0. 8. The formulation according to any one of claims 4 to 7, further comprising sodium hydroxide. 9. The formulation according to any one of claims 4 to 8, wherein the concentration of compound A or its hydrochloride is 0.1 to 5 mg/ml in terms of free base. 10. The formulation according to any one of claims 4 to 8, which is in a form suitable for infusion, and has a concentration of compound A or its hydrochloride of 0.01 to 0 in terms of free base. .2m
g/ml. 11. A process for preparing a formulation according to any of the preceding claims, comprising mixing Compound A or its hydrochloride salt with the remaining components in water. 12. Compound A or its hydrochloride and unsubstituted or substituted α
-, β-, or γ-cyclodextrin. 13. A complex of compound A and β-cyclodextrin, wherein the molar ratio of compound A to β-cyclodextrin is about 1:1.
Applications Claiming Priority (4)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
GB8729823 | 1987-12-22 | ||
GB878729823A GB8729823D0 (en) | 1987-12-22 | 1987-12-22 | Complexes |
GB8804422 | 1988-02-25 | ||
GB888804422A GB8804422D0 (en) | 1988-02-25 | 1988-02-25 | Complexes |
Publications (1)
Publication Number | Publication Date |
---|---|
JPH02210A true JPH02210A (en) | 1990-01-05 |
Family
ID=26293226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
JP63320759A Pending JPH02210A (en) | 1987-12-22 | 1988-12-21 | Aqueous recipe containing pyperidinylcyclopentylpentenic acid derivative |
Country Status (29)
Country | Link |
---|---|
JP (1) | JPH02210A (en) |
KR (1) | KR890009402A (en) |
CN (1) | CN1034132A (en) |
AT (1) | AT395943B (en) |
AU (1) | AU615245B2 (en) |
BE (1) | BE1001704A3 (en) |
CA (1) | CA1328078C (en) |
CH (1) | CH676665A5 (en) |
DE (1) | DE3843059A1 (en) |
DK (1) | DK712888A (en) |
ES (1) | ES2011727A6 (en) |
FI (1) | FI885920A (en) |
FR (1) | FR2624731B1 (en) |
GB (1) | GB2211737B (en) |
GR (1) | GR880100854A (en) |
HU (1) | HU204700B (en) |
IE (1) | IE61995B1 (en) |
IL (1) | IL88764A0 (en) |
IT (1) | IT1224835B (en) |
LU (1) | LU87411A1 (en) |
MY (1) | MY103952A (en) |
NL (1) | NL8803126A (en) |
NO (1) | NO885689L (en) |
NZ (1) | NZ227446A (en) |
PH (1) | PH24982A (en) |
PL (1) | PL276595A1 (en) |
PT (1) | PT89301B (en) |
SE (1) | SE502288C2 (en) |
ZW (1) | ZW18088A1 (en) |
Cited By (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100825736B1 (en) * | 2005-12-07 | 2008-04-29 | 한국전자통신연구원 | Apparatus for providing XML signnature in mobile environment and method thereof |
KR100832740B1 (en) * | 2007-01-17 | 2008-05-27 | 한국과학기술원 | Mutant microorganism with improved productivity of branched amino acid and method for preparing it using the same |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
GB8814725D0 (en) * | 1988-06-21 | 1988-07-27 | Glaxo Group Ltd | Medicaments |
AU616571B2 (en) * | 1988-10-28 | 1991-10-31 | Shiseido Company Ltd. | Cosmetic composition containing inclusion product with hydroxyalkylated cyclodextrin |
IT1269578B (en) * | 1994-04-22 | 1997-04-08 | Chiesi Farma Spa | MULTI-COMPONENT INCLUSION COMPLEXES WITH HIGH SOLUBILITY CONSISTING OF AN ACID TYPE DRUG, A CYCLODESTRINE AND A BASE. |
Citations (5)
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JPS574914A (en) * | 1980-05-09 | 1982-01-11 | Chinoin Gyogyszer Es Vegyeszet | Manufacture of aqueous solution of water- insoluble or water-hard-soluble compound |
JPS58116423A (en) * | 1981-12-28 | 1983-07-11 | Sumitomo Chem Co Ltd | Methanoprostacycline pharmaceutical composition |
JPS5946228A (en) * | 1982-09-08 | 1984-03-15 | Zeria Shinyaku Kogyo Kk | Preparation of water-soluble and lymph-transitional drug containing biologically active organic compound |
JPS5973576A (en) * | 1982-09-16 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Piperidinylcyclopentanolheptanoate |
JPS6327440A (en) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | Glucosylated branched cyclodextrin-containing composition |
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Publication number | Priority date | Publication date | Assignee | Title |
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JPS503362B1 (en) * | 1970-06-10 | 1975-02-04 | ||
JPS5443569B2 (en) * | 1972-07-05 | 1979-12-20 | ||
JPS57183772A (en) * | 1981-04-29 | 1982-11-12 | Glaxo Group Ltd | Aminocyclopentanol acids and esters, manufacture and medicinal composition |
JPS58192821A (en) * | 1982-04-30 | 1983-11-10 | Dainippon Pharmaceut Co Ltd | Remedy for anoxia of cranial nerve cells |
GB2127406B (en) * | 1982-09-16 | 1986-03-05 | Glaxo Group Ltd | Piperidinlycyclopentanolheptenoic acid salt |
DE3346123A1 (en) * | 1983-12-21 | 1985-06-27 | Janssen Pharmaceutica, N.V., Beerse | PHARMACEUTICAL PREPARATIONS OF SUBSTANCES MEDICAL OR UNSTABLE IN WATER AND METHOD FOR THE PRODUCTION THEREOF |
JPS60150039A (en) * | 1984-01-17 | 1985-08-07 | Minolta Camera Co Ltd | Amphibious fixed-focus camera |
DE3504044A1 (en) * | 1985-02-04 | 1986-08-07 | Schering AG, Berlin und Bergkamen, 1000 Berlin | 9-HALOGEN PROSTAGLANDIN CLATHRATE AND THEIR USE AS A MEDICINAL PRODUCT |
-
1988
- 1988-12-21 PH PH37963A patent/PH24982A/en unknown
- 1988-12-21 NZ NZ227446A patent/NZ227446A/en unknown
- 1988-12-21 NO NO88885689A patent/NO885689L/en unknown
- 1988-12-21 IE IE382088A patent/IE61995B1/en not_active IP Right Cessation
- 1988-12-21 AT AT0313088A patent/AT395943B/en not_active IP Right Cessation
- 1988-12-21 LU LU87411A patent/LU87411A1/en unknown
- 1988-12-21 AU AU27356/88A patent/AU615245B2/en not_active Ceased
- 1988-12-21 HU HU886537A patent/HU204700B/en not_active IP Right Cessation
- 1988-12-21 CA CA000586606A patent/CA1328078C/en not_active Expired - Fee Related
- 1988-12-21 PL PL27659588A patent/PL276595A1/en unknown
- 1988-12-21 GR GR880100854A patent/GR880100854A/en unknown
- 1988-12-21 BE BE8801423A patent/BE1001704A3/en not_active IP Right Cessation
- 1988-12-21 SE SE8804607A patent/SE502288C2/en not_active IP Right Cessation
- 1988-12-21 FI FI885920A patent/FI885920A/en not_active Application Discontinuation
- 1988-12-21 IT IT8848702A patent/IT1224835B/en active
- 1988-12-21 PT PT89301A patent/PT89301B/en not_active IP Right Cessation
- 1988-12-21 JP JP63320759A patent/JPH02210A/en active Pending
- 1988-12-21 DK DK712888A patent/DK712888A/en not_active Application Discontinuation
- 1988-12-21 DE DE3843059A patent/DE3843059A1/en not_active Ceased
- 1988-12-21 FR FR8816902A patent/FR2624731B1/en not_active Expired - Fee Related
- 1988-12-21 CH CH4758/88A patent/CH676665A5/de not_active IP Right Cessation
- 1988-12-21 ES ES8803876A patent/ES2011727A6/en not_active Expired - Fee Related
- 1988-12-21 NL NL8803126A patent/NL8803126A/en not_active Application Discontinuation
- 1988-12-21 CN CN88108916A patent/CN1034132A/en active Pending
- 1988-12-21 KR KR1019880017106A patent/KR890009402A/en not_active Application Discontinuation
- 1988-12-21 ZW ZW180/88A patent/ZW18088A1/en unknown
- 1988-12-21 GB GB8829793A patent/GB2211737B/en not_active Expired - Fee Related
- 1988-12-22 IL IL88764A patent/IL88764A0/en not_active IP Right Cessation
- 1988-12-22 MY MYPI88001508A patent/MY103952A/en unknown
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JPS574914A (en) * | 1980-05-09 | 1982-01-11 | Chinoin Gyogyszer Es Vegyeszet | Manufacture of aqueous solution of water- insoluble or water-hard-soluble compound |
JPS58116423A (en) * | 1981-12-28 | 1983-07-11 | Sumitomo Chem Co Ltd | Methanoprostacycline pharmaceutical composition |
JPS5946228A (en) * | 1982-09-08 | 1984-03-15 | Zeria Shinyaku Kogyo Kk | Preparation of water-soluble and lymph-transitional drug containing biologically active organic compound |
JPS5973576A (en) * | 1982-09-16 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Piperidinylcyclopentanolheptanoate |
JPS6327440A (en) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | Glucosylated branched cyclodextrin-containing composition |
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KR100825736B1 (en) * | 2005-12-07 | 2008-04-29 | 한국전자통신연구원 | Apparatus for providing XML signnature in mobile environment and method thereof |
KR100832740B1 (en) * | 2007-01-17 | 2008-05-27 | 한국과학기술원 | Mutant microorganism with improved productivity of branched amino acid and method for preparing it using the same |
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