CA1328078C - Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative - Google Patents
Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivativeInfo
- Publication number
- CA1328078C CA1328078C CA000586606A CA586606A CA1328078C CA 1328078 C CA1328078 C CA 1328078C CA 000586606 A CA000586606 A CA 000586606A CA 586606 A CA586606 A CA 586606A CA 1328078 C CA1328078 C CA 1328078C
- Authority
- CA
- Canada
- Prior art keywords
- compound
- cyclodextrin
- beta
- hydrochloride salt
- formulation
- 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.)
- Expired - Fee Related
Links
- 239000013011 aqueous formulation Substances 0.000 title claims abstract description 19
- JAIYKLJZOBJGSG-UHFFFAOYSA-N 2-cyclopentyl-3-piperidin-1-ylhept-2-enoic acid Chemical class C1CCCC1C(C(O)=O)=C(CCCC)N1CCCCC1 JAIYKLJZOBJGSG-UHFFFAOYSA-N 0.000 title abstract description 3
- 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 abstract description 39
- 238000002347 injection Methods 0.000 claims abstract description 15
- 239000007924 injection Substances 0.000 claims abstract description 15
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical class 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 11
- 238000002360 preparation method Methods 0.000 claims abstract description 7
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 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
- 235000010290 biphenyl Nutrition 0.000 claims abstract description 5
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims abstract description 5
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical class 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 3
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical class 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 3
- 229940126062 Compound A Drugs 0.000 claims description 65
- 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 65
- 229920000858 Cyclodextrin Polymers 0.000 claims description 56
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 32
- 239000000203 mixture Substances 0.000 claims description 31
- 238000009472 formulation Methods 0.000 claims description 24
- 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 24
- 238000001802 infusion Methods 0.000 claims description 6
- 238000000034 method Methods 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 239000012458 free base Substances 0.000 claims description 2
- 230000008569 process Effects 0.000 claims description 2
- 238000011282 treatment Methods 0.000 abstract description 5
- 230000001404 mediated effect Effects 0.000 abstract description 4
- 239000006188 syrup Substances 0.000 abstract description 3
- 235000020357 syrup Nutrition 0.000 abstract description 3
- 239000002775 capsule Substances 0.000 abstract description 2
- 239000000243 solution Substances 0.000 description 52
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 13
- 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
- -1 substituted - Chemical class 0.000 description 8
- 229940097362 cyclodextrins Drugs 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- 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 5
- 229930195725 Mannitol Natural products 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 5
- 239000000594 mannitol Substances 0.000 description 5
- 235000010355 mannitol Nutrition 0.000 description 5
- 239000007787 solid Substances 0.000 description 5
- 239000002585 base Substances 0.000 description 4
- 239000008363 phosphate buffer Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 239000011780 sodium chloride Substances 0.000 description 4
- 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
- 239000000872 buffer Substances 0.000 description 3
- 239000008121 dextrose Substances 0.000 description 3
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 3
- 238000001990 intravenous administration Methods 0.000 description 3
- 229910052751 metal Inorganic materials 0.000 description 3
- 239000002184 metal Substances 0.000 description 3
- 238000007911 parenteral administration Methods 0.000 description 3
- 235000019980 sodium acid phosphate Nutrition 0.000 description 3
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 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 2
- 239000008364 bulk solution Substances 0.000 description 2
- 150000001875 compounds Chemical class 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 0.000 description 2
- 201000010099 disease Diseases 0.000 description 2
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 2
- 229910000397 disodium phosphate Inorganic materials 0.000 description 2
- 235000019800 disodium phosphate Nutrition 0.000 description 2
- 238000001914 filtration Methods 0.000 description 2
- 239000011521 glass Substances 0.000 description 2
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000003756 stirring Methods 0.000 description 2
- 239000000725 suspension Substances 0.000 description 2
- 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 2
- LJIOTBMDLVHTBO-CUYJMHBOSA-N (2s)-2-amino-n-[(1r,2r)-1-cyano-2-[4-[4-(4-methylpiperazin-1-yl)sulfonylphenyl]phenyl]cyclopropyl]butanamide Chemical compound CC[C@H](N)C(=O)N[C@]1(C#N)C[C@@H]1C1=CC=C(C=2C=CC(=CC=2)S(=O)(=O)N2CCN(C)CC2)C=C1 LJIOTBMDLVHTBO-CUYJMHBOSA-N 0.000 description 1
- 206010002383 Angina Pectoris Diseases 0.000 description 1
- 201000001320 Atherosclerosis Diseases 0.000 description 1
- 101150058765 BACE1 gene Proteins 0.000 description 1
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 1
- 241001440267 Cyclodes Species 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
- 206010061216 Infarction Diseases 0.000 description 1
- 241001465754 Metazoa Species 0.000 description 1
- 229910019142 PO4 Inorganic materials 0.000 description 1
- 208000008469 Peptic Ulcer Diseases 0.000 description 1
- 208000018262 Peripheral vascular disease Diseases 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
- 241000700159 Rattus Species 0.000 description 1
- 208000017442 Retinal disease Diseases 0.000 description 1
- 206010038923 Retinopathy Diseases 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- NINIDFKCEFEMDL-UHFFFAOYSA-N Sulfur Chemical compound [S] NINIDFKCEFEMDL-UHFFFAOYSA-N 0.000 description 1
- 239000005864 Sulphur Substances 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000000443 aerosol Substances 0.000 description 1
- 150000008044 alkali metal hydroxides Chemical class 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- 210000001367 artery Anatomy 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000004305 biphenyl Substances 0.000 description 1
- 239000007853 buffer solution Substances 0.000 description 1
- 239000006172 buffering agent Substances 0.000 description 1
- 230000000747 cardiac effect Effects 0.000 description 1
- 239000000969 carrier Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 0.000 description 1
- 230000002844 continuous effect Effects 0.000 description 1
- 210000004351 coronary vessel Anatomy 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical class NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 230000000694 effects Effects 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
- 238000007429 general method Methods 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 208000010125 myocardial infarction Diseases 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000001175 peptic effect Effects 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000010452 phosphate Substances 0.000 description 1
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 description 1
- 210000002381 plasma Anatomy 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
- 239000002244 precipitate Substances 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- JWYIRZRIDBKTPH-UHFFFAOYSA-N propyl 2-hydroxybenzoate;sodium Chemical compound [Na].CCCOC(=O)C1=CC=CC=C1O JWYIRZRIDBKTPH-UHFFFAOYSA-N 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- 150000003839 salts Chemical class 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 239000005720 sucrose Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 238000002054 transplantation Methods 0.000 description 1
- 208000019553 vascular disease Diseases 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
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
- C08B37/0015—Inclusion compounds, i.e. host-guest compounds, e.g. polyrotaxanes
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Organic Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Molecular Biology (AREA)
- Animal Behavior & Ethology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nanotechnology (AREA)
- Epidemiology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Medical Informatics (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (AREA)
- Biophysics (AREA)
- Biotechnology (AREA)
- General Engineering & Computer Science (AREA)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Pulmonology (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Hydrogenated Pyridines (AREA)
- Plural Heterocyclic Compounds (AREA)
Abstract
ABSTRACT
AQUEOUS FORMULATIONS CONTAINING A
PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE
Aqueous formulations comprising [1R-[1.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid or its hydrochloride salt and an unsubstituted or substituted .alpha.-, .beta.- or .gamma.- cyclodextrin have been found which are particularly useful in the treatment or prophylexis of conditions mediated by thromboxene A2. Suitable aqueous formulations include injections, oral preparations such as syrups and capsules and inhalation preparations.
AQUEOUS FORMULATIONS CONTAINING A
PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE
Aqueous formulations comprising [1R-[1.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid or its hydrochloride salt and an unsubstituted or substituted .alpha.-, .beta.- or .gamma.- cyclodextrin have been found which are particularly useful in the treatment or prophylexis of conditions mediated by thromboxene A2. Suitable aqueous formulations include injections, oral preparations such as syrups and capsules and inhalation preparations.
Description
AQUEOUS FORMULATIONS CONTAINING A
PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE
This invention relate~ to aqueous formulation~ cont~ining as active ingredient rlR-[la(Z),2~,3~,5a]]-(l)-7-[5-[[(1,1'-biphenyl~-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (hereinafter referred to as 'Compound A'), to processe~ for their preparation and to their u~e in medicine.
Compound A i8 described in our British ~atent No. 2097397 as one of a group of aminocyclopentane derivatives ~aving endoperoxide and thromboxane antagonist activity, and it is reported therein that such compounds are of interest in the treatment of asthma and cardiovssdular diaeases. More recently, we discovered thst the hydrochloride salt of Compound A has edvantages over Compound A and other sfllts and solvates thereof both in its preparation and iQ its use in medicine. The hydrochloride salt is described in our British Patent No. 2127406.
Compound A ia ùnfortunately only sparingly soluble in water and formulations in water contsining the hydrochloride salt of Compound A
together with standard ex¢ipients and/or carriers have proved to be unacceptable for intravenous ~dministrstion a8 the hydrochloride salt of Compound A is converted to the virtually insoluble Compound A at near to physiological pH.
Wo have now found that the aolubility in water of Compound A or its hydrochloride salt st around physiologicsl pH is significantly improved in the pr~sence of an unsubstituted or substituted a~ or r-cyclodextrin (or a hydrate thereof). We have also found that aqusous formulations comprising Compound A or the hydrochloride salt thereof and an unsubstituted or substituted a-, ~- or y-cyclodextrin (or Q hydrate thereof) are suitable for use in medicine, more particularly for use in the treatment or prophylaxis of conditions mediated by thromboxsne A2, when administered either orally, by inhalstion or parenterally, in particular by injection (eg intravenously).
'.
- ' -Thu~, according to one aspect of the present invention, we provide an aqueou~ formuletion comprising Compound A or the hydrochloride sslt thereof with an unsubstituted or substituted -, ~-, or y-cyclodextrin (or a hydrate thereo~).
In another aspect of the invention, we provide an aqueous formulation as definod herein for u~e in medicine, more particularly for use in the treatment or prophylaxis of conditiona mediated by thromboxane A2.
According to anothsr aspect of the invention, we provide a method of tresting conditions mediated by thromboxane A2 which method comprise administering to the human or animal patient an effective amount of Compound A in an aqueous formulstion as defined herein.
Suitable conditions which msy be treated with aqueous formulations of the present invention include those conditions described in British Patents Nos. 2097397 and 2127406~treated using other (e.g. orel) formulation~ of Compound A and the hydrochloride salt of Compound A respectively. In particular, the aqueous formulations of the present invention may be used in the treatment or prophylaxis of occlusive vascular disease, including myocardial infarction, ¢ardiac fatalities, unstsble angina, transient i~chaemic attacks and cerebrsl infarction, atherosclerosis and vessel w811 disease, peripheral vascular disease, retinopathy, postoperative thrombosis and pulmonary embolism. The aqueous formulations msy also be us0d in the prophylaxis of peri- and postoperative complications following organ transplantation ~pQrticularly cardiac and renal), coronary artery bypass, peripheral artery bypass and thrombolysis.
The aqueous formulations are also of potential use in connection with peptic ulcei disease, more particularly for the prevention of relapse of healed peptic ulcers.
32807~
Preferably, in the aqueous formulat~ons of the present invention Compound A i9 used as its hydrochloride salt.
It will be appreciated by those skilled in the art that the benefits of the present invention may be achieved by utilising more th~n one cyclodextrin, ~lthough the use of a single cyclodextrin i8 generally preferred.
Where a substituted cyclodextrin is employed any suitable substituted cyclodextrin known in the art may be used according to the present invention. Suitable substituted cyclodextrins for use lo a~cording to the present invention will be resdily appreciated by peraons skilled in the art and will include sulphur-containing cyclodextrins, nitrogen-containing cyclodextrins, alkylQted (e.g.
methylated) cyclodextrins such as mono-, di- or trimethylated derivatives o~ a cyclodextrin (e.g. of ~q-cyclodextrin) and hydroxyalkyl (e.g. hydroxypropyl) cyclode~trins such as hydroxypropyl ,B-cyclodextrin and acylated derivatives thereof. Hydroxyalkyl (e.g.
hydroxypropyl) cyclodextrins such 88 hydroxypropyl ~cyclodextrin hsve been found to be psrticulsrly suitable for use according to the present invention.
Conveniently a single unsubstituted cyclodextrin i~ employed according to the present invention. Psrticulsrly preferred is ,B-cyslodextrin, conveniently used in its hydrsted form.
In order for the squeous formulation to exhibit the desired properties it is important that the correct molar ratio of Compound A
or its hydrochloride salt to the cyclodextrin(s) is used. We have found a molar r~tio of Compound A or its hydrochloride salt to the cyclodextrin(s) within the range 1:1 to 1:4 to be suitable.
It wili be spprecisted by persons skilled in the art that the squeoua formulstions of the pr~sent invention may, if desired, Qlso contsin one or more phsrmaceut~ical carIiers or excipients.
Suitable excipients which may be incorporated into the aqueous formulation include agents to make the preparation isotonic with blood plasma (e.g. ~odium chloride, dextrose or prefersbly mannitol) and buffering agents (e.g. phosphQte buffer or a mixture of sodium acid phosphate and disodium phosphate).
.,','. :' ` ' -:.
'., The aqueou~ formulQtions of the present invention are particularly suitable for parenteral adminiatration in particular by injection (eg intravenously). When presented for parenteral admini~tration it is desir~ble that the formulation is at about physiological pH. It may therefore be appropriate to adjust the pH to about physiological pH using conventional means, for example using a suitsble bsse such as a hydroxide (e.g. an alkali metal hydroxide such as sodium hydroxide ~olution). Conveniently, the pH is edjusted to about pH 6Ø
For parenteral administration, in particular for administration by in~ection ~eg intravenously), it is highly desirable for the formulation to be presented as a cle~r solution. A clear solution requires no further processing (e.g. constitution of a dry powder) and may be administer~d without delay. The use of a clear ~olution al~o enaures that the product C8~ be easily inspected for particulate or other visible contamination. Furthermore, intravenous in~ection of an aqueous solution of a drug can produce an immediate physiological action. We have found that at least one mole of the cyclodextrin must be used for every one mole of the hydrochloride of Compound A in order to obtsin a clear solution at near to physiological pH at normal etorage temperatures, and in th0 case of ~-cyclodextrin at least about 1.2 moles must be used.
In a preferred embodiment of the present invention, therefore, we provide a clear aqueous formulation comprising the hydrochloride salt of Compound A and ~-cyclodextrin ~or a hydrate thereof), at about physiological pH wherein the formulation contains at least about 1.2 moles of ~-cyclodextrin (e.g. 1.2 to 2 moles) for every one mole of the hydrochloride aalt of Ccmpound A. Preferably the molar ratio will be about 1:1.4. -The concentration of Compound A or the hydrochloride salt thereof in the aforementioned aqueous formulations suitable for parenteral administration, in perticular for administration by in~ection (eg intravenously), is conveniently within the range 0.1-lOmg/ml, e.g.
û.l-5mgtml, expressed as the free baae. Preferably, the concentration is lmgtml expressed a8 the free baae when the aqueous formulation is edministered by intravenous in~ection. If desired, a higher -'~
~ 5 ~ 1 328078 concentration may be used and the solution may be diluted prior to use with, for example, an isotonic aline solution or dextrose or mannitol solution. Conveniently, solution~ suitable for injection are presented in an appropriate dose volume (eg 1 - 100 ml). Dilutions suitable for continuou~ infusion may have a concentration of Compound A or its hydrochloride ~alt of 0.01 - 0.2mg/ml expressed ~ the free base. The ~olution for continuous infusion may be pre~ented in thi~
~orm, for example in packs of 50-lOOml, or may be presented in more concentrated forms for subsequent dilution before use with, for example, an isotonic saline solution or dextrose or manniltol solution. Altern~tively, smsll volumes of ~ more concen~rated solution (eg û.l - 5 mg/ml) may be utilised for continuo~s infusion conveniently administered at a rats of 0.5 to 9.9ml/h.
The aqueous formulationa described herein may conveniently be lS prepared by mixing Compound A or, more preferably, its hydrochloride salt with the remeining constituents in water. Prefersbly, Compound A
or its hydrochloride salt sre dissolved in water and the remaining constituents are added thereto. For parenteral administration, in particular by in~ection (eg intravenously), the bulk solution is preferably filtered, then filled into suitable containers and terminally sterilised, for example by heating. Alternatively, the solution may be sterilised by filtration and then aseptically filled into ~uitable containers.
It will b~ appreciated th~t water suitable for in~oction will be used when the p~renteral formulation is to be administered intravenoualy or by continuous infusion.
Formulations for in~ection may be presented in unit dose form in suitable containers such aa ampoules, vials or pre-filled syringes, or in multi-dose containers with an added prsservative.
As stated hereinbefore, the aqueoua formulations of the present invention are also suitable for oral administrstion teg a8 a capsule, syrup or aolution) or for sdmihiatration by inhalation (eg as an aerosol sproy conveniently presented as a nebuliser). British Patent Nos. 2097397 and 2127406 provide suitable general methods for the preparation of oral and inhQlation formulations which may be readily adapted without undua experimentation for present purposes.
Aqueous formulations may also be prepared by dissolving 8 solid cyclodextrin complex of Compound A or its hydrochloride salt in water together, where de~irable, with one or more other constituents as defined sbove.
'-:
Thus, in a further aspect of the present invention, we provide an aqueous formulation comprî~ing ~ complex of Compound A or the hydrochloride ~alt thereof and a cyclodextrin.
In another aspect of the invention, we provide a complex of Compound A or its hydrochloride salt and a cyclodextrin. The ratio of Compound A or the hydrochloride salt of Compound A with the cyclodextrin in the said complex will, of course, vary considerably depending on the cyclodextrin used and the conditions employed for preparing the complex. However, we have found a molar ratio of Compound A or its hydrochloride salt with the cyclodsxtrin within the range 1:1 to 1:3 to be suitable.
The cyclodextrin employed in the solid complex may be unsubstituted or substituted a-, ~- or r-cyclodextrin as defined previously or may be a mixture of such cyclodextrins (e.g a mixture of two such cyclodextrins). Preferably r-cyclodextrin or, more preferably, ~-cyclodextrin i8 employed.
In a psrticular sspect of the present invention we provide e complex of Compound A and ~-cyclodextrin in which the molsr ratio of Compound A to ~-cyclodextrin i8 within the range 1:1 to 1:2, snd is preferably about 121-In another perticùlar aspect of the present invention we provide a complex of Compound A and ~-cyclodrextrin in which the molar ratio of Compound A to ~-cyclodaxtrin is about 1:1.5.
Complexes of Compound A or the hydrochloride sslt thereof and cyclodextrin may be prepared by mixing Compound A or its hydrochloride salt with the cyclodextrin(s) or 8 hydrate thereof in a suitable solvent under conditions whereby the desired complex is formed. Thus, for exsmple; the oomplexes may be prepared by dissolving Compound A or it hydrochloride salt in water or an orgsnic solvent which is miscible with water (e.g. an alcohol such as methanol) and adding to the solution a solution of the appropriste cyclodextrin(s) or a hydrste thereof in water and/or an organic solvent which i8 miscible with water, The reaction may be effected at a temperature in the range of 0 to 80C; however the mixture is prefersbly kept st around room temperature and the desired complex obtained by concentrating the -l 328078 mixture under reduced pressure or by allowing the mixture to cool.
The mixing ratio of organic solvent with water may vary considerably according to the solubilities of the starting materials and products.
Preferably 1 to 4 moles of cyclodextrin are used for each mole of Compound A or its hydrochloric salt.
The resulting complexes msy be obtained a~ white solid with high thermsl atability and good water solubility. Such physical characteristics make them particularly suitable for formulation into pharmaceutic~l p~epar~tions for medical use. In addition to the aforementioned a~ueou~ formulations of complexes of Compound A or its hydrochloride sslt and cyclodextrin suitable particularly for parenteral sdmin~stration, the complexea may also be formulated for oral or parentersl administration or for administration by inhalation according to the genersl methods described in British Patent Nos.
2D97397 and 2127406.
An appropriate daily dose regime for Compound A or its hydrochloride ~alt when employed in one of the formulations of the present invention will, of course, depend on the specific condition to be treated, the age and condition of the patient and the route of administration. However, generally the dosages quoted in British Patent Nos. 2097397 and 2127406 will be suitable.
The following examples aro included by way of illu~trating the present invention and should not be construed as a limitation of the invention. In the following examples the molar ratioa were determined by 'H N.M.R. ~nalysis ~nd all temperatures are in C.
Example 1 (a) ~lR-~la(Z),23.3B~5a]]-(+)-7-~5-[[(1,1~-Biphenvl)-4-vl]methoxy~-3-hYdroxv-2~ piPeridinvl)cvclopentvl]-4-heptenoate: ~-cyclodextrin (1:1) complex ~ -Cyclodextrin hydrate (0.9~49) was nearly completely dissolved in water (3~ml). The suspension was filtered and the ~iltrate added to a solution of Compound A (0.29, Example 10 in GB-B-2097397) in methanol (lOml). The reaction solution was stirred at 21 for 26h to give a clear solution which was evaporated to a volume of 12ml when ' :
~light crystallisation beg~n to occur. The suspension was cooled to 5 for lh to produce a thick precipitate which w~ filtered off and dried to give the title compound (0.2739), m.p. >310, derkens above 230.
(b) The filtr~te from the above experiment began to precipitate more crystslline m~terial on standing and was thereforè evaporsted to lesve 8 white solid which wa~ dissolved in hot water (3ml), cooled (5) and sllowed to crystallise to give a white crystslline ~olid (121mg) shown by lH N.M.R. ~DMS0) snalysis to contain tlR-[la(Z).2~,3~,5a]]-(+)-7-t5-~ -biPhenvl)-4-vl]methoxv]-3-hvdroxy-2-(l-piperidinyl) cvclopentvl]-4-heptenoste : ~-cvclodextrin (1:1.5) complex.
Example 2 [lR-[la(Z),2~,33.5]]-(l)-7-~5-t~(l,l'-BiPhenyl)-4-vl]methoxv]-3-hvdroxv-2-(l-Piperidinyl)cvclopentyl]-4 heptenoete: ~-cvclodextrin (1:1.5) comPle-x A solution of r-cyclodextrin (1.099) in wster (25ml) wss sdded to 8 solution of Compour,d A (0.209) in methsnol (lO,ml). The resction solution wss stirred at 21 for 26h to produca ~ thick white suepension. The precipitste wss filtered off and dried in vscuo to lesve the title compound 8a a white solid (0.6129), m.p. >310, dsrkens sbove 250.
.
PhsrmsceuticRl ex~mPles of parenteral in~ections/infusions (i) Hydrochloride sslt of Compound A
equivslent to 50 mg bsse B-Cyclodextrin hydrste 143mg 166mg 238mg Sodium hydroxide solution to pH7 to pH7 to pH7 Wster suitable for in~ection to 50ml to 50ml to 50ml ., .
328~78 ~ :~
g The hydrochloride salt sf Compound A was dissolved in 35ml water ~uitable for injection and the ~-cyclodextrin waa added. This ---~olution wa~ titrated to pH7 with 0.02M eodium hydroxide solution and then adjusted to volume with water suitable for injection. -The solution may then be sterilised by filtration and filled into - j vials or empoules.
(ii) Hydrochloride salt of Compound A
equivalent to 50mg base ' : :' ~-Cyclodextrin hydrate 166mg Sodium chloride 450mg pH7.0 phosphate buffer 2.5ml Sodium hydroxide solution to pH7 W~ter suitable for inJection to 50ml The hydrochloride salt of Compound A wss dissolved in approximately 25ml water suitsble for in~ection. The ~-cyclodextrin was dissolved ther~in and the resulting solution was titrated to pH6 with 0.02M
sodium hydroxide solution snd the phosphate buffer sdded. The sodium chloride wss added to the solution snd the pH ad~usted to pH7 with sodium hydroxide. The solution was msde up to volume with water suitable for in~ection. A ssmple of this solution was filled into a glass vial which wss sealed with a rubber plug snd metal overseal.
This wss then autoclaved.
;.. , ,~ . . ., .. , .,.. .. ,. ." .- . . . ~ , . ,, ... , .. . , . . .. , ~ .
Hydrochloride salt of Compound A
equivalent to 50 mg base Hydroxypropyl-~-cyclodsxtrin 170mg Mannitol 2.59 pH 6.0 phosphate buffer 5.0ml Sodium hydroxide solution to pH 6 Water suitable for in~ection to 50ml ;The hydrochloride salt of Compound A was dissolved in spproximately 25ml weter suitable for in~ection and the hydroxypropyl-~-cyclodextrin was added. The msnnitol wss then added and the solution titrated to pH 6 with 0.02M aodium hydroxide solution. The phosphate buf,fer solution wes edded and the solution ad~usted to volume with water suitable for in~ection. The solution wes then filtered and filled into glass vials which were sealed with rubber plugs and metal overseals. These were then autoclaved.
(iv) Hydrochloride salt of Compound A
equivalent to 50mg base ~-Cyclodextrin hydrste 166mg Mennitol 2.59 Sodium acid phosphate ` 46mg Disodium phosphate, anhydrous 5mg Sodium hydroxide solution to pH 6 Water suitable for injection to 50n1 :: :
The hydrochloride salt of Compound A w~s dissolved in spproximately 25ml water suitable for injection. The ~-cyclodextrin snd mannitol were dissolved therein and the solution titrated to pH 6 with 0.02M ~odium hydroxide solution. The sodium acid phosphate and ~nhydrous disodium phosphate were dissolved in water suitsble for injection. This solution was added to the bulk solution which was msde up to volume with water suitsble for injection. The solution wa~
filtered and filled into 91888 ampoules which were sealed and then ~utoclaved.
(v) Cvclodextrin Mixture a ~ ~ + r .:
Hydrochloride sslt of Compound A
equivalent to 5ûmg bsse Cyclodextrin 143mg 190mg ll9mg 136mg Msnnitol 2.59 2.59 2.59 pH 6.0 Phosphste buffer 5.0ml 5.0ml 5.0ml Sodium hydroxide solution to pH 6 to pH 6 to pH6 Water suitsble for injection to 50ml to 5û ml to 50ml ' ' The hydrochloride sslt of Compound A was dissolved in spproximately 25ml wster suitable for injection snd the cyclodextrin(s) W~8 (were) edded. The mannitol wss then sdded snd the solution titrsted to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer 301ution was added and the solution was sdjusted to volume with wster suit~ble for in~ection. The solution wss then filtered and filled into gla~s visls which were sesled with rubber plugs snd metal oversesls.
~ .
-Pharmaceutical example of oral syrup Hydrochloride ~alt of Compound A
equiv~lent to 2.5mg base ~-cyclodextrin hydrate 9mg Citric acid to pH 4.5 lo Methyl hydroxybenzoQte sodium 5mg Propyl hydroxybenzoate sodium 2mg Liquid orange flsvour qs Sucroae 3.259 Purifie,d water to 5.0ml Dissolve the sucrose in a minimum quantity of water. Add the hydrochloride aalt of Compound A and then the ~-cyclodextrin with stirring; ad~ust the pH to 4.5 with citric acid. With continued atirring add a solution of the hydroxybenzoates and lsstly the flavour. Ad~u~t almost to volume with weter and stir. Check the pH
and ad~ust to 4.5 with citric acid if nece~ssry. Meke up to volume with water.
~ ;
~, '~' ' ' - 13 - :
Pharmaceutical example of solution for inhalation Per 2ml doQe Hydrochloride salt of Compound A
equivslent to 2mg bace ~-cyclodextrin hydrate 7mg Sodium chloride 18mg 10 Sodium hydroxide solution to pH 7.2 pH 7.2 phosphste buffer 0.2ml :
Wster suitable for injection to 2ml Dissolve the hydrochloride salt of Compound A in water ~uitsble for in~e¢tion. Dissolve the ~-cyclodextrin therein and titrate the resulting solution to pH6 with sodium hydroxide solution; add the phoaphate buffer solution. Add the sodium chloride end sd~ust to Z0 pH7.2 with sodlum hydroxide solution. Make the solution up to volume with water suitable for in~ection and sterilize the solution by ~iltration. F111 assptically into containers suitable ~or inhalation by nebulising.
.,~ ,.
~ , , ..
~ . ~
~ 35
PIPERIDINYLCYCLOPENTYLHEPTENOIC ACID DERIVATIVE
This invention relate~ to aqueous formulation~ cont~ining as active ingredient rlR-[la(Z),2~,3~,5a]]-(l)-7-[5-[[(1,1'-biphenyl~-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (hereinafter referred to as 'Compound A'), to processe~ for their preparation and to their u~e in medicine.
Compound A i8 described in our British ~atent No. 2097397 as one of a group of aminocyclopentane derivatives ~aving endoperoxide and thromboxane antagonist activity, and it is reported therein that such compounds are of interest in the treatment of asthma and cardiovssdular diaeases. More recently, we discovered thst the hydrochloride salt of Compound A has edvantages over Compound A and other sfllts and solvates thereof both in its preparation and iQ its use in medicine. The hydrochloride salt is described in our British Patent No. 2127406.
Compound A ia ùnfortunately only sparingly soluble in water and formulations in water contsining the hydrochloride salt of Compound A
together with standard ex¢ipients and/or carriers have proved to be unacceptable for intravenous ~dministrstion a8 the hydrochloride salt of Compound A is converted to the virtually insoluble Compound A at near to physiological pH.
Wo have now found that the aolubility in water of Compound A or its hydrochloride salt st around physiologicsl pH is significantly improved in the pr~sence of an unsubstituted or substituted a~ or r-cyclodextrin (or a hydrate thereof). We have also found that aqusous formulations comprising Compound A or the hydrochloride salt thereof and an unsubstituted or substituted a-, ~- or y-cyclodextrin (or Q hydrate thereof) are suitable for use in medicine, more particularly for use in the treatment or prophylaxis of conditions mediated by thromboxsne A2, when administered either orally, by inhalstion or parenterally, in particular by injection (eg intravenously).
'.
- ' -Thu~, according to one aspect of the present invention, we provide an aqueou~ formuletion comprising Compound A or the hydrochloride sslt thereof with an unsubstituted or substituted -, ~-, or y-cyclodextrin (or a hydrate thereo~).
In another aspect of the invention, we provide an aqueous formulation as definod herein for u~e in medicine, more particularly for use in the treatment or prophylaxis of conditiona mediated by thromboxane A2.
According to anothsr aspect of the invention, we provide a method of tresting conditions mediated by thromboxane A2 which method comprise administering to the human or animal patient an effective amount of Compound A in an aqueous formulstion as defined herein.
Suitable conditions which msy be treated with aqueous formulations of the present invention include those conditions described in British Patents Nos. 2097397 and 2127406~treated using other (e.g. orel) formulation~ of Compound A and the hydrochloride salt of Compound A respectively. In particular, the aqueous formulations of the present invention may be used in the treatment or prophylaxis of occlusive vascular disease, including myocardial infarction, ¢ardiac fatalities, unstsble angina, transient i~chaemic attacks and cerebrsl infarction, atherosclerosis and vessel w811 disease, peripheral vascular disease, retinopathy, postoperative thrombosis and pulmonary embolism. The aqueous formulations msy also be us0d in the prophylaxis of peri- and postoperative complications following organ transplantation ~pQrticularly cardiac and renal), coronary artery bypass, peripheral artery bypass and thrombolysis.
The aqueous formulations are also of potential use in connection with peptic ulcei disease, more particularly for the prevention of relapse of healed peptic ulcers.
32807~
Preferably, in the aqueous formulat~ons of the present invention Compound A i9 used as its hydrochloride salt.
It will be appreciated by those skilled in the art that the benefits of the present invention may be achieved by utilising more th~n one cyclodextrin, ~lthough the use of a single cyclodextrin i8 generally preferred.
Where a substituted cyclodextrin is employed any suitable substituted cyclodextrin known in the art may be used according to the present invention. Suitable substituted cyclodextrins for use lo a~cording to the present invention will be resdily appreciated by peraons skilled in the art and will include sulphur-containing cyclodextrins, nitrogen-containing cyclodextrins, alkylQted (e.g.
methylated) cyclodextrins such as mono-, di- or trimethylated derivatives o~ a cyclodextrin (e.g. of ~q-cyclodextrin) and hydroxyalkyl (e.g. hydroxypropyl) cyclode~trins such as hydroxypropyl ,B-cyclodextrin and acylated derivatives thereof. Hydroxyalkyl (e.g.
hydroxypropyl) cyclodextrins such 88 hydroxypropyl ~cyclodextrin hsve been found to be psrticulsrly suitable for use according to the present invention.
Conveniently a single unsubstituted cyclodextrin i~ employed according to the present invention. Psrticulsrly preferred is ,B-cyslodextrin, conveniently used in its hydrsted form.
In order for the squeous formulation to exhibit the desired properties it is important that the correct molar ratio of Compound A
or its hydrochloride salt to the cyclodextrin(s) is used. We have found a molar r~tio of Compound A or its hydrochloride salt to the cyclodextrin(s) within the range 1:1 to 1:4 to be suitable.
It wili be spprecisted by persons skilled in the art that the squeoua formulstions of the pr~sent invention may, if desired, Qlso contsin one or more phsrmaceut~ical carIiers or excipients.
Suitable excipients which may be incorporated into the aqueous formulation include agents to make the preparation isotonic with blood plasma (e.g. ~odium chloride, dextrose or prefersbly mannitol) and buffering agents (e.g. phosphQte buffer or a mixture of sodium acid phosphate and disodium phosphate).
.,','. :' ` ' -:.
'., The aqueou~ formulQtions of the present invention are particularly suitable for parenteral adminiatration in particular by injection (eg intravenously). When presented for parenteral admini~tration it is desir~ble that the formulation is at about physiological pH. It may therefore be appropriate to adjust the pH to about physiological pH using conventional means, for example using a suitsble bsse such as a hydroxide (e.g. an alkali metal hydroxide such as sodium hydroxide ~olution). Conveniently, the pH is edjusted to about pH 6Ø
For parenteral administration, in particular for administration by in~ection ~eg intravenously), it is highly desirable for the formulation to be presented as a cle~r solution. A clear solution requires no further processing (e.g. constitution of a dry powder) and may be administer~d without delay. The use of a clear ~olution al~o enaures that the product C8~ be easily inspected for particulate or other visible contamination. Furthermore, intravenous in~ection of an aqueous solution of a drug can produce an immediate physiological action. We have found that at least one mole of the cyclodextrin must be used for every one mole of the hydrochloride of Compound A in order to obtsin a clear solution at near to physiological pH at normal etorage temperatures, and in th0 case of ~-cyclodextrin at least about 1.2 moles must be used.
In a preferred embodiment of the present invention, therefore, we provide a clear aqueous formulation comprising the hydrochloride salt of Compound A and ~-cyclodextrin ~or a hydrate thereof), at about physiological pH wherein the formulation contains at least about 1.2 moles of ~-cyclodextrin (e.g. 1.2 to 2 moles) for every one mole of the hydrochloride aalt of Ccmpound A. Preferably the molar ratio will be about 1:1.4. -The concentration of Compound A or the hydrochloride salt thereof in the aforementioned aqueous formulations suitable for parenteral administration, in perticular for administration by in~ection (eg intravenously), is conveniently within the range 0.1-lOmg/ml, e.g.
û.l-5mgtml, expressed as the free baae. Preferably, the concentration is lmgtml expressed a8 the free baae when the aqueous formulation is edministered by intravenous in~ection. If desired, a higher -'~
~ 5 ~ 1 328078 concentration may be used and the solution may be diluted prior to use with, for example, an isotonic aline solution or dextrose or mannitol solution. Conveniently, solution~ suitable for injection are presented in an appropriate dose volume (eg 1 - 100 ml). Dilutions suitable for continuou~ infusion may have a concentration of Compound A or its hydrochloride ~alt of 0.01 - 0.2mg/ml expressed ~ the free base. The ~olution for continuous infusion may be pre~ented in thi~
~orm, for example in packs of 50-lOOml, or may be presented in more concentrated forms for subsequent dilution before use with, for example, an isotonic saline solution or dextrose or manniltol solution. Altern~tively, smsll volumes of ~ more concen~rated solution (eg û.l - 5 mg/ml) may be utilised for continuo~s infusion conveniently administered at a rats of 0.5 to 9.9ml/h.
The aqueous formulationa described herein may conveniently be lS prepared by mixing Compound A or, more preferably, its hydrochloride salt with the remeining constituents in water. Prefersbly, Compound A
or its hydrochloride salt sre dissolved in water and the remaining constituents are added thereto. For parenteral administration, in particular by in~ection (eg intravenously), the bulk solution is preferably filtered, then filled into suitable containers and terminally sterilised, for example by heating. Alternatively, the solution may be sterilised by filtration and then aseptically filled into ~uitable containers.
It will b~ appreciated th~t water suitable for in~oction will be used when the p~renteral formulation is to be administered intravenoualy or by continuous infusion.
Formulations for in~ection may be presented in unit dose form in suitable containers such aa ampoules, vials or pre-filled syringes, or in multi-dose containers with an added prsservative.
As stated hereinbefore, the aqueoua formulations of the present invention are also suitable for oral administrstion teg a8 a capsule, syrup or aolution) or for sdmihiatration by inhalation (eg as an aerosol sproy conveniently presented as a nebuliser). British Patent Nos. 2097397 and 2127406 provide suitable general methods for the preparation of oral and inhQlation formulations which may be readily adapted without undua experimentation for present purposes.
Aqueous formulations may also be prepared by dissolving 8 solid cyclodextrin complex of Compound A or its hydrochloride salt in water together, where de~irable, with one or more other constituents as defined sbove.
'-:
Thus, in a further aspect of the present invention, we provide an aqueous formulation comprî~ing ~ complex of Compound A or the hydrochloride ~alt thereof and a cyclodextrin.
In another aspect of the invention, we provide a complex of Compound A or its hydrochloride salt and a cyclodextrin. The ratio of Compound A or the hydrochloride salt of Compound A with the cyclodextrin in the said complex will, of course, vary considerably depending on the cyclodextrin used and the conditions employed for preparing the complex. However, we have found a molar ratio of Compound A or its hydrochloride salt with the cyclodsxtrin within the range 1:1 to 1:3 to be suitable.
The cyclodextrin employed in the solid complex may be unsubstituted or substituted a-, ~- or r-cyclodextrin as defined previously or may be a mixture of such cyclodextrins (e.g a mixture of two such cyclodextrins). Preferably r-cyclodextrin or, more preferably, ~-cyclodextrin i8 employed.
In a psrticular sspect of the present invention we provide e complex of Compound A and ~-cyclodextrin in which the molsr ratio of Compound A to ~-cyclodextrin i8 within the range 1:1 to 1:2, snd is preferably about 121-In another perticùlar aspect of the present invention we provide a complex of Compound A and ~-cyclodrextrin in which the molar ratio of Compound A to ~-cyclodaxtrin is about 1:1.5.
Complexes of Compound A or the hydrochloride sslt thereof and cyclodextrin may be prepared by mixing Compound A or its hydrochloride salt with the cyclodextrin(s) or 8 hydrate thereof in a suitable solvent under conditions whereby the desired complex is formed. Thus, for exsmple; the oomplexes may be prepared by dissolving Compound A or it hydrochloride salt in water or an orgsnic solvent which is miscible with water (e.g. an alcohol such as methanol) and adding to the solution a solution of the appropriste cyclodextrin(s) or a hydrste thereof in water and/or an organic solvent which i8 miscible with water, The reaction may be effected at a temperature in the range of 0 to 80C; however the mixture is prefersbly kept st around room temperature and the desired complex obtained by concentrating the -l 328078 mixture under reduced pressure or by allowing the mixture to cool.
The mixing ratio of organic solvent with water may vary considerably according to the solubilities of the starting materials and products.
Preferably 1 to 4 moles of cyclodextrin are used for each mole of Compound A or its hydrochloric salt.
The resulting complexes msy be obtained a~ white solid with high thermsl atability and good water solubility. Such physical characteristics make them particularly suitable for formulation into pharmaceutic~l p~epar~tions for medical use. In addition to the aforementioned a~ueou~ formulations of complexes of Compound A or its hydrochloride sslt and cyclodextrin suitable particularly for parenteral sdmin~stration, the complexea may also be formulated for oral or parentersl administration or for administration by inhalation according to the genersl methods described in British Patent Nos.
2D97397 and 2127406.
An appropriate daily dose regime for Compound A or its hydrochloride ~alt when employed in one of the formulations of the present invention will, of course, depend on the specific condition to be treated, the age and condition of the patient and the route of administration. However, generally the dosages quoted in British Patent Nos. 2097397 and 2127406 will be suitable.
The following examples aro included by way of illu~trating the present invention and should not be construed as a limitation of the invention. In the following examples the molar ratioa were determined by 'H N.M.R. ~nalysis ~nd all temperatures are in C.
Example 1 (a) ~lR-~la(Z),23.3B~5a]]-(+)-7-~5-[[(1,1~-Biphenvl)-4-vl]methoxy~-3-hYdroxv-2~ piPeridinvl)cvclopentvl]-4-heptenoate: ~-cyclodextrin (1:1) complex ~ -Cyclodextrin hydrate (0.9~49) was nearly completely dissolved in water (3~ml). The suspension was filtered and the ~iltrate added to a solution of Compound A (0.29, Example 10 in GB-B-2097397) in methanol (lOml). The reaction solution was stirred at 21 for 26h to give a clear solution which was evaporated to a volume of 12ml when ' :
~light crystallisation beg~n to occur. The suspension was cooled to 5 for lh to produce a thick precipitate which w~ filtered off and dried to give the title compound (0.2739), m.p. >310, derkens above 230.
(b) The filtr~te from the above experiment began to precipitate more crystslline m~terial on standing and was thereforè evaporsted to lesve 8 white solid which wa~ dissolved in hot water (3ml), cooled (5) and sllowed to crystallise to give a white crystslline ~olid (121mg) shown by lH N.M.R. ~DMS0) snalysis to contain tlR-[la(Z).2~,3~,5a]]-(+)-7-t5-~ -biPhenvl)-4-vl]methoxv]-3-hvdroxy-2-(l-piperidinyl) cvclopentvl]-4-heptenoste : ~-cvclodextrin (1:1.5) complex.
Example 2 [lR-[la(Z),2~,33.5]]-(l)-7-~5-t~(l,l'-BiPhenyl)-4-vl]methoxv]-3-hvdroxv-2-(l-Piperidinyl)cvclopentyl]-4 heptenoete: ~-cvclodextrin (1:1.5) comPle-x A solution of r-cyclodextrin (1.099) in wster (25ml) wss sdded to 8 solution of Compour,d A (0.209) in methsnol (lO,ml). The resction solution wss stirred at 21 for 26h to produca ~ thick white suepension. The precipitste wss filtered off and dried in vscuo to lesve the title compound 8a a white solid (0.6129), m.p. >310, dsrkens sbove 250.
.
PhsrmsceuticRl ex~mPles of parenteral in~ections/infusions (i) Hydrochloride sslt of Compound A
equivslent to 50 mg bsse B-Cyclodextrin hydrste 143mg 166mg 238mg Sodium hydroxide solution to pH7 to pH7 to pH7 Wster suitable for in~ection to 50ml to 50ml to 50ml ., .
328~78 ~ :~
g The hydrochloride salt sf Compound A was dissolved in 35ml water ~uitable for injection and the ~-cyclodextrin waa added. This ---~olution wa~ titrated to pH7 with 0.02M eodium hydroxide solution and then adjusted to volume with water suitable for injection. -The solution may then be sterilised by filtration and filled into - j vials or empoules.
(ii) Hydrochloride salt of Compound A
equivalent to 50mg base ' : :' ~-Cyclodextrin hydrate 166mg Sodium chloride 450mg pH7.0 phosphate buffer 2.5ml Sodium hydroxide solution to pH7 W~ter suitable for inJection to 50ml The hydrochloride salt of Compound A wss dissolved in approximately 25ml water suitsble for in~ection. The ~-cyclodextrin was dissolved ther~in and the resulting solution was titrated to pH6 with 0.02M
sodium hydroxide solution snd the phosphate buffer sdded. The sodium chloride wss added to the solution snd the pH ad~usted to pH7 with sodium hydroxide. The solution was msde up to volume with water suitable for in~ection. A ssmple of this solution was filled into a glass vial which wss sealed with a rubber plug snd metal overseal.
This wss then autoclaved.
;.. , ,~ . . ., .. , .,.. .. ,. ." .- . . . ~ , . ,, ... , .. . , . . .. , ~ .
Hydrochloride salt of Compound A
equivalent to 50 mg base Hydroxypropyl-~-cyclodsxtrin 170mg Mannitol 2.59 pH 6.0 phosphate buffer 5.0ml Sodium hydroxide solution to pH 6 Water suitable for in~ection to 50ml ;The hydrochloride salt of Compound A was dissolved in spproximately 25ml weter suitable for in~ection and the hydroxypropyl-~-cyclodextrin was added. The msnnitol wss then added and the solution titrated to pH 6 with 0.02M aodium hydroxide solution. The phosphate buf,fer solution wes edded and the solution ad~usted to volume with water suitable for in~ection. The solution wes then filtered and filled into glass vials which were sealed with rubber plugs and metal overseals. These were then autoclaved.
(iv) Hydrochloride salt of Compound A
equivalent to 50mg base ~-Cyclodextrin hydrste 166mg Mennitol 2.59 Sodium acid phosphate ` 46mg Disodium phosphate, anhydrous 5mg Sodium hydroxide solution to pH 6 Water suitable for injection to 50n1 :: :
The hydrochloride salt of Compound A w~s dissolved in spproximately 25ml water suitable for injection. The ~-cyclodextrin snd mannitol were dissolved therein and the solution titrated to pH 6 with 0.02M ~odium hydroxide solution. The sodium acid phosphate and ~nhydrous disodium phosphate were dissolved in water suitsble for injection. This solution was added to the bulk solution which was msde up to volume with water suitsble for injection. The solution wa~
filtered and filled into 91888 ampoules which were sealed and then ~utoclaved.
(v) Cvclodextrin Mixture a ~ ~ + r .:
Hydrochloride sslt of Compound A
equivalent to 5ûmg bsse Cyclodextrin 143mg 190mg ll9mg 136mg Msnnitol 2.59 2.59 2.59 pH 6.0 Phosphste buffer 5.0ml 5.0ml 5.0ml Sodium hydroxide solution to pH 6 to pH 6 to pH6 Water suitsble for injection to 50ml to 5û ml to 50ml ' ' The hydrochloride sslt of Compound A was dissolved in spproximately 25ml wster suitable for injection snd the cyclodextrin(s) W~8 (were) edded. The mannitol wss then sdded snd the solution titrsted to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer 301ution was added and the solution was sdjusted to volume with wster suit~ble for in~ection. The solution wss then filtered and filled into gla~s visls which were sesled with rubber plugs snd metal oversesls.
~ .
-Pharmaceutical example of oral syrup Hydrochloride ~alt of Compound A
equiv~lent to 2.5mg base ~-cyclodextrin hydrate 9mg Citric acid to pH 4.5 lo Methyl hydroxybenzoQte sodium 5mg Propyl hydroxybenzoate sodium 2mg Liquid orange flsvour qs Sucroae 3.259 Purifie,d water to 5.0ml Dissolve the sucrose in a minimum quantity of water. Add the hydrochloride aalt of Compound A and then the ~-cyclodextrin with stirring; ad~ust the pH to 4.5 with citric acid. With continued atirring add a solution of the hydroxybenzoates and lsstly the flavour. Ad~u~t almost to volume with weter and stir. Check the pH
and ad~ust to 4.5 with citric acid if nece~ssry. Meke up to volume with water.
~ ;
~, '~' ' ' - 13 - :
Pharmaceutical example of solution for inhalation Per 2ml doQe Hydrochloride salt of Compound A
equivslent to 2mg bace ~-cyclodextrin hydrate 7mg Sodium chloride 18mg 10 Sodium hydroxide solution to pH 7.2 pH 7.2 phosphste buffer 0.2ml :
Wster suitable for injection to 2ml Dissolve the hydrochloride salt of Compound A in water ~uitsble for in~e¢tion. Dissolve the ~-cyclodextrin therein and titrate the resulting solution to pH6 with sodium hydroxide solution; add the phoaphate buffer solution. Add the sodium chloride end sd~ust to Z0 pH7.2 with sodlum hydroxide solution. Make the solution up to volume with water suitable for in~ection and sterilize the solution by ~iltration. F111 assptically into containers suitable ~or inhalation by nebulising.
.,~ ,.
~ , , ..
~ . ~
~ 35
Claims (13)
1. An aqueous formulation comprising [1B-[1.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-(5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (Compound A) or the hydrochloride salt thereof with an unsubstituted or substituted .alpha.-, .beta.- or .gamma.-cyclodextrin or a hydrate thereof.
2. A formulation as claimed in claim 1 wherein Compound A is used as its hydrochloride salt.
3. A formulation as claimed in claim 1 or claim 2 wherein the cyclodextrin is .beta.-cyclodextrin.
4. A formulation as claimed in claim 1 in a form suitable for injection.
5. A clear aqueous formulation as claimed in claim 4 comprising the hydrochloride salt of Compound A and .beta.-cyclodextrin or a hydrate thereof at about physiological pH
wherein the formulation contains at least about 1.2 moles of .beta.-cyclodextrin for every one mole of the hydrochloride salt of Compound A.
wherein the formulation contains at least about 1.2 moles of .beta.-cyclodextrin for every one mole of the hydrochloride salt of Compound A.
6. A formulation as claimed in claim 5 wherein the molar ratio of the hydrochloride salt of Compound A to .beta.-cyclodextrin is about 1:1.4.
7. A formulation as claimed in claim 4, claim 5 or claim 6 in which the pH is about pH 6Ø
8. A formulation as claimed in claim 4, claim 5 or claim 6 also comprising sodium hydroxide.
9. A formulation as claimed in claim 4, claim 5 or claim 6 having a concentration of 0.1-5mg/ml Compound A or the hydrochloride salt thereof expressed as the free base.
10. A formulation as claimed in claim 4, claim 5 or claim 6 in a form suitable for continuous infusion having a concentration of 0.01-0.2 mg/ml Compound A or the hydrochloride salt thereof expressed as the free bass.
11. A process for the preparation of a formulation as claimed in claim 1 or claim 2 which comprises mixing Compound A or its hydrochloride salt with the remaining constituents in water.
12. A complex of [1R-[.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid (Compound A) or its hydrochloride salt and an unsubstituted or substituted .alpha.-, .beta.- or .gamma.-cyclodextrin.
13. A complex of [1R-[.alpha.(Z),2.beta.,3.beta.,5.alpha.]]-(+)-7-[5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid (Compound A) and .beta.-cyclodextrin in which the molar ratio of Compound A to .beta.-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 |
GB888804422A GB8804422D0 (en) | 1988-02-25 | 1988-02-25 | Complexes |
GB8804422 | 1988-02-25 |
Publications (1)
Publication Number | Publication Date |
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CA1328078C true CA1328078C (en) | 1994-03-29 |
Family
ID=26293226
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
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CA000586606A Expired - Fee Related CA1328078C (en) | 1987-12-22 | 1988-12-21 | Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative |
Country Status (29)
Country | Link |
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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) |
Families Citing this family (5)
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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. |
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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JPS503362B1 (en) * | 1970-06-10 | 1975-02-04 | ||
JPS5443569B2 (en) * | 1972-07-05 | 1979-12-20 | ||
HU181703B (en) * | 1980-05-09 | 1983-11-28 | Chinoin Gyogyszer Es Vegyeszet | Process for producing aqueus solutuins of water insoluble or hardly soluble vitamines, steroides, localanesthetics, prostanoides and non-steroid and antiphlogistic agents |
JPS57183772A (en) * | 1981-04-29 | 1982-11-12 | Glaxo Group Ltd | Aminocyclopentanol acids and esters, manufacture and medicinal composition |
JPS58116423A (en) * | 1981-12-28 | 1983-07-11 | Sumitomo Chem Co Ltd | Methanoprostacycline pharmaceutical composition |
JPS58192821A (en) * | 1982-04-30 | 1983-11-10 | Dainippon Pharmaceut Co Ltd | Remedy for anoxia of cranial nerve cells |
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 |
GB2127406B (en) * | 1982-09-16 | 1986-03-05 | Glaxo Group Ltd | Piperidinlycyclopentanolheptenoic acid salt |
JPS5973576A (en) * | 1982-09-16 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Piperidinylcyclopentanolheptanoate |
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 |
JPS6327440A (en) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | Glucosylated branched cyclodextrin-containing composition |
-
1988
- 1988-12-21 NL NL8803126A patent/NL8803126A/en not_active Application Discontinuation
- 1988-12-21 JP JP63320759A patent/JPH02210A/en active Pending
- 1988-12-21 FI FI885920A patent/FI885920A/en not_active Application Discontinuation
- 1988-12-21 CN CN88108916A patent/CN1034132A/en active Pending
- 1988-12-21 ES ES8803876A patent/ES2011727A6/en not_active Expired - Fee Related
- 1988-12-21 IE IE382088A patent/IE61995B1/en not_active IP Right Cessation
- 1988-12-21 DK DK712888A patent/DK712888A/en not_active Application Discontinuation
- 1988-12-21 NO NO88885689A patent/NO885689L/en unknown
- 1988-12-21 SE SE8804607A patent/SE502288C2/en not_active IP Right Cessation
- 1988-12-21 GB GB8829793A patent/GB2211737B/en not_active Expired - Fee Related
- 1988-12-21 ZW ZW180/88A patent/ZW18088A1/en unknown
- 1988-12-21 LU LU87411A patent/LU87411A1/en unknown
- 1988-12-21 BE BE8801423A patent/BE1001704A3/en not_active IP Right Cessation
- 1988-12-21 FR FR8816902A patent/FR2624731B1/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 PH PH37963A patent/PH24982A/en unknown
- 1988-12-21 PT PT89301A patent/PT89301B/en not_active IP Right Cessation
- 1988-12-21 AU AU27356/88A patent/AU615245B2/en not_active Ceased
- 1988-12-21 CH CH4758/88A patent/CH676665A5/de not_active IP Right Cessation
- 1988-12-21 HU HU886537A patent/HU204700B/en not_active IP Right Cessation
- 1988-12-21 DE DE3843059A patent/DE3843059A1/en not_active Ceased
- 1988-12-21 IT IT8848702A patent/IT1224835B/en active
- 1988-12-21 KR KR1019880017106A patent/KR890009402A/en not_active Application Discontinuation
- 1988-12-21 NZ NZ227446A patent/NZ227446A/en unknown
- 1988-12-21 AT AT0313088A patent/AT395943B/en not_active IP Right Cessation
- 1988-12-21 CA CA000586606A patent/CA1328078C/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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