ES2278647T3 - Nuevos procedimientos y composiciones que comprenden opioides y antagonistas de opioides. - Google Patents
Nuevos procedimientos y composiciones que comprenden opioides y antagonistas de opioides. Download PDFInfo
- Publication number
- ES2278647T3 ES2278647T3 ES00992256T ES00992256T ES2278647T3 ES 2278647 T3 ES2278647 T3 ES 2278647T3 ES 00992256 T ES00992256 T ES 00992256T ES 00992256 T ES00992256 T ES 00992256T ES 2278647 T3 ES2278647 T3 ES 2278647T3
- Authority
- ES
- Spain
- Prior art keywords
- opioid
- compound
- opioids
- compounds
- acid
- 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 - Lifetime
Links
- 229940005483 opioid analgesics Drugs 0.000 title claims description 35
- 239000000203 mixture Substances 0.000 title claims description 30
- 238000000034 method Methods 0.000 title description 20
- 239000003887 narcotic antagonist Substances 0.000 title description 4
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- 230000002093 peripheral effect Effects 0.000 claims abstract description 17
- 239000008203 oral pharmaceutical composition Substances 0.000 claims abstract description 3
- BQJCRHHNABKAKU-KBQPJGBKSA-N morphine Chemical compound O([C@H]1[C@H](C=C[C@H]23)O)C4=C5[C@@]12CCN(C)[C@@H]3CC5=CC=C4O BQJCRHHNABKAKU-KBQPJGBKSA-N 0.000 claims description 32
- 239000005557 antagonist Substances 0.000 claims description 17
- 229960005181 morphine Drugs 0.000 claims description 16
- XADCESSVHJOZHK-UHFFFAOYSA-N Meperidine Chemical compound C=1C=CC=CC=1C1(C(=O)OCC)CCN(C)CC1 XADCESSVHJOZHK-UHFFFAOYSA-N 0.000 claims description 6
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- RBOXVHNMENFORY-DNJOTXNNSA-N dihydrocodeine Chemical compound C([C@H]1[C@H](N(CC[C@@]112)C)C3)C[C@H](O)[C@@H]1OC1=C2C3=CC=C1OC RBOXVHNMENFORY-DNJOTXNNSA-N 0.000 claims description 3
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- 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
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- A61K31/4748—Quinolines; Isoquinolines forming part of bridged ring systems
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- A—HUMAN NECESSITIES
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- 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
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- A—HUMAN NECESSITIES
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- 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
- A61K31/47—Quinolines; Isoquinolines
- A61K31/485—Morphinan derivatives, e.g. morphine, codeine
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
Landscapes
- Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
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- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Emergency Medicine (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US450806 | 1982-12-17 | ||
| US45080699A | 1999-11-29 | 1999-11-29 |
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| ES2278647T3 true ES2278647T3 (es) | 2007-08-16 |
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| ES00992256T Expired - Lifetime ES2278647T3 (es) | 1999-11-29 | 2000-11-29 | Nuevos procedimientos y composiciones que comprenden opioides y antagonistas de opioides. |
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| NZ (1) | NZ518562A (enExample) |
| PT (1) | PT1244447E (enExample) |
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| US6274591B1 (en) | 1997-11-03 | 2001-08-14 | Joseph F. Foss | Use of methylnaltrexone and related compounds |
| AU773642C (en) | 1997-12-22 | 2006-04-06 | Mundipharma Pty Limited | Opioid agonist/antagonist combinations |
| EA004876B1 (ru) | 2000-02-08 | 2004-08-26 | Эро-Селтик, С.А. | Устойчивые к порче композиции опиоидных агонистов для перорального введения |
| CN1525851A (zh) | 2001-05-11 | 2004-09-01 | ������ҩ������˾ | 抗滥用阿片样物质控释剂型 |
| EP1404323B1 (en) * | 2001-06-05 | 2009-10-28 | The University of Chicago | Use of methylnaltrexone to treat immune suppression |
| SI1416842T1 (sl) | 2001-07-18 | 2009-06-30 | Euro Celtique Sa | Farmacevtske kombinacije oksikodona in naloksona |
| WO2003013433A2 (en) | 2001-08-06 | 2003-02-20 | Euro-Celtique S.A. | Sequestered antagonist formulations |
| NZ530971A (en) | 2001-08-06 | 2004-08-27 | Euro Celtique S | Oral dosage forms comprising an opioid agonist with releasable and sequestered opioid antagonists |
| EP2316428A1 (en) | 2002-04-05 | 2011-05-04 | Euro-Celtique S.A. | Matrix for sustained, invariant and independent release of active compounds |
| AU2003270778B2 (en) | 2002-09-20 | 2009-10-08 | Alpharma Pharmaceuticals, Llc | Sequestering subunit and related compositions and methods |
| SI2368553T1 (sl) | 2003-04-08 | 2015-05-29 | Progenics Pharmaceuticals, Inc. | Farmacevtske formulacije, vsebujoče metilnatrekson |
| TWI347201B (en) | 2003-04-21 | 2011-08-21 | Euro Celtique Sa | Pharmaceutical products,uses thereof and methods for preparing the same |
| US6992090B2 (en) * | 2003-06-16 | 2006-01-31 | Adolor Corporation | Substituted piperidine compounds and methods of their use |
| US7700626B2 (en) * | 2004-06-04 | 2010-04-20 | Adolor Corporation | Compositions containing opioid antagonists |
| CA2594987A1 (en) * | 2004-12-14 | 2006-06-22 | Shionogi & Co., Ltd. | Therapeutic agent for constipation |
| EP1702558A1 (en) | 2005-02-28 | 2006-09-20 | Euro-Celtique S.A. | Method and device for the assessment of bowel function |
| US20060211733A1 (en) * | 2005-03-04 | 2006-09-21 | Adolor Corporation | Methods of preventing and treating opioid bowel dysfunction |
| CN101171010B (zh) | 2005-03-07 | 2014-09-17 | 芝加哥大学 | 阿片样物质拮抗剂用于减少内皮细胞增殖和迁移的用途 |
| US8524731B2 (en) | 2005-03-07 | 2013-09-03 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US9662325B2 (en) | 2005-03-07 | 2017-05-30 | The University Of Chicago | Use of opioid antagonists to attenuate endothelial cell proliferation and migration |
| US8518962B2 (en) | 2005-03-07 | 2013-08-27 | The University Of Chicago | Use of opioid antagonists |
| AR057325A1 (es) | 2005-05-25 | 2007-11-28 | Progenics Pharm Inc | Sintesis de (s)-n-metilnaltrexona, composiciones farmaceuticas y usos |
| AR057035A1 (es) | 2005-05-25 | 2007-11-14 | Progenics Pharm Inc | SíNTESIS DE (R)-N-METILNALTREXONA, COMPOSICIONES FARMACÉUTICAS Y USOS |
| WO2006126529A1 (ja) * | 2005-05-25 | 2006-11-30 | Shionogi & Co., Ltd. | 6,7-不飽和-7-カルバモイル置換モルヒナン誘導体 |
| EP1762569A1 (en) * | 2005-09-12 | 2007-03-14 | Alcasynn Pharmaceuticals Gmbh | Novel 6-amino-morphinan derivatives, method of manufacturing them and their application as analgesics |
| CN101426481B (zh) | 2006-04-21 | 2012-12-05 | 帝斯曼知识产权资产管理有限公司 | 阿片受体拮抗剂的用途 |
| PT2484346T (pt) | 2006-06-19 | 2017-04-26 | Alpharma Pharmaceuticals Llc | Composições farmacêuticas |
| TWI489984B (zh) | 2006-08-04 | 2015-07-01 | Wyeth Corp | 用於非經腸道傳輸化合物之配方及其用途 |
| CA2945356C (en) | 2007-03-29 | 2021-03-23 | Progenics Pharmaceuticals, Inc. | (r)-n-methylnaltrexone bromide and pharmaceutical compostitions therof useful as peripheral .mu. opioid receptor antagonist |
| PT2565195E (pt) | 2007-03-29 | 2015-07-28 | Wyeth Llc | Antagonistas e receptor opióide periférico e respectivas utilizações |
| PL2137191T3 (pl) | 2007-03-29 | 2016-12-30 | Antagoniści obwodowego receptora opioidowego i ich zastosowania | |
| MX2010001371A (es) * | 2007-08-09 | 2010-03-10 | Rensselaer Polytech Inst | Carboxamidas opioides cuaternarias. |
| WO2009045985A1 (en) * | 2007-10-01 | 2009-04-09 | The University Of Chicago | Treatment of drug-induced nausea with opioid antagonists |
| AU2008331235C1 (en) * | 2007-11-30 | 2013-01-17 | Purdue Pharma L.P. | Benzomorphan Compounds |
| US8623418B2 (en) | 2007-12-17 | 2014-01-07 | Alpharma Pharmaceuticals Llc | Pharmaceutical composition |
| CN101959892B (zh) | 2008-02-06 | 2014-01-08 | 普罗热尼奇制药公司 | (r),(r)-2,2’-二-甲基纳曲酮的制备和用途 |
| AU2009225434B2 (en) | 2008-03-21 | 2014-05-22 | The University Of Chicago | Treatment with opioid antagonists and mTOR inhibitors |
| CA2676881C (en) | 2008-09-30 | 2017-04-25 | Wyeth | Peripheral opioid receptor antagonists and uses thereof |
| KR20140141727A (ko) | 2009-03-10 | 2014-12-10 | 유로-셀티큐 에스.에이. | 옥시코돈 및 날록손을 포함하는 즉시 방출 제약 조성물 |
| CA2782529C (en) | 2009-12-04 | 2015-05-26 | Alkermes, Inc. | Morphinan derivatives for the treatment of drug overdose |
| ES2582306T3 (es) | 2010-03-22 | 2016-09-12 | Rensselaer Polytechnic Institute | Derivados de morfinano que contienen un grupo carboxamida como ligandos de receptores opioides |
| HUE041981T2 (hu) | 2010-08-23 | 2019-06-28 | Alkermes Pharma Ireland Ltd | Eljárások antipszichotikum által kiváltott súlygyarapodás kezelésére |
| PL2725908T3 (pl) | 2011-06-29 | 2017-10-31 | Alkermes Inc | Działające obwodowo związki opioidowe |
| US9211293B2 (en) | 2011-12-15 | 2015-12-15 | Alkermes Pharma Ireland Limited | Opioid agonist antagonist combinations |
| EP2986294A4 (en) * | 2013-04-17 | 2016-11-16 | Biopharma Works | PROCESS FOR PAIN TREATMENT |
| EP2986295A4 (en) * | 2013-04-17 | 2016-11-09 | Biopharma Works | PROCESS FOR PAIN TREATMENT |
| WO2015011189A1 (en) | 2013-07-23 | 2015-01-29 | Euro-Celtique S.A. | A combination of oxycodone and naloxone for use in treating pain in patients suffering from pain and a disease resulting in intestinal dysbiosis and/or increasing the risk for intestinal bacterial translocation |
| KR102201609B1 (ko) * | 2019-04-19 | 2021-01-12 | 연성정밀화학(주) | 날데메딘의 제조방법 |
| EP4243768A1 (en) | 2020-11-12 | 2023-09-20 | Alkermes Pharma Ireland Limited | Immediate release multilayer tablet |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4457933A (en) * | 1980-01-24 | 1984-07-03 | Bristol-Myers Company | Prevention of analgesic abuse |
| GB8332556D0 (en) * | 1983-12-06 | 1984-01-11 | Reckitt & Colmann Prod Ltd | Analgesic compositions |
| US4769372A (en) * | 1986-06-18 | 1988-09-06 | The Rockefeller University | Method of treating patients suffering from chronic pain or chronic cough |
| PH24752A (en) * | 1987-04-16 | 1990-10-01 | Lilly Co Eli | Piperidine opioid antagonists |
| US5250542A (en) * | 1991-03-29 | 1993-10-05 | Eli Lilly And Company | Peripherally selective piperidine carboxylate opioid antagonists |
-
2000
- 2000-11-29 NZ NZ518562A patent/NZ518562A/en unknown
- 2000-11-29 JP JP2001539402A patent/JP2003528819A/ja active Pending
- 2000-11-29 AU AU39706/01A patent/AU784541B2/en not_active Ceased
- 2000-11-29 EP EP00992256A patent/EP1244447B1/en not_active Expired - Lifetime
- 2000-11-29 DK DK00992256T patent/DK1244447T3/da active
- 2000-11-29 PT PT00992256T patent/PT1244447E/pt unknown
- 2000-11-29 ES ES00992256T patent/ES2278647T3/es not_active Expired - Lifetime
- 2000-11-29 DE DE60032940T patent/DE60032940T2/de not_active Expired - Lifetime
- 2000-11-29 IL IL14960000A patent/IL149600A0/xx unknown
- 2000-11-29 CA CA002392362A patent/CA2392362A1/en not_active Abandoned
- 2000-11-29 WO PCT/US2000/042315 patent/WO2001037785A2/en not_active Ceased
- 2000-11-29 MX MXPA02005335A patent/MXPA02005335A/es active IP Right Grant
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2002
- 2002-05-12 IL IL149600A patent/IL149600A/en not_active IP Right Cessation
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2007
- 2007-03-07 CY CY20071100318T patent/CY1106359T1/el unknown
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|---|---|
| IL149600A0 (en) | 2002-11-10 |
| EP1244447A4 (en) | 2003-06-04 |
| WO2001037785A9 (en) | 2002-08-29 |
| AU3970601A (en) | 2001-06-04 |
| DE60032940T2 (de) | 2007-11-08 |
| WO2001037785A3 (en) | 2002-01-10 |
| MXPA02005335A (es) | 2003-01-28 |
| WO2001037785A2 (en) | 2001-05-31 |
| CY1106359T1 (el) | 2011-10-12 |
| CA2392362A1 (en) | 2001-05-31 |
| EP1244447B1 (en) | 2007-01-10 |
| DE60032940D1 (de) | 2007-02-22 |
| DK1244447T3 (da) | 2007-04-23 |
| PT1244447E (pt) | 2007-02-28 |
| EP1244447A2 (en) | 2002-10-02 |
| NZ518562A (en) | 2005-04-29 |
| AU784541B2 (en) | 2006-04-27 |
| IL149600A (en) | 2010-06-16 |
| JP2003528819A (ja) | 2003-09-30 |
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