AU615245B2 - Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative - Google Patents
Aqueous formulations containing a piperidinylcyclopentylheptenoic acid derivative Download PDFInfo
- Publication number
- AU615245B2 AU615245B2 AU27356/88A AU2735688A AU615245B2 AU 615245 B2 AU615245 B2 AU 615245B2 AU 27356/88 A AU27356/88 A AU 27356/88A AU 2735688 A AU2735688 A AU 2735688A AU 615245 B2 AU615245 B2 AU 615245B2
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- Australia
- Prior art keywords
- compound
- cyclodextrin
- hydrochloride salt
- formulation
- solution
- Prior art date
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- 239000013011 aqueous formulation Substances 0.000 title claims description 26
- 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 1
- 229920000858 Cyclodextrin Polymers 0.000 claims description 74
- 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
- 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 48
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 45
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 40
- 238000002347 injection Methods 0.000 claims description 29
- 239000007924 injection Substances 0.000 claims description 29
- 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 25
- 238000009472 formulation Methods 0.000 claims description 21
- 238000000034 method Methods 0.000 claims description 7
- 238000001802 infusion Methods 0.000 claims description 6
- 239000012458 free base Substances 0.000 claims description 5
- 238000002360 preparation method Methods 0.000 claims description 5
- 239000000470 constituent Substances 0.000 claims description 4
- 125000001511 cyclopentyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C1([H])[H] 0.000 claims description 4
- 230000001404 mediated effect Effects 0.000 claims description 4
- 238000002156 mixing Methods 0.000 claims description 4
- 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 claims description 3
- 241001465754 Metazoa Species 0.000 claims description 2
- 235000010290 biphenyl Nutrition 0.000 claims description 2
- ZUOUZKKEUPVFJK-UHFFFAOYSA-N phenylbenzene Natural products C1=CC=CC=C1C1=CC=CC=C1 ZUOUZKKEUPVFJK-UHFFFAOYSA-N 0.000 claims description 2
- 239000000243 solution Substances 0.000 description 56
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical compound [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 12
- 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
- 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
- 239000002585 base Substances 0.000 description 8
- 229940097362 cyclodextrins Drugs 0.000 description 8
- 238000007911 parenteral administration Methods 0.000 description 7
- 239000008363 phosphate buffer Substances 0.000 description 6
- 239000007787 solid Substances 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 5
- 239000003814 drug Substances 0.000 description 5
- 239000011780 sodium chloride Substances 0.000 description 5
- 239000011521 glass Substances 0.000 description 4
- -1 hydroxypropyl Chemical group 0.000 description 4
- 229910052751 metal Inorganic materials 0.000 description 4
- 239000002184 metal Substances 0.000 description 4
- 238000011321 prophylaxis Methods 0.000 description 4
- 150000003839 salts Chemical class 0.000 description 4
- 238000011282 treatment Methods 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
- 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
- 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
- 238000001914 filtration Methods 0.000 description 3
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 description 3
- 239000003960 organic solvent Substances 0.000 description 3
- 239000000546 pharmaceutical excipient Substances 0.000 description 3
- 239000008055 phosphate buffer solution Substances 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
- 238000003756 stirring Methods 0.000 description 3
- 239000000725 suspension Substances 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 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
- 239000008364 bulk solution Substances 0.000 description 2
- 230000000747 cardiac effect Effects 0.000 description 2
- 239000012895 dilution Substances 0.000 description 2
- 238000010790 dilution Methods 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
- 238000010253 intravenous injection Methods 0.000 description 2
- 239000002244 precipitate Substances 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- 239000001488 sodium phosphate Substances 0.000 description 2
- 239000005720 sucrose Substances 0.000 description 2
- 239000006188 syrup Substances 0.000 description 2
- 235000020357 syrup Nutrition 0.000 description 2
- 206010002388 Angina unstable Diseases 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- 206010065559 Cerebral arteriosclerosis Diseases 0.000 description 1
- 241001331845 Equus asinus x caballus Species 0.000 description 1
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 1
- 206010061216 Infarction Diseases 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
- 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
- 239000005864 Sulphur Substances 0.000 description 1
- 208000032109 Transient ischaemic attack Diseases 0.000 description 1
- 208000025865 Ulcer Diseases 0.000 description 1
- 208000007814 Unstable Angina Diseases 0.000 description 1
- RTWWFMQOTPTCMP-UHFFFAOYSA-N [Na].[Na].COC(=O)C1=CC=CC=C1O.CCCOC(=O)C1=CC=CC=C1O Chemical compound [Na].[Na].COC(=O)C1=CC=CC=C1O.CCCOC(=O)C1=CC=CC=C1O RTWWFMQOTPTCMP-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid 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
- 239000006172 buffering agent 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
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000011109 contamination Methods 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
- NISGSNTVMOOSJQ-UHFFFAOYSA-N cyclopentanamine Chemical class NC1CCCC1 NISGSNTVMOOSJQ-UHFFFAOYSA-N 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
- 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
- 238000010438 heat treatment Methods 0.000 description 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-M hydroxide Chemical compound [OH-] XLYOFNOQVPJJNP-UHFFFAOYSA-M 0.000 description 1
- 125000002768 hydroxyalkyl group Chemical group 0.000 description 1
- 230000007574 infarction Effects 0.000 description 1
- 201000004332 intermediate coronary syndrome Diseases 0.000 description 1
- 201000005851 intracranial arteriosclerosis Diseases 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 230000002107 myocardial effect Effects 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 239000007968 orange flavor Substances 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 230000002093 peripheral effect Effects 0.000 description 1
- 239000000825 pharmaceutical preparation Substances 0.000 description 1
- 210000002381 plasma Anatomy 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
- 230000002265 prevention Effects 0.000 description 1
- 238000012545 processing Methods 0.000 description 1
- 239000008213 purified water Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-N salicylic acid Chemical class OC(=O)C1=CC=CC=C1O YGSDEFSMJLZEOE-UHFFFAOYSA-N 0.000 description 1
- JBJWASZNUJCEKT-UHFFFAOYSA-M sodium;hydroxide;hydrate Chemical compound O.[OH-].[Na+] JBJWASZNUJCEKT-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 239000002904 solvent Substances 0.000 description 1
- 239000007921 spray Substances 0.000 description 1
- 239000007858 starting material Substances 0.000 description 1
- 230000002537 thrombolytic effect Effects 0.000 description 1
- 239000002396 thromboxane receptor blocking agent Substances 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)
- Animal Behavior & Ethology (AREA)
- Molecular Biology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nanotechnology (AREA)
- Biochemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- General Engineering & Computer Science (AREA)
- Medical Informatics (AREA)
- Biotechnology (AREA)
- Crystallography & Structural Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Materials Engineering (AREA)
- Polymers & Plastics (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)
Description
AUSTRALIA
PATENTS ACT 1952 65 2 4 COMPLETE SPECIFICATION
(ORIGINAL)
FOR OFFICE USE Application Number: Lodged: Complete Specification Lodged: Accepted: Published: Priority: Related Art: TO BE COMPLETED BY APPLICANT Name of Applicant: GLAXO GROUP LIMITED *Address of Applicant: Clarges House, 6-12 Clarges Street, London W1Y 8DH, England Actual Inventor: Harry Finch Anthony John Phillips Address for Service: ARTHUR S. CAVE CO.
Patent Trade Mark Attorneys Level 10 Barrack Street SYDNEY N.S.W. 2000 S. AUSTRALIA "AQUEOUS FORMULATIONS CONTAINING A PIPERIDINYLCYCLOPENTYLHEPTENOIC i ACID DERIVATIVE".
S The following statement is a full description of this invention S including the best method of performing it known to me:- 1 7 ,:ASC 49 2g~.
la This invention relates to aqueous formulations containing as active ingredient 4-yl]methoxy]-3-hydroxy-2-(1-piperidinyl)cyclopentyl]-4-heptenoic acid (hereinafter referred to as 'Compound to processes for their preparation and to their use in medicine.
Compound A is described in our British Fatent No. 2097397 as one of a group of aminocyclopentane derivatives having endoperoxide and thromboxane antagonist activity, and it is reported therein that such compounds are of interest in the treatment of asthma and S. 10 cardiovascular diseases. More recently, we discovered that the S* hydrochloride salt of Compound A has advantages Jver Compound A and other salts and solvates thereof both in its preparation and in its use in medicine. The hydrochloride salt is described in our British 0* Patent No. 2127406.
Compound A is unfortunately only sparingly soluble in water and formulations in water containing the hydrochloride salt of Compound A together with standard excipients and/or carriers have proved to be unacceptable for intravenous administration as the hydrochloride salt of Compound A is converted to the virtually insoluble Compound A at ****near to physiological pH.
We have now found that the solubility in water of Compound A or its hydrochloride salt at around physiological pH is significantly improved in the presence of an unsubstituted or substituted p- or y-cyclodextrin (or a hydrate thereof). We have also found that aqueous formulations comprising Compound A or the hydrochloride salt thereof and an unsubstituted or substituted p- or y-cyclodextrin (or a hydrate thereof) are soitable for use in medicine, more particularly for use in the treatment or prophylaxis of conditions mediated by thromboxane A 2 when administered either orally, by inhalation or parenterally, in particular by injection (eg intravenously).
Thus, according to one aspect of the present invention, we provide an aqueous formulation comprising Compound A or the KI hydrochloride salt thereof with an unsubstituted or substituted a-, "I P or y-cyclodextrin (or a hydrate thereof).
5 In another aspect of the invention, we provide an aqueous formulation as defined herein for use in medicine, more particularly for use in the treatment or prophylaxis of conditions mediated by i ithromboxane A 2 According to another aspect of the invention, we provide a method of treating conditions mediated by thromboxane A 2 which method 'i .comprise administering to the human or animal patient an effective amount of Compound A in an aqueous formulation as defined herein.
Suitable conditions which may be treated with aqueous formulations of the present invention include those conditions 15 described in British Patents Nos. 2097397 and 2127406 treated using other oral) formulations 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 i 20 infarction, cardiac fatalities, unstable angina, transient ischaemic attacks and cerebral infarction, atherosclerosis and vessel wall .disease, peripheral vascular disease, retinopathy, postoperative thrombosis and pulmonary embolism. The aqueous formulations may also be used in the prophylaxis of peri- and postoperative complications following organ transplantation (particularly cardiac and renal), coronary artery bypass, peripheral artery bypass and thrombolysis.
The aqueous formulations are also of potential use in connection with j jpeptic ulcer disease, more particularly for the prevention of relapse of healed peptic ulcers.
-3- Preferably, in the aqueous formulations of the present invention Compound A is 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 than one cyclodextrin, although the use of a single cyclodextrin is generally preferred.
SWhere 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 abcording to the present invention will be readily appreciated by persons skilled in the art and will include sulphur-containing cyclodextrins, nitrogen-containing cyclodextrins, alkylated (e.g.
methylated) cyclodextrins such as mono-, di- or trimethylated derivatives of a cyclodextrin of p-cyclodextrin) and 15 hydroxyalkyl hydroxypropyl) cyclodextrins such as hydroxypropyl p-cyclodextrin and acylated derivatives thereof. Hydroxyalkyl (e.g.
hydroxypropyl) cyclodextrins such as hydroxypropyl p-cyclodextrin have been found to be particularly suitable for use according to the present invention.
20 Conveniently a single unsubstituted cyclodextrin is employed according to the present invention. Particularly preferred is p-cyclodextrin, conveniently used in its hydrated form.
In order for the aqueous formulation to exhibit the desired properties it is important that the correct molar ratio of Compound A i 25 or its hydrochloride salt to the cyclodextrin(s) is used. We have I found a molar ratio of Compound A or its hydrochloride salt to the cyclodextrin(s) within the range 1:1 to 1:4 to be suitable.
It will be appreciated by persons skilled in the art that the aqueous formulations of the present invention may, if desired, also contain one or more pharmaceutical carriers or excipients.
Suitable excipients which may be incorporated into the aqueous formulation include agents to make the preparation isotonic with blood plasma sodium chloride, dextrose or preferably mannitol) and buffering agents phosphate buffer or a mixture of sodium acid phosphate and disodium phosphate).
-4- The aqueous formulations of the present invention are particularly suitable for parenteral administration in particular by injection (eg intravenously). When presented for parenteral administration it is desirable 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 suitable base such as a hydroxide an alkali metal hydroxide such ii as sodium hydroxide solution). Conveniently, the pH is adjusted to about pH i 10 For parenteral administration, in particular for administration by injection (eg intravenously), it is highly desirable for the !i formulation to be presented as a clear solution. A clear solution S requires no further processing constitution of a dry powder) and may be administered without delay. The use of a clear solution 15 also ensures that the product can be easily inspected for particuleite i; or other visible contamination. Furthermore, intravenous injection 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 mule of the hydrochloride of Compound A in order 20 to obtain a clear solution at near to physiological pH at normal storage temperatures, and in the case of p-cyclodextrin at least about 1.2 moles must be used.
S In a preferred embodiment of the present invention, therefore, we provide a clear aqueous formulation comprising the hydrochloride salt 25 of Compound A and p-cyclodextrin (or a hydrate thereof), at about .physiological pH wherein the formulation contains at least about 1.2 I, moles of P-cyclodextrin 1.2 to 2 moles) for every one mole of the hydrochloride salt of Compound 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 particular for administration by injection (eg intravenously), is conveniently within the range 0.l-lOmg/ml, e.g.
0.1-5mg/ml, expressed as the free base. Preferably, the concentration is lmg/ml expressed as the free base when the aqueous formulation is administered by intravenous injection. If desired, a higher -I II -IIC---r_-LIIC I~-----c-rma~ur 5 concentration may be used and the solution may be diluted prior to use with, for example, an isotonic saline solution or dextrose or mannitol solution. Conveniently, solutions suitable for injection are presented in. an appropriate dose volume (eg 1 100 ml). Dilutions suitable for continuous infusion may have a concentration of Compound ji A or its hydrochloride salt of 0.01 0.2mg/ml expressed as the free base. The solution for continuous infusion may be presented in this form, for example in packs of 50-100ml, or may be presented in more concentrated forms for subsequent dilution before use with, for example, an isotonic saline solution or dextrose or mannitol solution. Alternatively, small volumes of a more concen rated solution (eg 0.1 5 mg/ml) may be utilised for continuods infusion I conveniently administered at a rate of 0.5 to 9.9ml/h.
The aqueous formulations described herein may conveniently be i 15 prepared by mixing Compound A or, more preferably, its hydrochloride 0 salt with the remaining constituents in water. Preferably, Compound A or its hydrochloride salt are dissolved in water and the remaining constituents are added thereto. For parenteral administration, in particular by injection (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 suitable containers.
It will be appreciated that water suitable for injection will be used when the parenteral formulation is to be administered intravenously or by continuous infusion.
o Formulations for injection may be presented in unit dose form in .suitable containers such as ampoules, vials or pre-filled syringes, or in multi-dose containers with an added preservative.
As stated hereinbefore, the aqueous formulations of the present invention are also suitable for oral administration (eg as a capsule, syrup or solution) or for admihistration by inhalation (eg as an aerosol spray conveniently presented as a nebuliser). British Patent Nos. 2097397 and 2127406 provide suitable general methods for the preparation of oral and inhalation formulations which may be readily adapted without undue experimentation for present purposes.
Aqueous formulations may also be prepared by dissolving a solid cyclodextrin complex of Compound A or its hydrochloride salt in water together, where desirable, with one or more other constituents as defined above.
-4
A
6 Thus, in a further aspect of the present invention, we provide an aqueous formulation comprising a complex of Compound A or the hydrochloride salt 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 cyclodextrin within the range 1:1 to 1:3 to be suitable.
The cyclodextrin employed in the solid complex may be i unsubstituted or substituted p- or y-cyclodextrin as defined previously or may be a mixture of such cyclodextrins (e.g a mixture of two such cyclodextrins). Preferably y-cyclodextrin or, more i preferably, p-cyclodextrin is employed.
In a particular aspect of the present invention we provide a complex of Compound A and p-cyclodextrin in which the molar ratio of Compound A to p-cyclodextrin is within the range 1:1 to 1:2, and is 20 preferably about 1:1.
SIn another particular aspect of the present invention we provide a complex of Compound A and y-cyclodrextrin in which the molar ratio i of Compound A to y-cyclodextrin is about 1:1.5.
Complexes of Compound A or the hydrochloride salt thereof and cyclodextrin may be prepared by mixing Compound A or its hydrochloride salt with the cyclodextrin(s) or a hydrate thereof in a suitable solvent under conditions whereby the desired complex is formed. Thus, for example, the complexes may be prepared by dissolving Compound A or it hydrochloride salt in water or an organic solvent which is miscible with water an alcohol such as methanol) and adding to the solution a solution of the appropriate cyclodextrin(s) or a hydrate thereof in water and/or an organic solvent which is miscible with water. The reaction may be effected at a temperature in the range of 00 to 80 0 C; however the mixture is preferably kept at around room temperature and the desired complex obtained by concentrating the L 7i 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 may be obtained as white solids with high thermal stability and good water solubility, Such physical characteristics make them particularly suitable for formulation into pharmaceutical preparations for medical use. In addition to the aforementioned aqueous formulations of complexes of Compound A or its Shydrochloride salt and cyclodextrin suitable particularly for parenteral administration, the complexes may also be formulated for oral or parenteral administration or for administration by inhalation i according to the general methods described in British Patent Nos.
i: 1 2097397 and 2127406.
i An appropriate daily dose regime for Compound A or its hydrochloride salt when employed in one of the formulations of the present invention will, of course, depend on the specific condition to i be treated, the age and condition of the patient and the route of 20 administration. However, generally the dosages quoted in British Patent Nos. 2097397 and 2127406 will be suitable.
e The following examples are included by way of illustrating the present invention and should not be construed as a limitation of the invention. In the following examples the molar ratios were determined S 25 by 'H N.M.R. analysis and all temperatures are in OC.
I Example 1 [lR-[la(Z),20,3p,5a]]-(+)-7-[5-[[(1,1'-Biphenyl)-4-yl]methoxy]-3hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoate: P-cyclodextrin (lI1) complex P-Cyclodextrin hydrate (0.954g) was nearly completely dissolved in water (35ml). The suspension was filtered and the filtrate added to a solution of Compound A (0.2g, Example 10 in GB-B-2097397) in methanol (10ml). The reaction solution was stirred at 210 for 26h to give a clear solution which was evaporated to a volume of 12ml when
V
3 i 5 1 -t
I
I'?i =A l 7 8 slight crystallisation began to occur. The suspension was cooled to 50 for lh to produce a thick precipitate which was filtered off and dried to give the title compound (0.273g), m.p. >3100, darkens above 2300.
The filtrate from the above experiment began to precipitate more crystalline material on standing and was therefore evaporated to leave a white solid which was dissolved in hot water (3ml), cooled (50) and allowed to crystallise to give a white crystalline solid (121mg) shown by 1 H N.M.R. (DMSO) analysis to contain [5-[[(1,1'-biphenyl)-4-yl]methoxy]-3-hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoate p-cyclodextrin complex.
I I m I i. S.
i.i i i:i
;I
j Q i *5
S
o 5**
S
Example 2 [1R-[la(Z),2g,3p,5a3]-(+)-7-[5-[[(1,l'-Biphenyl)-4-yl]methoxy]-3- 15 hydroxy-2-(l-piperidinyl)cyclopentyl]-4-heptenoate: y-cyclodextrin complex A solution of y-cyclodextrin (1.09g) in water (25ml) was added to a solution of Compound A (0.20g) in methanol (lOml). The reaction solution was stirred at 210 for 26h to produce a thick white 20 suspension. The precipitate was filtered off and dried in vacuo to leave the title compound as a white solid (0.612g), m.p. >3100, darkens above 2500.
Pharmaceutical examples of parenteral injections/infusions Hydrochloride salt of Compound A equivalent to 50 mg base p-Cyclodextrin hydrate Sodium hydroxide solution Water suitable for injection 143mg 166mg 238mg to pH7 to pH7 to pH7 to 50ml to 50ml to 9 The hydrochloride salt of Compound A was dissolved in 35ml water suitable for injection and the p-cyclodextrin was added. This solution was titrated to pH7 with 0.02M sodium hydroxide solution and then adjusted to volume with water suitable for injection.
The solution may then be sterilised by filtration and filled into vials or ampoules.
(ii) Hydrochloride salt of Compound A equivalent to 50mg base p-Cyclodextrin hydrate 166mg Sodium chloride 450mg 15 pH7.0 phosphate buffer Sodium hydroxide solution to pH7 20 Water suitable for injection to The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection. The p-cyclodextrin was dissolved therein and the resulting solution was titrated to pH6 with 0.02M sodium hydroxide solution and the phosphate buffer added. The sodium chloride was added to the solution and the pH adjusted to pH7 with sodium hydroxide. The solution was made up to volume with water suitable for injection. A sample of this solution was filled into a glass vial which was sealed with a rubber plug and metal overseal.
This was then autoclaved.
1 I 10 (iii) Hydrochloride salt of Compound A equivalent to 50 mg base 1 Hydroxypropyl-p-cyclodextrin 170mg Mannitol pH 6.0 phosphate buffer V 10 Sodium hydroxide solution to pH 6 0 Water suitable for injection to 'The hydrochloride salt of Compound A was dissolved in 15 approximately 25ml water suitable for injection and the hydroxypropyl-p-cyclodextrin was added. The mannitol was then added i and the solution titrated to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer solution was added and the solution adjusted to volume with water suitable for injection. The solution 20 was then filtered and filled into glass vials which were sealed with i rubber plugs and metal overseals. These were then autoclaved.
I (iv) Hydrochloride salt of Compound A I equivalent to 50mg base S" p-Cyclodextrin hydrate 166mg Mannitol Sodium acid phosphate 46mg Disodium phosphate, anhydrous Sodium hydroxide solution to pH 6 Water suitable for injection to 11 The hydrochloride salt of Compound A was dissolved ir approximately 25ml water suitable for injection. The p-cyclodextrin and mannitol were dissolved therein and the solution titrated to pH 6 with 0.02M sodium hydroxide solution. The sodium acid phosphate and anhydrous disodium phosphate were dissolved in water suitable for S injection. This solution was added to the bulk solution which was made up to volume with water suitable for injection. The solution was filtered and filled into glass ampoules which were sealed and then autoclaved.
i Cyclodextrin Mixture *c j s n 5 Hydrochloride salt of Compound A equivalent to 50mg base e Cyclodextrin 143mg 190mg 119mg 136mg Mannitol 2.5g 2.5g pH 6.0 Phosphate buffer 5.0ml 5.0ml *i Sodium hydroxide solution to pH 6 to pH 6 to pH6 Water suitable for injection to 50ml to 50 ml to I The hydrochloride salt of Compound A was dissolved in approximately 25ml water suitable for injection and the cyclodextrin(s) was (were) added. The mannitol was then added and the solution titrated to pH 6 with 0.02M sodium hydroxide solution. The phosphate buffer solution was added and the solution was adjusted to volume with water suitable for injection. The solution was then filtered and filled into glass vials which were sealed with rubber plugs and metal oveseals.
plugs and metal overseals.
j i ~lanc~ rxu-LI-
I
12 Pharmaceutical example of oral syrup Hydrochloride salt of Compound A equivalent to 2.5mg base p-cyclodextrin hydrate 9mg Citric acid to pH S* S
S*
Methyl hydroxybenzoate sodium Propyl hydroxybenzoate sodium Liquid orange flavour Sucrose 3.25g Purified water to
I
S
S
Dissolve the sucrose in a minimum quantity of water. Add the hydrochloride salt of Compound A and then the p-cyclodextrin with stirring; adjust the pH to 4.5 with citric acid. With continued stirring add a solution of the hydroxybenzoates and lastly the flavour. Adjust almost to volume with water and stir. Check the pH 2 and adjust to 4.5 with citric acid if necessary. Make up to volume with water.
t -i
'F:
i d i i: r tx i i i ::j
~L"
i
T
-13 j Pharmaceutical example of solution for inhalation Per 2ml dose Hydrochloride salt of Compound A equivalent to 2mg base p p-cyclodextrin hydrate 7mg j Sodium chloride 18mg Sodium hydroxide solution to pH 7.2 pH 7.2 phosphate buffer 0.2ml S* Water suitable for injection to 2ml Dissolve the hydrochloride salt of Compound A in water suitable for injection. Dissolve the p-cyclodextrin therein and titrate the resulting solution to pH6 with sodium hydroxide solution; add the phosphate buffer solution. Add the sodium chloride and adjust to 20 pH7.2 with sodium hydroxide solution. Make the solution up to volume with water suitable for injection and sterilize the solution by filtration. Fill aseptically into containers suitable for inhalation S* by nebulising.
3..
.1
Claims (11)
1. An aqueous formulation comprising [[(1,1'-biphenyl)-4-yl]mnethoxy]-3-hydroxy-2-(1-piperidinyl) cyclopentyl]-4-heptenoic acid (Compound A) or the hydrochloride salt thereof with an unsubstituted or substituted p- or y-cyclodextrin or a hydrate thereof.
2. A formulation as claimed in its hydrochloride salt.
3. A formulation as claimed in cyclodextrin is p-cyclodextrin.
4. A formulation as claimed in suitable for injection. claim 1 wherein Compound A is used as claim 1 or claim 2 wherein the any preceding claim in a form A clear aqueous formulation as claimed in claim 4 comprising the hydrochloride salt of Compound A and p-cyclodextrin or a hydrate thereof at about physiological pH wherein the formulation contains at least 1.2 moles of p-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 p-cyclodextrin is 1:1.4. P:: i; i i t Ji *e «e
7. A formulation as claimed in any of claims 4-6 in which the pH is
8. A formulation as claimed in any of claims 4-7 also comprising sodium hydroxide.
9. A formulation as claimed in any of claims 4-8 having a concentration of 0.1-5mg/ml Compound A or the hydrochloride salt thereof expressed as the free base. 15 A formulation as claimed in any of claims 4-8 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 base.
11. A process for the preparation of a formulation as claimed in any preceding claim which comprises mixing Compound A or its hydrochloride salt with the remaining constituents in water. 1 12. A complex of Compound A or its hydrochloride salt and an unsubstituted or substituted p- or y-cyclodextrin.
13. A complex of Compound A and p-cyclodextrin in which the molar ratio of Compound A to p-cyclodextrin is 1:1.
14. A method of treating conditions mediated by.thromboxane A 2 which method comprises administering to a human or animal patient an effective amount of a formulation as claimed in any one of claims 1 to 10 or a complex as claimed in claim 12 or 13. S DATED this llth day of July 1991. GLAXO GROUP LIMITED S* By Its Patent Attorneys ARTHUR S. CAVE CO. S. i
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 (2)
| Publication Number | Publication Date |
|---|---|
| AU2735688A AU2735688A (en) | 1989-06-22 |
| AU615245B2 true AU615245B2 (en) | 1991-09-26 |
Family
ID=26293226
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| AU27356/88A Ceased AU615245B2 (en) | 1987-12-22 | 1988-12-21 | Aqueous formulations containing a piperidinylcyclopentylheptenoic 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) |
Families Citing this family (5)
| 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. |
| 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 |
Family Cites Families (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| JPS5973576A (en) * | 1982-09-16 | 1984-04-25 | グラクソ・グル−プ・リミテツド | Piperidinylcyclopentanolheptanoate |
| 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 |
| JPS6327440A (en) * | 1986-07-18 | 1988-02-05 | Sanraku Inc | Glucosylated branched cyclodextrin-containing composition |
-
1988
- 1988-12-21 ZW ZW180/88A patent/ZW18088A1/en unknown
- 1988-12-21 IT IT8848702A patent/IT1224835B/en active
- 1988-12-21 CA CA000586606A patent/CA1328078C/en not_active Expired - Fee Related
- 1988-12-21 GR GR880100854A patent/GR880100854A/en unknown
- 1988-12-21 PT PT89301A patent/PT89301B/en not_active IP Right Cessation
- 1988-12-21 CN CN88108916A patent/CN1034132A/en active Pending
- 1988-12-21 LU LU87411A patent/LU87411A1/en unknown
- 1988-12-21 CH CH4758/88A patent/CH676665A5/de not_active IP Right Cessation
- 1988-12-21 DE DE3843059A patent/DE3843059A1/en not_active Ceased
- 1988-12-21 IE IE382088A patent/IE61995B1/en not_active IP Right Cessation
- 1988-12-21 NZ NZ227446A patent/NZ227446A/en unknown
- 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 AT AT0313088A patent/AT395943B/en not_active IP Right Cessation
- 1988-12-21 FR FR8816902A patent/FR2624731B1/en not_active Expired - Fee Related
- 1988-12-21 AU AU27356/88A patent/AU615245B2/en not_active Ceased
- 1988-12-21 BE BE8801423A patent/BE1001704A3/en not_active IP Right Cessation
- 1988-12-21 DK DK712888A patent/DK712888A/en not_active Application Discontinuation
- 1988-12-21 HU HU886537A patent/HU204700B/en not_active IP Right Cessation
- 1988-12-21 SE SE8804607A patent/SE502288C2/en not_active IP Right Cessation
- 1988-12-21 PL PL27659588A patent/PL276595A1/en unknown
- 1988-12-21 NO NO88885689A patent/NO885689L/en unknown
- 1988-12-21 ES ES8803876A patent/ES2011727A6/en not_active Expired - Fee Related
- 1988-12-21 PH PH37963A patent/PH24982A/en unknown
- 1988-12-21 NL NL8803126A patent/NL8803126A/en not_active Application Discontinuation
- 1988-12-21 GB GB8829793A patent/GB2211737B/en not_active Expired - Fee Related
- 1988-12-21 KR KR1019880017106A patent/KR890009402A/en not_active Application Discontinuation
- 1988-12-22 MY MYPI88001508A patent/MY103952A/en unknown
- 1988-12-22 IL IL88764A patent/IL88764A0/en not_active IP Right Cessation
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