EA036091B1 - ВОДНЫЕ СОСТАВЫ АНТИДОТОВ ФАКТОРА Xa (fXa) ДЛЯ ПРЕДУПРЕЖДЕНИЯ ИЛИ УМЕНЬШЕНИЯ КРОВОТЕЧЕНИЯ И ИХ ПРИМЕНЕНИЕ - Google Patents
ВОДНЫЕ СОСТАВЫ АНТИДОТОВ ФАКТОРА Xa (fXa) ДЛЯ ПРЕДУПРЕЖДЕНИЯ ИЛИ УМЕНЬШЕНИЯ КРОВОТЕЧЕНИЯ И ИХ ПРИМЕНЕНИЕ Download PDFInfo
- Publication number
- EA036091B1 EA036091B1 EA201790415A EA201790415A EA036091B1 EA 036091 B1 EA036091 B1 EA 036091B1 EA 201790415 A EA201790415 A EA 201790415A EA 201790415 A EA201790415 A EA 201790415A EA 036091 B1 EA036091 B1 EA 036091B1
- Authority
- EA
- Eurasian Patent Office
- Prior art keywords
- seq
- arginine
- mannitol
- sucrose
- composition
- Prior art date
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/36—Blood coagulation or fibrinolysis factors
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- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
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- A61K38/43—Enzymes; Proenzymes; Derivatives thereof
- A61K38/46—Hydrolases (3)
- A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
- A61K38/482—Serine endopeptidases (3.4.21)
- A61K38/4846—Factor VII (3.4.21.21); Factor IX (3.4.21.22); Factor Xa (3.4.21.6); Factor XI (3.4.21.27); Factor XII (3.4.21.38)
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- 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
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
- A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
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- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- 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
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- A—HUMAN NECESSITIES
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- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
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- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6432—Coagulation factor Xa (3.4.21.6)
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21006—Coagulation factor Xa (3.4.21.6)
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| US201462039809P | 2014-08-20 | 2014-08-20 | |
| PCT/US2015/046173 WO2016029061A1 (en) | 2014-08-20 | 2015-08-20 | Lyophilized formulations for factor xa antidote |
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| EA201790415A1 EA201790415A1 (ru) | 2017-08-31 |
| EA036091B1 true EA036091B1 (ru) | 2020-09-25 |
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| EA201790415A EA036091B1 (ru) | 2014-08-20 | 2015-08-20 | ВОДНЫЕ СОСТАВЫ АНТИДОТОВ ФАКТОРА Xa (fXa) ДЛЯ ПРЕДУПРЕЖДЕНИЯ ИЛИ УМЕНЬШЕНИЯ КРОВОТЕЧЕНИЯ И ИХ ПРИМЕНЕНИЕ |
| EA202091385A EA202091385A3 (ru) | 2014-08-20 | 2015-08-20 | Лиофилизированные составы для антидота фактора ха |
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| EA202091385A EA202091385A3 (ru) | 2014-08-20 | 2015-08-20 | Лиофилизированные составы для антидота фактора ха |
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| PL3604510T3 (pl) * | 2009-03-30 | 2025-07-28 | Alexion Pharmaceuticals, Inc. | Antidota na inhibitory czynnika xa i sposoby ich stosowania |
| KR20250150675A (ko) * | 2014-08-20 | 2025-10-20 | 포톨라 파마슈티컬스, 인코포레이티드 | 인자 xa 해독제용 동결건조된 제형 |
| CN108883160B (zh) | 2016-02-24 | 2022-06-28 | 博尔托拉制药公司 | 因子xa解毒剂的冻干制剂 |
| EP3926044B1 (en) | 2016-06-17 | 2025-06-04 | Alexion Pharmaceuticals, Inc. | Preparation of factor xa derivatives |
| EP3624828B1 (en) * | 2017-05-18 | 2024-08-07 | Merck Sharp & Dohme LLC | Pharmaceutical formulation comprising incretin-insulin conjugates |
| JP7549530B2 (ja) * | 2018-05-21 | 2024-09-11 | 中外製薬株式会社 | ガラス容器に封入された凍結乾燥製剤 |
| CN110760479A (zh) * | 2019-05-17 | 2020-02-07 | 上海交通大学医学院附属瑞金医院 | 靶向血小板表达的凝血因子Xa及其应用 |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000048635A1 (en) * | 1999-02-22 | 2000-08-24 | Baxter International Inc. | Novel albumin-free factor viii formulations |
| US20040180827A1 (en) * | 2003-01-08 | 2004-09-16 | Chiron Corporation | Stabilized lyophilized compositions comprising tissue factor pathway inhibitor or tissue factor pathway inhibitor variants |
| US20110015128A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
| WO2011088152A1 (en) * | 2010-01-12 | 2011-07-21 | Portola Pharmaceuticals, Inc. | Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof |
| WO2011131720A1 (en) * | 2010-04-20 | 2011-10-27 | Octapharma Ag | New stabilizing agent for pharmaceutical proteins |
| US20130252979A1 (en) * | 2010-12-03 | 2013-09-26 | Portola Pharmaceuticals, Inc. | Pharmaceutical compositions, dosage forms and new forms of the compound of mula (i), and methods of use thereof |
Family Cites Families (15)
| Publication number | Priority date | Publication date | Assignee | Title |
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| JPH08504769A (ja) | 1992-12-15 | 1996-05-21 | コルバス・インターナショナル、インコーポレイテッド | 因子Ｘａの新規インヒビター |
| US6586574B1 (en) * | 1999-08-17 | 2003-07-01 | Nn A/S | Stabilization of freeze-dried cake |
| WO2001064642A2 (en) | 2000-02-29 | 2001-09-07 | Cor Therapeutics, Inc. | Benzamides and related inhibitors of factor xa |
| US6586584B2 (en) * | 2001-01-29 | 2003-07-01 | Becton, Dickinson And Company | Sequences and methods for detection of Hepatitis C virus |
| CN101304971B (zh) | 2005-11-08 | 2011-09-07 | 米伦纽姆医药公司 | Xa因子抑制剂n-(5-氯-2-吡啶基)-2-[[4-[(二甲氨基)亚氨基甲基]苯甲酰基]氨基]-5-甲氧基-苯甲酰胺的医药盐和多晶型 |
| US9283260B2 (en) * | 2006-04-21 | 2016-03-15 | Amgen Inc. | Lyophilized therapeutic peptibody formulations |
| KR102069498B1 (ko) | 2007-09-28 | 2020-01-23 | 포톨라 파마슈티컬스, 인코포레이티드 | 인자 Ｘａ 저해제에 대한 안티도트 및 그것을 사용하는 방법 |
| KR101691070B1 (ko) | 2008-09-03 | 2016-12-29 | 옥타파마 아게 | 재조합에 의해 제조된 인자 ⅷ을 위한 신규한 보호 조성물 |
| CA2743496C (en) * | 2008-11-14 | 2018-03-27 | Portola Pharmaceuticals, Inc. | Antidotes for factor xa inhibitors and methods of using the same in combination with blood coagulating agents |
| PL3604510T3 (pl) * | 2009-03-30 | 2025-07-28 | Alexion Pharmaceuticals, Inc. | Antidota na inhibitory czynnika xa i sposoby ich stosowania |
| WO2011017070A1 (en) * | 2009-07-28 | 2011-02-10 | Merck Sharp & Dohme Corp. | Methods for producing high concentration lyophilized pharmaceutical formulations |
| US9683020B2 (en) * | 2011-08-01 | 2017-06-20 | Emory University | VLPS containing ligands and methods related thereto |
| JP6514893B2 (ja) * | 2011-09-30 | 2019-05-15 | ザ・チルドレンズ・ホスピタル・オブ・フィラデルフィアＴｈｅ Ｃｈｉｌｄｒｅｎ’Ｓ Ｈｏｓｐｉｔａｌ Ｏｆ Ｐｈｉｌａｄｅｌｐｈｉａ | 止血を調節するための組成物および方法 |
| GB201310946D0 (en) * | 2013-06-19 | 2013-07-31 | Cambridge Entpr Ltd | Antidote |
| KR20250150675A (ko) * | 2014-08-20 | 2025-10-20 | 포톨라 파마슈티컬스, 인코포레이티드 | 인자 xa 해독제용 동결건조된 제형 |
-
2015
- 2015-08-20 KR KR1020257032508A patent/KR20250150675A/ko active Pending
- 2015-08-20 AU AU2015305413A patent/AU2015305413B2/en active Active
- 2015-08-20 EP EP20170763.5A patent/EP3750556A1/en active Pending
- 2015-08-20 EA EA201790415A patent/EA036091B1/ru unknown
- 2015-08-20 EA EA202091385A patent/EA202091385A3/ru unknown
- 2015-08-20 KR KR1020227045749A patent/KR102867491B1/ko active Active
- 2015-08-20 CA CA2961739A patent/CA2961739C/en active Active
- 2015-08-20 CN CN202110363277.0A patent/CN113171447B/zh active Active
- 2015-08-20 EP EP15834421.8A patent/EP3182993B1/en active Active
- 2015-08-20 CN CN201580048166.3A patent/CN107073082B/zh active Active
- 2015-08-20 WO PCT/US2015/046173 patent/WO2016029061A1/en not_active Ceased
- 2015-08-20 DK DK15834421.8T patent/DK3182993T3/da active
- 2015-08-20 SG SG11201701247RA patent/SG11201701247RA/en unknown
- 2015-08-20 ES ES15834421T patent/ES2814157T3/es active Active
- 2015-08-20 JP JP2017509739A patent/JP6742986B2/ja active Active
- 2015-08-20 KR KR1020177007503A patent/KR102482517B1/ko active Active
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2016
- 2016-04-22 US US15/136,810 patent/US20160237420A1/en not_active Abandoned
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2017
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- 2017-03-10 ZA ZA2017/01764A patent/ZA201701764B/en unknown
- 2017-11-21 US US15/820,265 patent/US20180320160A1/en not_active Abandoned
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2019
- 2019-09-12 JP JP2019165981A patent/JP2019206595A/ja not_active Withdrawn
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2020
- 2020-06-08 US US16/895,448 patent/US11028382B2/en active Active
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- 2020-08-26 IL IL276960A patent/IL276960B/en unknown
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2021
- 2021-05-28 US US17/334,427 patent/US20210284986A1/en not_active Abandoned
- 2021-10-22 JP JP2021172975A patent/JP7416549B2/ja active Active
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2023
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2024
- 2024-09-13 AU AU2024219698A patent/AU2024219698A1/en active Pending
- 2024-11-05 US US18/937,646 patent/US20250163399A1/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2000048635A1 (en) * | 1999-02-22 | 2000-08-24 | Baxter International Inc. | Novel albumin-free factor viii formulations |
| US20040180827A1 (en) * | 2003-01-08 | 2004-09-16 | Chiron Corporation | Stabilized lyophilized compositions comprising tissue factor pathway inhibitor or tissue factor pathway inhibitor variants |
| US20110015128A1 (en) * | 2009-07-15 | 2011-01-20 | Portola Pharmaceuticals, Inc. | Unit dose formulation of antidotes for factor xa inhibitors and methods of using the same |
| WO2011088152A1 (en) * | 2010-01-12 | 2011-07-21 | Portola Pharmaceuticals, Inc. | Pharmaceutical composition and dosage forms of elinogrel and methods of use thereof |
| WO2011131720A1 (en) * | 2010-04-20 | 2011-10-27 | Octapharma Ag | New stabilizing agent for pharmaceutical proteins |
| US20130252979A1 (en) * | 2010-12-03 | 2013-09-26 | Portola Pharmaceuticals, Inc. | Pharmaceutical compositions, dosage forms and new forms of the compound of mula (i), and methods of use thereof |
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