CA2526957C - Long lasting insulin derivatives and methods thereof - Google Patents
Long lasting insulin derivatives and methods thereof Download PDFInfo
- Publication number
- CA2526957C CA2526957C CA2526957A CA2526957A CA2526957C CA 2526957 C CA2526957 C CA 2526957C CA 2526957 A CA2526957 A CA 2526957A CA 2526957 A CA2526957 A CA 2526957A CA 2526957 C CA2526957 C CA 2526957C
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- CA
- Canada
- Prior art keywords
- insulin
- derivative
- chain
- conjugate
- group
- 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
- A61K38/22—Hormones
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- 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
- A61K47/51—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 non-active ingredient being a modifying agent
- A61K47/62—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 non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
- A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
- A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
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- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A61P15/00—Drugs for genital or sexual disorders; Contraceptives
- A61P15/08—Drugs for genital or sexual disorders; Contraceptives for gonadal disorders or for enhancing fertility, e.g. inducers of ovulation or of spermatogenesis
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- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A—HUMAN NECESSITIES
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- A61P5/00—Drugs for disorders of the endocrine system
- A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
- A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
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- C—CHEMISTRY; METALLURGY
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- C07K—PEPTIDES
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
- C07K14/62—Insulins
Landscapes
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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| US60/556,585 | 2004-03-25 | ||
| PCT/CA2004/001409 WO2005012346A1 (en) | 2003-07-25 | 2004-07-26 | Long lasting insulin derivatives and methods thereof |
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| US20090175821A1 (en) * | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
| US6514500B1 (en) | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| CA2363712C (en) * | 1999-05-17 | 2011-05-10 | Conjuchem Inc. | Long lasting insulinotropic peptides |
| ATE396202T1 (de) | 2001-02-16 | 2008-06-15 | Conjuchem Biotechnologies Inc | Lang wirkendes glucagon-ähnliches peptid-2 für die behandlung von gastrointestinalen krankheiten und störungen |
| TWI376234B (en) | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
| EP1846447B1 (en) | 2005-02-02 | 2013-08-21 | Novo Nordisk A/S | Insulin derivatives |
| MX2008014061A (es) * | 2006-05-09 | 2008-11-14 | Novo Nordisk As | Derivado de insulina. |
| DK2074141T3 (en) | 2006-09-22 | 2016-11-28 | Novo Nordisk As | The protease resistant insulin analogues. |
| US7982018B2 (en) | 2006-10-16 | 2011-07-19 | Conjuchem, Llc | Modified corticotropin releasing factor peptides and uses thereof |
| US9387176B2 (en) | 2007-04-30 | 2016-07-12 | Novo Nordisk A/S | Method for drying a protein composition, a dried protein composition and a pharmaceutical composition comprising the dried protein |
| WO2009112583A2 (en) | 2008-03-14 | 2009-09-17 | Novo Nordisk A/S | Protease-stabilized insulin analogues |
| CN102037008B (zh) | 2008-03-18 | 2016-08-31 | 诺沃-诺迪斯克有限公司 | 蛋白酶稳定化的、酰化胰岛素类似物 |
| ES2563553T3 (es) * | 2008-04-01 | 2016-03-15 | Novo Nordisk A/S | Conjugados de insulina-albúmina |
| WO2010088286A1 (en) * | 2009-01-28 | 2010-08-05 | Smartcells, Inc. | Synthetic conjugates and uses thereof |
| US9481721B2 (en) | 2012-04-11 | 2016-11-01 | Novo Nordisk A/S | Insulin formulations |
| CN108524919A (zh) | 2012-05-17 | 2018-09-14 | 延伸生物科学股份有限公司 | 用于改进的药物递送的载体 |
| AU2014333979B2 (en) | 2013-10-07 | 2018-02-15 | Novo Nordisk A/S | Novel derivative of an insulin analogue |
| EP3098235A4 (en) | 2014-01-20 | 2017-10-18 | Hanmi Pharm. Co., Ltd. | Long-acting insulin and use thereof |
| AR100639A1 (es) | 2014-05-29 | 2016-10-19 | Hanmi Pharm Ind Co Ltd | Composición para tratar diabetes que comprende conjugados de análogos de insulina de acción prolongada y conjugados de péptidos insulinotrópicos de acción prolongada |
| TWI684458B (zh) | 2014-05-30 | 2020-02-11 | 南韓商韓美藥品股份有限公司 | 包含胰島素及ｇｌｐ-１/昇糖素雙重促效劑之治療糖尿病之組成物 |
| KR20160001391A (ko) * | 2014-06-27 | 2016-01-06 | 한미약품 주식회사 | 신규한 지속형 인슐린 아날로그 결합체 및 이의 용도 |
| US9789197B2 (en) | 2014-10-22 | 2017-10-17 | Extend Biosciences, Inc. | RNAi vitamin D conjugates |
| WO2016065052A1 (en) | 2014-10-22 | 2016-04-28 | Extend Biosciences, Inc. | Insulin vitamin d conjugates |
| US9585934B2 (en) | 2014-10-22 | 2017-03-07 | Extend Biosciences, Inc. | Therapeutic vitamin D conjugates |
| AU2016258091B2 (en) | 2015-05-07 | 2020-10-01 | Codexis, Inc. | Penicillin-G acylases |
| UY36870A (es) | 2015-08-28 | 2017-03-31 | Hanmi Pharm Ind Co Ltd | Análogos de insulina novedosos |
| RU2764197C1 (ru) | 2016-09-23 | 2022-01-14 | Ханми Фарм. Ко., Лтд. | Аналоги инсулина с пониженной аффинностью к рецептору инсулина и их применение |
| TWI700091B (zh) | 2016-12-16 | 2020-08-01 | 丹麥商諾佛 儂迪克股份有限公司 | 含胰島素醫藥組成物 |
| AR111341A1 (es) | 2017-03-23 | 2019-07-03 | Hanmi Pharm Ind Co Ltd | Un conjugado del análogo de insulina con afinidad reducida para el receptor de insulina y uso del mismo |
| CN113773400B (zh) * | 2020-06-09 | 2023-08-18 | 宁波鲲鹏生物科技有限公司 | 一种门冬胰岛素衍生物及其应用 |
| CN113855678A (zh) * | 2021-09-08 | 2021-12-31 | 武汉生命奥义生物科技有限公司 | 一种用于辅助治疗二型糖尿病的组合物 |
| EP4593867A2 (en) | 2022-09-30 | 2025-08-06 | Extend Biosciences, Inc. | Long-acting parathyroid hormone |
| CN115894719B (zh) * | 2022-11-24 | 2023-10-20 | 武汉禾元生物科技股份有限公司 | 一种人血清白蛋白胰岛素偶联物及其制备方法 |
Family Cites Families (57)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3509120A (en) * | 1966-12-28 | 1970-04-28 | Squibb & Sons Inc | N-terminal mono- and diaminoacyl-insulin |
| GB1381273A (en) * | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
| GB1381274A (en) * | 1971-01-28 | 1975-01-22 | Nat Res Dev | Insulin derivatives |
| JPS5272284A (en) * | 1975-12-12 | 1977-06-16 | Dainippon Pharmaceutical Co | Enzymeeimmunoassay reagent |
| CA1196863A (en) * | 1983-06-08 | 1985-11-19 | Mattheus F.A. Goosen | Slow release injectable insulin composition |
| PH25772A (en) * | 1985-08-30 | 1991-10-18 | Novo Industri As | Insulin analogues, process for their preparation |
| US5514646A (en) * | 1989-02-09 | 1996-05-07 | Chance; Ronald E. | Insulin analogs modified at position 29 of the B chain |
| US5612034A (en) * | 1990-10-03 | 1997-03-18 | Redcell, Inc. | Super-globuling for in vivo extended lifetimes |
| US5422339A (en) * | 1991-03-19 | 1995-06-06 | Joslin Diabetes Center, Inc. | Peptides having insulin autoantibody but not insulin receptor binding capacity |
| FR2686899B1 (fr) * | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| GB9316895D0 (en) * | 1993-08-13 | 1993-09-29 | Guy S And St Thomas Hospitals | Hepatoselective insulin analogues |
| DK72793D0 (da) * | 1993-06-21 | 1993-06-21 | Novo Nordisk As | Nyt produkt |
| US6342225B1 (en) * | 1993-08-13 | 2002-01-29 | Deutshces Wollforschungsinstitut | Pharmaceutical active conjugates |
| US5474978A (en) * | 1994-06-16 | 1995-12-12 | Eli Lilly And Company | Insulin analog formulations |
| US5461031A (en) * | 1994-06-16 | 1995-10-24 | Eli Lilly And Company | Monomeric insulin analog formulations |
| US5693609A (en) * | 1994-11-17 | 1997-12-02 | Eli Lilly And Company | Acylated insulin analogs |
| US6251856B1 (en) * | 1995-03-17 | 2001-06-26 | Novo Nordisk A/S | Insulin derivatives |
| DE19616486C5 (de) * | 1996-04-25 | 2016-06-30 | Royalty Pharma Collection Trust | Verfahren zur Senkung des Blutglukosespiegels in Säugern |
| US6576636B2 (en) * | 1996-05-22 | 2003-06-10 | Protarga, Inc. | Method of treating a liver disorder with fatty acid-antiviral agent conjugates |
| US5866538A (en) * | 1996-06-20 | 1999-02-02 | Novo Nordisk A/S | Insulin preparations containing NaCl |
| DE19726167B4 (de) * | 1997-06-20 | 2008-01-24 | Sanofi-Aventis Deutschland Gmbh | Insulin, Verfahren zu seiner Herstellung und es enthaltende pharmazeutische Zubereitung |
| US20020155994A1 (en) * | 1997-10-24 | 2002-10-24 | Svend Havelund | Aggregates of human insulin derivatives |
| US6444641B1 (en) * | 1997-10-24 | 2002-09-03 | Eli Lilly Company | Fatty acid-acylated insulin analogs |
| EA200000453A1 (ru) * | 1997-10-24 | 2000-10-30 | Эли Лилли Энд Компани | Композиции нерастворимого инсулина |
| ZA989744B (en) * | 1997-10-31 | 2000-04-26 | Lilly Co Eli | Method for administering acylated insulin. |
| AU766219B2 (en) * | 1998-02-02 | 2003-10-09 | 1149336 Ontario Inc. | Method of regulating glucose metabolism, and reagents related thereto |
| EP1063973B1 (en) * | 1998-03-19 | 2016-11-16 | Bristol-Myers Squibb Company | Biphasic controlled release delivery system for high solubility pharmaceuticals and method |
| EP1086130A1 (en) * | 1998-06-12 | 2001-03-28 | Kings College London | Insulin analogue |
| US20030190740A1 (en) * | 1998-10-13 | 2003-10-09 | The University Of Georgia Research Foundation, Inc | Stabilized bioactive peptides and methods of identification, synthesis, and use |
| EP1121425B1 (en) * | 1998-10-13 | 2005-06-29 | The University Of Georgia Research Foundation, Inc. | Stabilized bioactive peptides and methods of identification, synthesis and use |
| US20090175821A1 (en) * | 1999-05-17 | 2009-07-09 | Bridon Dominique P | Modified therapeutic peptides with extended half-lives in vivo |
| US6887470B1 (en) * | 1999-09-10 | 2005-05-03 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| CA2363712C (en) * | 1999-05-17 | 2011-05-10 | Conjuchem Inc. | Long lasting insulinotropic peptides |
| PT1105409E (pt) * | 1999-05-17 | 2006-07-31 | Conjuchem Inc | Proteccao de peptidos terapeuticos endogenos da actividade de peptidases por conjugacao a componentes do sangue |
| US7169889B1 (en) * | 1999-06-19 | 2007-01-30 | Biocon Limited | Insulin prodrugs hydrolyzable in vivo to yield peglylated insulin |
| US6309633B1 (en) * | 1999-06-19 | 2001-10-30 | Nobex Corporation | Amphiphilic drug-oligomer conjugates with hydroyzable lipophile components and methods for making and using the same |
| US6323311B1 (en) * | 1999-09-22 | 2001-11-27 | University Of Utah Research Foundation | Synthesis of insulin derivatives |
| US6586438B2 (en) * | 1999-11-03 | 2003-07-01 | Bristol-Myers Squibb Co. | Antidiabetic formulation and method |
| EP1299418A1 (en) * | 2000-07-10 | 2003-04-09 | BTG INTERNATIONAL LIMITED (Company No. 2664412) | Insulin derivatives and synthesis thereof |
| US7060675B2 (en) * | 2001-02-15 | 2006-06-13 | Nobex Corporation | Methods of treating diabetes mellitus |
| AU2002254940A1 (en) * | 2001-03-12 | 2002-09-24 | Novartis Pharma Gmbh | Combination of nateglinide or repaglinide with at least one further antidiabetic compound |
| US6828297B2 (en) * | 2001-06-04 | 2004-12-07 | Nobex Corporation | Mixtures of insulin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same |
| UA74912C2 (en) * | 2001-07-06 | 2006-02-15 | Merck & Co Inc | Beta-aminotetrahydroimidazo-(1,2-a)-pyrazines and tetratriazolo-(4,3-a)-pyrazines as inhibitors of dipeptylpeptidase for the treatment or prevention of diabetes |
| US7166571B2 (en) * | 2001-09-07 | 2007-01-23 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7312192B2 (en) * | 2001-09-07 | 2007-12-25 | Biocon Limited | Insulin polypeptide-oligomer conjugates, proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US6913903B2 (en) * | 2001-09-07 | 2005-07-05 | Nobex Corporation | Methods of synthesizing insulin polypeptide-oligomer conjugates, and proinsulin polypeptide-oligomer conjugates and methods of synthesizing same |
| US7196059B2 (en) * | 2001-09-07 | 2007-03-27 | Biocon Limited | Pharmaceutical compositions of insulin drug-oligomer conjugates and methods of treating diseases therewith |
| EP1506003A1 (en) * | 2002-05-07 | 2005-02-16 | Novo Nordisk A/S | Soluble formulations comprising insulin aspart and insulin detemir |
| AU2003236521A1 (en) * | 2002-06-13 | 2003-12-31 | Nobex Corporation | Methods of reducing hypoglycemic episodes in the treatment of diabetes mellitus |
| US20040138099A1 (en) * | 2002-11-29 | 2004-07-15 | Draeger Eberhard Kurt | Insulin administration regimens for the treatment of subjects with diabetes |
| US20050065066A1 (en) * | 2002-12-20 | 2005-03-24 | Kaarsholm Niels Christian | Stabilised insulin compositions |
| GB0309154D0 (en) * | 2003-01-14 | 2003-05-28 | Aventis Pharma Inc | Use of insulin glargine to reduce or prevent cardiovascular events in patients being treated for dysglycemia |
| CA2521381C (en) * | 2003-04-11 | 2020-05-26 | Rezolute, Inc. | Method for preparation of site-specific protein conjugates |
| JO2625B1 (en) * | 2003-06-24 | 2011-11-01 | ميرك شارب اند دوم كوربوريشن | Phosphoric acid salts of dipeptidyl betidase inhibitor 4 |
| MXPA06001283A (es) * | 2003-08-05 | 2006-04-11 | Novo Nordisk As | Derivados de insulina novedosos. |
| BRPI0513508B1 (pt) * | 2004-07-19 | 2021-06-01 | Biocon Limited | Conjugados de insulina-oligômero, formulações e usos desses |
| WO2007121256A2 (en) * | 2006-04-12 | 2007-10-25 | Biodel, Inc. | Rapid acting and long acting insulin combination formulations |
-
2004
- 2004-07-26 DE DE602004021603T patent/DE602004021603D1/de not_active Expired - Lifetime
- 2004-07-26 ES ES04801809T patent/ES2328579T3/es not_active Expired - Lifetime
- 2004-07-26 EP EP09159269A patent/EP2085406A1/en not_active Withdrawn
- 2004-07-26 US US10/565,900 patent/US20060241019A1/en not_active Abandoned
- 2004-07-26 EP EP04801809A patent/EP1648933B1/en not_active Revoked
- 2004-07-26 BR BRPI0412252-6A patent/BRPI0412252A/pt not_active IP Right Cessation
- 2004-07-26 PL PL04801809T patent/PL1648933T3/pl unknown
- 2004-07-26 WO PCT/CA2004/001409 patent/WO2005012346A1/en not_active Ceased
- 2004-07-26 AU AU2004261319A patent/AU2004261319B2/en not_active Ceased
- 2004-07-26 AT AT04801809T patent/ATE433994T1/de active
- 2004-07-26 CA CA2526957A patent/CA2526957C/en not_active Expired - Fee Related
- 2004-07-26 EA EA200600305A patent/EA008433B1/ru not_active IP Right Cessation
- 2004-07-26 JP JP2006521357A patent/JP2007520441A/ja active Pending
- 2004-07-26 DK DK04801809T patent/DK1648933T3/da active
- 2004-07-26 SI SI200431199T patent/SI1648933T1/sl unknown
-
2006
- 2006-02-23 NO NO20060888A patent/NO20060888L/no not_active Application Discontinuation
-
2011
- 2011-03-22 AU AU2011201278A patent/AU2011201278A1/en not_active Abandoned
- 2011-08-26 JP JP2011184958A patent/JP2012062311A/ja active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| DE602004021603D1 (de) | 2009-07-30 |
| AU2011201278A1 (en) | 2011-04-07 |
| DK1648933T3 (da) | 2009-09-07 |
| HK1091843A1 (en) | 2007-01-26 |
| EP2085406A1 (en) | 2009-08-05 |
| WO2005012346A1 (en) | 2005-02-10 |
| EP1648933B1 (en) | 2009-06-17 |
| EA008433B1 (ru) | 2007-06-29 |
| EA200600305A1 (ru) | 2006-06-30 |
| NO20060888L (no) | 2006-04-25 |
| BRPI0412252A (pt) | 2006-09-19 |
| JP2012062311A (ja) | 2012-03-29 |
| ATE433994T1 (de) | 2009-07-15 |
| JP2007520441A (ja) | 2007-07-26 |
| ES2328579T3 (es) | 2009-11-16 |
| EP1648933A4 (en) | 2007-02-28 |
| AU2004261319A1 (en) | 2005-02-10 |
| CA2526957A1 (en) | 2005-02-10 |
| PL1648933T3 (pl) | 2010-01-29 |
| SI1648933T1 (sl) | 2010-01-29 |
| US20060241019A1 (en) | 2006-10-26 |
| EP1648933A1 (en) | 2006-04-26 |
| AU2004261319B2 (en) | 2010-12-23 |
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