KR920000306B1 - 니모디핀-함유 제제의 제조방법 - Google Patents
니모디핀-함유 제제의 제조방법 Download PDFInfo
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- KR920000306B1 KR920000306B1 KR1019840002390A KR840002390A KR920000306B1 KR 920000306 B1 KR920000306 B1 KR 920000306B1 KR 1019840002390 A KR1019840002390 A KR 1019840002390A KR 840002390 A KR840002390 A KR 840002390A KR 920000306 B1 KR920000306 B1 KR 920000306B1
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- Prior art keywords
- weight
- nimodipine
- solvent
- ethanol
- propylene glycol
- Prior art date
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- UIAGMCDKSXEBJQ-IBGZPJMESA-N 3-o-(2-methoxyethyl) 5-o-propan-2-yl (4s)-2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COCCOC(=O)C1=C(C)NC(C)=C(C(=O)OC(C)C)[C@H]1C1=CC=CC([N+]([O-])=O)=C1 UIAGMCDKSXEBJQ-IBGZPJMESA-N 0.000 title claims description 17
- 229960000715 nimodipine Drugs 0.000 title claims description 17
- 238000002360 preparation method Methods 0.000 title claims description 10
- 238000004519 manufacturing process Methods 0.000 title description 2
- DNIAPMSPPWPWGF-UHFFFAOYSA-N Propylene glycol Chemical compound CC(O)CO DNIAPMSPPWPWGF-UHFFFAOYSA-N 0.000 claims description 15
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000002904 solvent Substances 0.000 claims description 8
- 229920001223 polyethylene glycol Polymers 0.000 claims description 6
- 239000002202 Polyethylene glycol Substances 0.000 claims description 5
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 5
- 239000000654 additive Substances 0.000 claims description 2
- 238000000034 method Methods 0.000 claims 2
- 230000007971 neurological deficit Effects 0.000 description 4
- 238000011282 treatment Methods 0.000 description 4
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 239000003086 colorant Substances 0.000 description 3
- 208000001286 intracranial vasospasm Diseases 0.000 description 3
- 230000000302 ischemic effect Effects 0.000 description 3
- 239000007788 liquid Substances 0.000 description 3
- 206010059109 Cerebral vasoconstriction Diseases 0.000 description 2
- 208000008457 Neurologic Manifestations Diseases 0.000 description 2
- FDSDTBUPSURDBL-LOFNIBRQSA-N canthaxanthin Chemical compound CC=1C(=O)CCC(C)(C)C=1/C=C/C(/C)=C/C=C/C(/C)=C/C=C/C=C(C)C=CC=C(C)C=CC1=C(C)C(=O)CCC1(C)C FDSDTBUPSURDBL-LOFNIBRQSA-N 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 235000012732 erythrosine Nutrition 0.000 description 2
- 239000004174 erythrosine Substances 0.000 description 2
- 238000001361 intraarterial administration Methods 0.000 description 2
- 238000001990 intravenous administration Methods 0.000 description 2
- 239000000243 solution Substances 0.000 description 2
- 239000003381 stabilizer Substances 0.000 description 2
- YNGDWRXWKFWCJY-UHFFFAOYSA-N 1,4-Dihydropyridine Chemical compound C1C=CNC=C1 YNGDWRXWKFWCJY-UHFFFAOYSA-N 0.000 description 1
- WLDHEUZGFKACJH-ZRUFZDNISA-K Amaranth Chemical compound [Na+].[Na+].[Na+].C12=CC=C(S([O-])(=O)=O)C=C2C=C(S([O-])(=O)=O)C(O)=C1\N=N\C1=CC=C(S([O-])(=O)=O)C2=CC=CC=C12 WLDHEUZGFKACJH-ZRUFZDNISA-K 0.000 description 1
- 208000032843 Hemorrhage Diseases 0.000 description 1
- OOUTWVMJGMVRQF-DOYZGLONSA-N Phoenicoxanthin Natural products CC(=C/C=C/C=C(C)/C=C/C=C(C)/C=C/C1=C(C)C(=O)C(O)CC1(C)C)C=CC=C(/C)C=CC2=C(C)C(=O)CCC2(C)C OOUTWVMJGMVRQF-DOYZGLONSA-N 0.000 description 1
- 208000032851 Subarachnoid Hemorrhage Diseases 0.000 description 1
- 208000003443 Unconsciousness Diseases 0.000 description 1
- 230000001154 acute effect Effects 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- 239000003708 ampul Substances 0.000 description 1
- DFMMVLFMMAQXHZ-CMGSAFQJSA-N apocarotenal Chemical compound O=CC(/C)=C/C=C/C(/C)=C/C=C/C=C(\C)/C=C/C=C(\C)C=CC1=C(C)CCCC1(C)C DFMMVLFMMAQXHZ-CMGSAFQJSA-N 0.000 description 1
- 229940019834 apocarotenal Drugs 0.000 description 1
- 208000034158 bleeding Diseases 0.000 description 1
- 230000000740 bleeding effect Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000004556 brain Anatomy 0.000 description 1
- 208000029028 brain injury Diseases 0.000 description 1
- 235000012682 canthaxanthin Nutrition 0.000 description 1
- 239000001659 canthaxanthin Substances 0.000 description 1
- 229940008033 canthaxanthin Drugs 0.000 description 1
- 150000001875 compounds Chemical class 0.000 description 1
- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- IINNWAYUJNWZRM-UHFFFAOYSA-L erythrosin B Chemical compound [Na+].[Na+].[O-]C(=O)C1=CC=CC=C1C1=C2C=C(I)C(=O)C(I)=C2OC2=C(I)C([O-])=C(I)C=C21 IINNWAYUJNWZRM-UHFFFAOYSA-L 0.000 description 1
- 229940011411 erythrosine Drugs 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 208000014674 injury Diseases 0.000 description 1
- 238000010253 intravenous injection Methods 0.000 description 1
- 238000011835 investigation Methods 0.000 description 1
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 230000000069 prophylactic effect Effects 0.000 description 1
- 238000011321 prophylaxis Methods 0.000 description 1
- 210000003625 skull Anatomy 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- NLJMYIDDQXHKNR-UHFFFAOYSA-K sodium citrate Chemical group O.O.[Na+].[Na+].[Na+].[O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O NLJMYIDDQXHKNR-UHFFFAOYSA-K 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000004173 sunset yellow FCF Substances 0.000 description 1
- 238000001356 surgical procedure Methods 0.000 description 1
- 239000004149 tartrazine Substances 0.000 description 1
- 230000008733 trauma Effects 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Dermatology (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Hydrogenated Pyridines (AREA)
- Medicinal Preparation (AREA)
Abstract
내용 없음.
Description
본 발명은 니모디핀이 용매중에 용해된 니모디핀-함유 비경구용 제제를 제조하는 방법에 관한 것이다.
또한, 본 발명은 니모디핀-함유 비경구용 제제 및 이 제제를 질병 치료에 사용하는 용도에 관한 것이다.
니모디핀은 3-β-메톡시에틸 5-이소프로필 1,4-디하이드로-2,6-디메틸-4-(3-니트로페닐)피리딘-3,5-디카복실레이트라는 명칭의 디하이드로피리딘 유도체로 독일연방공화국 공개특허공보 제2,815,578호에 기술되어 있다. 뇌 혈행 장해의 치료에 사용되는 니모디핀의 용도는 상기 공개특허공보에 상세히 기술되어 있다.
의식이 없거나 마취된 환자는 그 상태에서 활성 화합물을 섭취할 수 없기 때문에 내복약에 이용하는 니모디핀의 비경구용 제제를 제조하는데 대한 필요성이 대두되었다.
본 발명은 30 내지 70중량%, 바람직하게는 45 내지 70중량%의 물, 15 내지 40중량%, 바람직하게는 15 내지 30중량%의 프로필렌 글리콜 및/또는 바람직하게는 평균분자량이 200,400 및 600인 폴리에틸렌 글리콜, 15 내지 30중량%, 바람직하게는 15 내지 25중량%의 에탄올로 구성된 용매 100중량부에 대해 0.01 내지 0.4중량%의 니모디핀 및 적절하게는 통상적인 보조제 및/또는 첨가제를 함유함을 특징으로 하는 니모디핀-함유 비경구용 제제에 관한 것이다.
비경구라는 용어는 특히 정맥내, 동맥내 및 지망막하조내(intracisternal)를 포함한다.
니모디핀은 태양 광선에 대해 감광성이 있기 때문에 빛으로부터의 보호와 안정화의 목적으로 액제에 착색제를 첨가할 필요가 있다. 적합한 착색제에는 예를들어 아포카로텐알, 칸타크산틴, 타트라진(E 102), 아마란스(E 123) 및 에리스로신(E 127), 특히 이엘로우-오렌지 에스(E 110)가 있다. 착색제를 사용할 경우 농도는 액제를 기준하여 0.01 내지 0.5중량%, 바람직하게는 0.1 내지 0.4중량%이다.
광선으로부터의 보호를 위해 액제 대신 특정파장의 빛이 전혀 또는 거의 투과하지 못하도록 빛에 불투명한 주사용 바이알제 또는 앰플제를 제조할 수도 있다.
본 발명에 따른 제제의 제조는 우선 용매, 에탄올, 프로필렌 글리콜 및/또는 폴리에틸렌 글리콜에 니모디핀을 용해시키고, 계속해서 물을 첨가하여 수행한다. 용액의 통상적인 안정화제는 용액을 안정화시키는데 필요하고, 안정화제에는 예를들어 용매의 100중량부를 기준으로 하여 0.15 내지 2.5, 바람직하게는 1.8 내지 2.2중량%의 3급 나트륨 시트레이트 및/또는 0.2 내지 0.6, 바람직하게는 0.2 내지 0.5중량%의 시트르산이 있다.
본 발명에 따르는 제제는 급성 뇌혈행장해, 예를들어 뇌혈관경련에 따르는 허혈성 신경학적 결손, 두 개골의 외상, 허혈성 뇌손상 또는 뇌소생의 치료에 적합하다.
통상적으로 유효한 결과를 달성하는데 니모디핀을 다음 용량으로 투여하는 것이 유리하다 :
정맥내 투여시 약 0.5 내지 0.4mg/시간, 바람직하게는 1 내지 3mg/시간; 동맥내투여시 약 0.05 내지 0.5mg/시간, 바람직하게는 0.1 내지 0.25mg/시간; 및 지망막하조내 투여시 약 100 내지 300㎍. 경우에 따라, 상기 용량에서 벗어날 필요가 있는데 특히 체중, 약제에 대한 개체의 반응 또는 투여 시간 또는 간격에 따라 용량을 조절한다. 어떤 경우에는 상기 서술한 최소량이하로 처리함으로써 충분하고, 또 어떤 경우에는 상기 서술한 상한량을 초과해야만 한다.
[실시예]
[임상결과]
뇌 혈관경련에 의한 신경학적 결손의 탁월한 억제작용 및 사망율의 감소를 지망막하 출혈환자에게 예방적으로 수술시 지망막하조내로 니모디핀 200㎍을 투여하고, 연이어 수일간 계속 정맥내로 니모디핀 1 내지 3mg/시간을 투여함으로써 확인할 수 있었다. 70명의 환자중 신경학적 결손을 일으키는 환자는 한명도 없었고 사망한 환자도 없었다. 이와는 반대로, 유사한 환자로 구성된 대조 그룹에서 환자의 10 내지 32%가 심한 허혈성 합병증을 일으켜서 사망에 이르렀음이 공지 문헌에 보고되어 있다.
2차 시험에서, 지망막하 출혈후 뇌 혈관 경련에 따르는 신경학적 결손을 치료하기 위해 니모디핀을 0.5 내지 3mg/시간 용량으로 정맥내 주입시 사망율은 18%였으며, 이와는 달리 공지의 문헌은 이 임상적 상태에서 사망율이 20 내지 50%임을 보고하고 있다. 비록 환자를 불리한 판단기준으로 선택했지만, 환자의 2/3는 치료완료 후 완전히 회복되거나 탁월하게 개선되었다.
실시예 1을 조사의 기본으로 사용하였다.
Claims (3)
- 니모디핀을 용매인 에탄올 및 프로필렌 글리콜 및/또는 폴리에틸렌 글리콜에 용해시킨 후 물을 첨가함을 특징으로 하여, 30 내지 70중량%의 물, 15 내지 40중량%의 프로필렌 글리콜 및/또는 폴리에틸렌 글리콜, 및 15 내지 30중량%의 에탄올로 구성된 용매 100중량부를 기준으로 하여 0.01 내지 0.4중량%의 니모디핀, 및 경우에 따라, 통상적인 보조제 및/또는 첨가제를 함유하는 니모디핀-함유 비경구용 제제를 제조하는 방법.
- 제1항에 있어서, 용매가 45 내지 70중량%의 물, 15 내지 30중량%의 프로필렌 글리콜 및/또는 폴리에틸렌 글리콜, 및 15 내지 25중량%의 에탄올로 구성됨을 특징으로 하는 방법.
- 제1항 또는 2항에 있어서, 용매가 평균 분자량 200,400 및/또는 600의 폴리에틸렌 글리콜을 함유함을 특징으로 하는 방법.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19833316510 DE3316510A1 (de) | 1983-05-06 | 1983-05-06 | Parenterale formulierung von nimodipin, ein verfahren zu ihrer herstellung sowie ihre verwendung bei der bekaempfung von erkrankungen |
| DEP3316510.6 | 1983-05-06 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| KR840009031A KR840009031A (ko) | 1984-12-24 |
| KR920000306B1 true KR920000306B1 (ko) | 1992-01-11 |
Family
ID=6198265
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| KR1019840002390A KR920000306B1 (ko) | 1983-05-06 | 1984-05-03 | 니모디핀-함유 제제의 제조방법 |
Country Status (19)
| Country | Link |
|---|---|
| US (1) | US5114956A (ko) |
| EP (1) | EP0126315B1 (ko) |
| JP (1) | JPS59206305A (ko) |
| KR (1) | KR920000306B1 (ko) |
| AT (1) | ATE24835T1 (ko) |
| AU (1) | AU562293B2 (ko) |
| BE (1) | BE899564A (ko) |
| CA (1) | CA1220424A (ko) |
| DE (2) | DE3316510A1 (ko) |
| DK (1) | DK164148C (ko) |
| ES (1) | ES531995A0 (ko) |
| FR (1) | FR2545354B1 (ko) |
| GR (1) | GR81609B (ko) |
| HK (1) | HK75889A (ko) |
| IL (1) | IL71744A (ko) |
| IT (1) | IT1181804B (ko) |
| PT (1) | PT78542B (ko) |
| SG (1) | SG44489G (ko) |
| ZA (1) | ZA843352B (ko) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JPS60246313A (ja) * | 1984-05-22 | 1985-12-06 | Yamanouchi Pharmaceut Co Ltd | 塩酸ニカルジピンの注射剤およびその製法 |
| FR2585574B1 (fr) * | 1985-07-31 | 1988-09-09 | Corbiere Jerome | Nouvelles compositions pharmaceutiques anti-glaucomateuses a base de 1,4-dihydropyridines et leur procede d'obtention |
| DE3544692A1 (de) * | 1985-12-18 | 1987-06-19 | Bayer Ag | Dihydropyridinspray, verfahren zu seiner herstellung und seine pharmazeutische verwendung |
| AT387518B (de) * | 1985-12-18 | 1989-02-10 | Bayer Ag | Verfahren zur herstellung von fluessigen spruehpraeparaten von dihydropyridinen |
| DE3702105A1 (de) * | 1987-01-24 | 1988-08-04 | Bayer Ag | Parenterale loesung |
| BE1003647A5 (fr) * | 1989-02-28 | 1992-05-12 | Syntex Inc | Composition pharmaceutique de nicardipine pour administration parenterale. |
| RU1804845C (ru) * | 1991-02-15 | 1993-03-30 | Институт Органического Синтеза Латвийской Ан | Ноотропное вещество |
| KR100517210B1 (ko) * | 1994-12-12 | 2006-06-07 | 오메로스 코포레이션 | 통증,염증및경련억제용관주용액 |
| US6492332B1 (en) | 1995-12-12 | 2002-12-10 | Omeros Corporation | Irrigation solution and methods for inhibition of tumor cell adhesion, pain and inflammation |
| EP0799051B1 (en) * | 1994-12-12 | 2005-07-27 | Omeros Corporation | Irrigation solution and use thereof for perioperatively inhibiting pain, inflammation and spasm at a wound |
| BR9509985A (pt) | 1995-12-12 | 1998-11-03 | Omeros Med Sys Inc | Solução para irrigação e método para inibição de dor inflamação e esparmo |
| US6413961B1 (en) | 1995-12-12 | 2002-07-02 | Omeros Medical Systems, Inc. | Irrigation solution and method for inhibition of pain and inflammation |
| US6136799A (en) * | 1998-04-08 | 2000-10-24 | Abbott Laboratories | Cosolvent formulations |
| DE10142416A1 (de) * | 2001-08-31 | 2003-03-20 | Molecular And Clinical Drug Re | Verfahren zur Herstellung von Lösungen |
| DE10142417A1 (de) * | 2001-08-31 | 2003-03-20 | Molecular And Clinical Drug Re | Arzneimittel |
| US8034762B2 (en) * | 2004-09-02 | 2011-10-11 | Cognosci, Inc. | Treatment of subarachnoid hemorrhage with Apo E analogs |
| WO2007047406A2 (en) * | 2005-10-14 | 2007-04-26 | Transform Pharmaceuticals, Inc. | Liquid pharmaceutical compositions of nimodipine |
| WO2007125028A1 (de) * | 2006-04-28 | 2007-11-08 | Basf Se | Verfahren zur solubilisierung von hydrophoben wirkstoffen in wässrigem medium |
| EP2531548A1 (de) | 2010-02-05 | 2012-12-12 | Basf Se | Verfahren zur solubilisierung von hydrophoben wirkstoffen in wässrigem medium |
| US8728504B2 (en) | 2010-02-05 | 2014-05-20 | Basf Se | Process for solubilizing hydrophobic active ingredients in aqueous medium |
| MX360638B (es) | 2011-04-28 | 2018-11-12 | Univ Texas | Formulaciones parenterales mejoradas de agentes farmacéuticos lipofílicos y métodos para prepararlos y usarlos. |
| EP4032527A1 (en) | 2016-04-13 | 2022-07-27 | Grace Therapeutics Inc. | Stable nimodipine parenteral formulation |
| US10092553B2 (en) | 2016-04-13 | 2018-10-09 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
| WO2019165066A2 (en) | 2018-02-22 | 2019-08-29 | Nortic Holdings Inc. | Stable nimodipine parenteral formulation |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE2117571C3 (de) * | 1971-04-10 | 1979-10-11 | Bayer Ag, 5090 Leverkusen | Unsymmetrische 1,4-Dihydropyridin-33-dicarbonsäureester, Verfahren zu ihrer Herstellung sowie ihre Verwendung als Arzneimittel |
| US4154839A (en) * | 1975-11-05 | 1979-05-15 | Bayer Aktiengesellschaft | 2,6-Dimethyl-3-carboxymethoxy-4-(2-nitrophenyl)-5-carbisobutoxy-1,4-dihydropyridine |
| DE2650013C3 (de) * | 1976-10-30 | 1981-04-02 | Bayer Ag, 5090 Leverkusen | 1.4-Dihydro-2.6-dimethyl-4-(3-nitrophenyl)-3.5-pyridindicarbonsäureisopropyl-(2-propoxy-äthyl)-ester, Verfahren zu seiner Herstellung sowie ihn enthaltende Arzneimittel |
| DE2815578C2 (de) * | 1978-04-11 | 1986-01-16 | Bayer Ag, 5090 Leverkusen | Neue pharmazeutische Verwendung von Nimodipin |
| DE2841667A1 (de) * | 1978-09-25 | 1980-04-10 | Bayer Ag | Fluorhaltige 1,4-dihydropyridine, verfahren zu ihrer herstellung sowie ihre verwendung als arzneimittel |
-
1983
- 1983-05-06 DE DE19833316510 patent/DE3316510A1/de not_active Withdrawn
-
1984
- 1984-04-24 DE DE8484104563T patent/DE3461988D1/de not_active Expired
- 1984-04-24 AT AT84104563T patent/ATE24835T1/de not_active IP Right Cessation
- 1984-04-24 EP EP84104563A patent/EP0126315B1/de not_active Expired
- 1984-04-27 ES ES531995A patent/ES531995A0/es active Granted
- 1984-05-01 JP JP59086280A patent/JPS59206305A/ja active Granted
- 1984-05-02 AU AU27583/84A patent/AU562293B2/en not_active Expired
- 1984-05-03 IL IL71744A patent/IL71744A/xx not_active IP Right Cessation
- 1984-05-03 BE BE0/212864A patent/BE899564A/fr not_active IP Right Cessation
- 1984-05-03 KR KR1019840002390A patent/KR920000306B1/ko not_active IP Right Cessation
- 1984-05-04 FR FR8406974A patent/FR2545354B1/fr not_active Expired
- 1984-05-04 PT PT78542A patent/PT78542B/pt unknown
- 1984-05-04 ZA ZA843352A patent/ZA843352B/xx unknown
- 1984-05-04 CA CA000453627A patent/CA1220424A/en not_active Expired
- 1984-05-04 DK DK224184A patent/DK164148C/da not_active IP Right Cessation
- 1984-05-04 IT IT48139/84A patent/IT1181804B/it active
- 1984-05-04 GR GR74600A patent/GR81609B/el unknown
-
1989
- 1989-07-25 SG SG44489A patent/SG44489G/en unknown
- 1989-09-21 HK HK758/89A patent/HK75889A/xx not_active IP Right Cessation
-
1991
- 1991-01-15 US US07/641,323 patent/US5114956A/en not_active Expired - Lifetime
Also Published As
| Publication number | Publication date |
|---|---|
| FR2545354B1 (fr) | 1986-09-26 |
| ZA843352B (en) | 1984-12-24 |
| ES8505542A1 (es) | 1985-06-01 |
| DE3316510A1 (de) | 1984-11-08 |
| PT78542A (en) | 1984-06-01 |
| CA1220424A (en) | 1987-04-14 |
| ES531995A0 (es) | 1985-06-01 |
| AU562293B2 (en) | 1987-06-04 |
| DK224184D0 (da) | 1984-05-04 |
| US5114956A (en) | 1992-05-19 |
| DE3461988D1 (en) | 1987-02-19 |
| FR2545354A1 (fr) | 1984-11-09 |
| PT78542B (en) | 1986-07-14 |
| DK164148B (da) | 1992-05-18 |
| EP0126315A1 (de) | 1984-11-28 |
| IL71744A (en) | 1988-04-29 |
| ATE24835T1 (de) | 1987-01-15 |
| BE899564A (fr) | 1984-11-05 |
| EP0126315B1 (de) | 1987-01-14 |
| GR81609B (ko) | 1984-12-11 |
| JPH0422888B2 (ko) | 1992-04-20 |
| SG44489G (en) | 1989-11-17 |
| DK164148C (da) | 1992-10-26 |
| IT8448139A0 (it) | 1984-05-04 |
| JPS59206305A (ja) | 1984-11-22 |
| AU2758384A (en) | 1984-11-08 |
| IL71744A0 (en) | 1984-09-30 |
| HK75889A (en) | 1989-09-29 |
| IT1181804B (it) | 1987-09-30 |
| DK224184A (da) | 1984-11-07 |
| KR840009031A (ko) | 1984-12-24 |
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