ES2209885T3 - Peptidos insulinotropicos de larga duracion. - Google Patents
Peptidos insulinotropicos de larga duracion.Info
- Publication number
- ES2209885T3 ES2209885T3 ES00930796T ES00930796T ES2209885T3 ES 2209885 T3 ES2209885 T3 ES 2209885T3 ES 00930796 T ES00930796 T ES 00930796T ES 00930796 T ES00930796 T ES 00930796T ES 2209885 T3 ES2209885 T3 ES 2209885T3
- Authority
- ES
- Spain
- Prior art keywords
- fmoc
- lys
- baselineskip
- peptide
- glp
- 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
- 108090000765 processed proteins & peptides Proteins 0.000 title claims abstract description 200
- 230000002473 insulinotropic effect Effects 0.000 title claims abstract description 89
- 102000004196 processed proteins & peptides Human genes 0.000 title description 75
- 230000007774 longterm Effects 0.000 title 1
- 239000012634 fragment Substances 0.000 claims abstract description 44
- 239000012503 blood component Substances 0.000 claims abstract description 29
- 125000003396 thiol group Chemical group [H]S* 0.000 claims abstract description 17
- DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 69
- 210000004369 blood Anatomy 0.000 claims description 54
- 239000008280 blood Substances 0.000 claims description 53
- NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical compound N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 claims description 52
- 238000000034 method Methods 0.000 claims description 35
- 150000001875 compounds Chemical class 0.000 claims description 30
- 238000001727 in vivo Methods 0.000 claims description 29
- 229940125396 insulin Drugs 0.000 claims description 27
- 102000004877 Insulin Human genes 0.000 claims description 25
- 108090001061 Insulin Proteins 0.000 claims description 25
- 239000000306 component Substances 0.000 claims description 24
- NGJOFQZEYQGZMB-KTKZVXAJSA-N (4S)-5-[[2-[[(2S,3R)-1-[[(2S)-1-[[(2S,3R)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[2-[[(2S)-5-amino-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[(2S)-1-[[(2S)-1-[[(2S,3S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-1-[[(2S)-6-amino-1-[[2-[[(1S)-4-carbamimidamido-1-carboxybutyl]amino]-2-oxoethyl]amino]-1-oxohexan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(1H-indol-3-yl)-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-3-methyl-1-oxopentan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-1-oxohexan-2-yl]amino]-1-oxopropan-2-yl]amino]-1-oxopropan-2-yl]amino]-1,5-dioxopentan-2-yl]amino]-2-oxoethyl]amino]-4-carboxy-1-oxobutan-2-yl]amino]-4-methyl-1-oxopentan-2-yl]amino]-3-(4-hydroxyphenyl)-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-methyl-1-oxobutan-2-yl]amino]-3-carboxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxopropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-1-oxo-3-phenylpropan-2-yl]amino]-3-hydroxy-1-oxobutan-2-yl]amino]-2-oxoethyl]amino]-4-[[(2S)-2-[[(2S)-2-amino-3-(1H-imidazol-4-yl)propanoyl]amino]propanoyl]amino]-5-oxopentanoic acid Chemical group C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(O)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 NGJOFQZEYQGZMB-KTKZVXAJSA-N 0.000 claims description 23
- 102000009027 Albumins Human genes 0.000 claims description 23
- 108010088751 Albumins Proteins 0.000 claims description 23
- 101800004295 Glucagon-like peptide 1(7-36) Proteins 0.000 claims description 23
- 206010012601 diabetes mellitus Diseases 0.000 claims description 18
- 239000000203 mixture Substances 0.000 claims description 17
- 108010071390 Serum Albumin Proteins 0.000 claims description 14
- 102000007562 Serum Albumin Human genes 0.000 claims description 14
- QNAYBMKLOCPYGJ-UWTATZPHSA-N D-alanine Chemical compound C[C@@H](N)C(O)=O QNAYBMKLOCPYGJ-UWTATZPHSA-N 0.000 claims description 12
- 239000003814 drug Substances 0.000 claims description 11
- 108091005601 modified peptides Proteins 0.000 claims description 11
- 102000004506 Blood Proteins Human genes 0.000 claims description 10
- 108010017384 Blood Proteins Proteins 0.000 claims description 10
- HXMVNCMPQGPRLN-UHFFFAOYSA-N 2-hydroxyputrescine Chemical compound NCCC(O)CN HXMVNCMPQGPRLN-UHFFFAOYSA-N 0.000 claims description 8
- 230000014509 gene expression Effects 0.000 claims description 8
- 238000004519 manufacturing process Methods 0.000 claims description 5
- FWMNVWWHGCHHJJ-SKKKGAJSSA-N 4-amino-1-[(2r)-6-amino-2-[[(2r)-2-[[(2r)-2-[[(2r)-2-amino-3-phenylpropanoyl]amino]-3-phenylpropanoyl]amino]-4-methylpentanoyl]amino]hexanoyl]piperidine-4-carboxylic acid Chemical compound C([C@H](C(=O)N[C@H](CC(C)C)C(=O)N[C@H](CCCCN)C(=O)N1CCC(N)(CC1)C(O)=O)NC(=O)[C@H](N)CC=1C=CC=CC=1)C1=CC=CC=C1 FWMNVWWHGCHHJJ-SKKKGAJSSA-N 0.000 claims description 3
- 102100025101 GATA-type zinc finger protein 1 Human genes 0.000 claims 4
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims 4
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 147
- -1 carboxy, phosphoryl Chemical group 0.000 description 129
- 229920005989 resin Polymers 0.000 description 70
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- 235000001014 amino acid Nutrition 0.000 description 63
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- 229940024606 amino acid Drugs 0.000 description 60
- 150000001413 amino acids Chemical class 0.000 description 60
- REITVGIIZHFVGU-IBGZPJMESA-N (2s)-2-(9h-fluoren-9-ylmethoxycarbonylamino)-3-[(2-methylpropan-2-yl)oxy]propanoic acid Chemical compound C1=CC=C2C(COC(=O)N[C@@H](COC(C)(C)C)C(O)=O)C3=CC=CC=C3C2=C1 REITVGIIZHFVGU-IBGZPJMESA-N 0.000 description 57
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Classifications
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- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
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- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
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- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
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- A61P41/00—Drugs used in surgical methods, e.g. surgery adjuvants for preventing adhesion or for vitreum substitution
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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
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
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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
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- C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
- C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
Landscapes
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- Chemical & Material Sciences (AREA)
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- Endocrinology (AREA)
- Molecular Biology (AREA)
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- Hospice & Palliative Care (AREA)
- Surgery (AREA)
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Applications Claiming Priority (4)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US13440699P | 1999-05-17 | 1999-05-17 | |
| US134406P | 1999-05-17 | ||
| US15978399P | 1999-10-15 | 1999-10-15 | |
| US159783P | 1999-10-15 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ES2209885T3 true ES2209885T3 (es) | 2004-07-01 |
Family
ID=26832298
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ES00930796T Expired - Lifetime ES2209885T3 (es) | 1999-05-17 | 2000-05-17 | Peptidos insulinotropicos de larga duracion. |
Country Status (16)
| Country | Link |
|---|---|
| US (4) | US6329336B1 (enExample) |
| EP (1) | EP1180121B9 (enExample) |
| JP (5) | JP4115671B2 (enExample) |
| CN (1) | CN1191273C (enExample) |
| AT (1) | ATE252601T1 (enExample) |
| AU (1) | AU754770B2 (enExample) |
| BR (1) | BR0010750A (enExample) |
| CA (2) | CA2363712C (enExample) |
| DE (1) | DE60006100T2 (enExample) |
| DK (1) | DK1180121T3 (enExample) |
| EA (1) | EA003922B1 (enExample) |
| ES (1) | ES2209885T3 (enExample) |
| NO (1) | NO20015584L (enExample) |
| PT (1) | PT1180121E (enExample) |
| SI (1) | SI1180121T1 (enExample) |
| WO (1) | WO2000069911A1 (enExample) |
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| FR2686899B1 (fr) | 1992-01-31 | 1995-09-01 | Rhone Poulenc Rorer Sa | Nouveaux polypeptides biologiquement actifs, leur preparation et compositions pharmaceutiques les contenant. |
| US6605648B1 (en) * | 1999-04-06 | 2003-08-12 | Phillips Plastics Corporation | Sinterable structures and method |
| US7601691B2 (en) | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
| PT1180121E (pt) * | 1999-05-17 | 2004-03-31 | Conjuchem Inc | Peptidos insulinotropicos de longa duracao |
| US6514500B1 (en) | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| 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 |
| US20040266673A1 (en) * | 2002-07-31 | 2004-12-30 | Peter Bakis | Long lasting natriuretic peptide derivatives |
| US6849714B1 (en) * | 1999-05-17 | 2005-02-01 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US7087411B2 (en) | 1999-06-08 | 2006-08-08 | Regeneron Pharmaceuticals, Inc. | Fusion protein capable of binding VEGF |
| US6447772B1 (en) * | 1999-10-01 | 2002-09-10 | Klaire Laboratories, Inc. | Compositions and methods relating to reduction of symptoms of autism |
| US6926898B2 (en) | 2000-04-12 | 2005-08-09 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| SI1724284T1 (sl) * | 2000-12-07 | 2009-12-31 | Lilly Co Eli | Glp-1 fuzijski proteini |
| CA2435563A1 (en) | 2001-02-02 | 2002-08-15 | Conjuchem Inc. | Long lasting growth hormone releasing factor derivatives |
| DK1360202T3 (da) | 2001-02-16 | 2008-09-22 | Conjuchem Biotechnologies Inc | Langvarigt glucagon-lignende peptid 2 (GLP-2) til behandling af gastrointestinale sygdomme og lidelser |
| CN1162446C (zh) * | 2001-05-10 | 2004-08-18 | 上海华谊生物技术有限公司 | 促胰岛素分泌肽衍生物 |
| ES2242860T3 (es) | 2001-05-31 | 2005-11-16 | Conjuchem, Inc. | Inhibidores peptidicos de fusion de larga vida contra infecciones por vih. |
| EP1411968B1 (en) * | 2001-07-31 | 2008-09-17 | THE GOVERNMENT OF THE UNITED STATES OF AMERICA, as represented by THE SECRETARY, DEPARTMENT OF HEALTH AND HUMAN SERVICES | Glp-1 exendin-4 peptide analogs and uses thereof |
| US6642003B2 (en) | 2001-08-02 | 2003-11-04 | Cedars-Sinai Medical Center | Human glucose-dependent insulin-secreting cell line |
| US7176278B2 (en) * | 2001-08-30 | 2007-02-13 | Biorexis Technology, Inc. | Modified transferrin fusion proteins |
| US20030226155A1 (en) * | 2001-08-30 | 2003-12-04 | Biorexis Pharmaceutical Corporation | Modified transferrin-antibody fusion proteins |
| US20070031440A1 (en) * | 2001-08-30 | 2007-02-08 | Prior Christopher P | Modified transferin-antibody fusion proteins |
| US8129504B2 (en) | 2001-08-30 | 2012-03-06 | Biorexis Technology, Inc. | Oral delivery of modified transferrin fusion proteins |
| CN1628126A (zh) * | 2001-08-30 | 2005-06-15 | 比奥雷克西斯药物公司 | 经修饰的运铁蛋白融合蛋白 |
| GEP20063908B (en) * | 2001-10-18 | 2006-08-25 | Bristol Myers Squibb Co | Human glucagon-like-peptide-1 mimics and their use in the treatment of diabetes and related conditions |
| CA2841097A1 (en) | 2001-12-21 | 2003-07-24 | Human Genome Sciences, Inc. | Albumin and g-csf fusion proteins |
| WO2005003296A2 (en) | 2003-01-22 | 2005-01-13 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| WO2003059934A2 (en) * | 2001-12-21 | 2003-07-24 | Human Genome Sciences, Inc. | Albumin fusion proteins |
| AU2003213047A1 (en) * | 2002-02-13 | 2003-09-04 | Medbridge, Inc. | Protein carrier system for therapeutic oligonucleotides |
| AU2003208945B2 (en) * | 2002-02-20 | 2008-05-01 | Emisphere Technologies, Inc | Method for administering GLP-1 molecules |
| US7141240B2 (en) * | 2002-03-12 | 2006-11-28 | Cedars-Sinai Medical Center | Glucose-dependent insulin-secreting cells transfected with a nucleotide sequence encoding GLP-1 |
| AU2003239478A1 (en) * | 2002-06-04 | 2003-12-22 | Eli Lilly And Company | Modified glucagon-like peptide-1 analogs |
| EP1837031B1 (en) * | 2002-06-07 | 2009-10-14 | Waratah Pharmaceuticals, Inc. | Compositions and methods for treating diabetes |
| MXPA04012497A (es) | 2002-07-04 | 2005-07-14 | Zealand Pharma As | Glp-1 y metodos para tratar la diabetes. |
| CN102268094A (zh) * | 2002-08-30 | 2011-12-07 | 比奥雷克西斯药物公司 | 被修饰的转铁蛋白抗体的融合蛋白 |
| CN1327897C (zh) * | 2002-09-24 | 2007-07-25 | 重庆前沿生物技术有限公司 | Hiv感染的肽衍生物融合抑制剂 |
| BR0314996A (pt) | 2002-10-02 | 2005-08-09 | Zealand Pharma As | Composição, composição farmaceuticamente aceitável, método para produzir a composição, métodos para estabilizar a exendina-4 (1-39) ou uma sua variante, derivado ou análogo contra a degradação, antes, durante ou após o uso pretendido, para tratar doenças, para tratar de estados de doenças associados com nìveis elevados de glicose do sangue, para a regulação dos nìveis de glicose do sangue, para a regulação do esvaziamento gástrico, para estimular a liberação de insulina em um mamìfero para reduzir o nìvel de glicose do sangue em um mamìfero, para reduzir o nìvel de lipìdeos plasmáticos em um mamìfero, para reduzir a mortalidade e a morbidez após o infarto miocárdico em um mamìfero, para estimular a liberação de insulina em um mamìfero, e para produzir uma exendina (1-39) estabilizada, e, exendina (1-39) estabilizada |
| US20040229810A1 (en) * | 2002-10-22 | 2004-11-18 | Antonio Cruz | Gastrin compositions and formulations, and methods of use and preparation |
| US7790681B2 (en) * | 2002-12-17 | 2010-09-07 | Amylin Pharmaceuticals, Inc. | Treatment of cardiac arrhythmias with GLP-1 receptor ligands |
| US20040209803A1 (en) * | 2002-12-19 | 2004-10-21 | Alain Baron | Compositions for the treatment and prevention of nephropathy |
| US7731947B2 (en) | 2003-11-17 | 2010-06-08 | Intarcia Therapeutics, Inc. | Composition and dosage form comprising an interferon particle formulation and suspending vehicle |
| NZ541365A (en) * | 2002-12-27 | 2009-09-25 | Diobex Inc | Compositions and methods for the prevention and control of insulin-induced hypoglycemia |
| US7655618B2 (en) * | 2002-12-27 | 2010-02-02 | Diobex, Inc. | Compositions and methods for the prevention and control of insulin-induced hypoglycemia |
| US20070060512A1 (en) * | 2003-03-04 | 2007-03-15 | Homayoun Sadeghi | Dipeptidyl-peptidase protected protein |
| US20040242568A1 (en) | 2003-03-25 | 2004-12-02 | Syrrx, Inc. | Dipeptidyl peptidase inhibitors |
| BRPI0408978B8 (pt) * | 2003-04-08 | 2021-07-27 | Novo Nordisk As | processos para regenerar uma fase estacionária cromatográfica |
| WO2004089985A1 (en) * | 2003-04-11 | 2004-10-21 | Novo Nordisk A/S | Stable pharmaceutical compositions |
| US7530968B2 (en) | 2003-04-23 | 2009-05-12 | Valeritas, Inc. | Hydraulically actuated pump for long duration medicament administration |
| SG141430A1 (en) | 2003-05-30 | 2008-04-28 | Ranbaxy Lab Ltd | Substituted pyrrole derivatives and their use as hmg-co inhibitors |
| ES2371072T3 (es) | 2003-06-12 | 2011-12-27 | Eli Lilly And Company | Proteínas de fusión análogas de glp-1. |
| SI1648933T1 (sl) * | 2003-07-25 | 2010-01-29 | Conjuchem Biotechnologies Inc | Dolgo delujoäś inzulinski derivat in metoda zanj |
| CN1964989B (zh) * | 2003-07-25 | 2012-02-01 | 康久化学生物技术公司 | 长效胰岛素衍生物及其方法 |
| MXPA06001601A (es) | 2003-08-13 | 2006-08-25 | Takeda Pharmaceutical | Derivados de 4-pirimidona y su uso como inhibidores de dipeptidilpeptidasa. |
| US20060205037A1 (en) * | 2003-08-28 | 2006-09-14 | Homayoun Sadeghi | Modified transferrin fusion proteins |
| JP2007512001A (ja) * | 2003-08-28 | 2007-05-17 | バイオレクシス ファーマシューティカル コーポレイション | Ｅｐｏミメティックペプチドおよび融合タンパク質 |
| US20070275877A1 (en) * | 2003-08-29 | 2007-11-29 | Amylin Pharmaceuticals, Inc. | Methods for Treating or Ameliorating Ghrelin-Associated Diseases and Disorders |
| WO2005026148A1 (en) * | 2003-09-08 | 2005-03-24 | Takeda San Diego, Inc. | Dipeptidyl peptidase inhibitors |
| US7214190B1 (en) | 2003-09-09 | 2007-05-08 | Kitchener Clark Wilson | Apparatus and method for noninvasive monitoring of analytes in body fluids |
| CN101665538A (zh) * | 2003-12-18 | 2010-03-10 | 诺沃挪第克公司 | 与白蛋白样物质相连的新glp-1类似物 |
| US20060286129A1 (en) * | 2003-12-19 | 2006-12-21 | Emisphere Technologies, Inc. | Oral GLP-1 formulations |
| BRPI0507189A (pt) * | 2004-01-30 | 2007-06-26 | Waratah Pharmaceuticals Inc | uso combinado de um agonista de glp-1 e compostos de gastrina |
| CN102816241B (zh) | 2004-02-09 | 2015-07-22 | 人类基因科学公司 | 清蛋白融合蛋白 |
| US8076288B2 (en) * | 2004-02-11 | 2011-12-13 | Amylin Pharmaceuticals, Inc. | Hybrid polypeptides having glucose lowering activity |
| CN102079743B (zh) * | 2004-03-15 | 2020-08-25 | 武田药品工业株式会社 | 二肽基肽酶抑制剂 |
| ES2347902T3 (es) * | 2004-04-23 | 2010-11-22 | Conjuchem Biotechnologies Inc. Canadian Corporation 4528590 | Fase solida para uso en un procedimiento para la purificacion de conjugados de albumina. |
| CN1318587C (zh) * | 2004-04-30 | 2007-05-30 | 成都芝田生物工程有限公司 | 酰胺化Exendin－4多肽的重组制备方法 |
| US9089636B2 (en) | 2004-07-02 | 2015-07-28 | Valeritas, Inc. | Methods and devices for delivering GLP-1 and uses thereof |
| AU2012202855B2 (en) * | 2004-09-03 | 2015-02-26 | Philipps-Universitat Marburg | GLP-1 and exendin related invention |
| DE102004043153B4 (de) * | 2004-09-03 | 2013-11-21 | Philipps-Universität Marburg | Erfindung betreffend GLP-1 und Exendin |
| JP2008515856A (ja) | 2004-10-07 | 2008-05-15 | ノボ ノルディスク アクティーゼルスカブ | 遅延性ｇｌｐ−１化合物 |
| JP5107713B2 (ja) * | 2004-10-07 | 2012-12-26 | ノヴォ ノルディスク アー／エス | 遅延性のエキセンディン−４化合物 |
| CN101056650A (zh) * | 2004-11-12 | 2007-10-17 | 诺和诺德公司 | 促胰岛素肽的稳定制剂 |
| JP2008524331A (ja) * | 2004-12-21 | 2008-07-10 | 武田薬品工業株式会社 | ジペプチジルペプチダーゼ阻害剤 |
| US8716221B2 (en) * | 2005-01-14 | 2014-05-06 | Wuxi Grandchamp Pharmaceutical Technology Co., Ltd. | Modified exendins and uses thereof |
| TWI376234B (en) | 2005-02-01 | 2012-11-11 | Msd Oss Bv | Conjugates of a polypeptide and an oligosaccharide |
| US11246913B2 (en) | 2005-02-03 | 2022-02-15 | Intarcia Therapeutics, Inc. | Suspension formulation comprising an insulinotropic peptide |
| WO2006083761A2 (en) | 2005-02-03 | 2006-08-10 | Alza Corporation | Solvent/polymer solutions as suspension vehicles |
| TWI362392B (en) | 2005-03-18 | 2012-04-21 | Novo Nordisk As | Acylated glp-1 compounds |
| ES2484796T3 (es) | 2005-03-18 | 2014-08-12 | Novo Nordisk A/S | Compuestos de GLP-1 extendidos |
| EP1922336B1 (en) * | 2005-08-11 | 2012-11-21 | Amylin Pharmaceuticals, LLC | Hybrid polypeptides with selectable properties |
| NZ566799A (en) * | 2005-09-14 | 2011-04-29 | Takeda Pharmaceutical | Dipeptidyl peptidase inhibitors for treating diabetes |
| WO2007033265A1 (en) * | 2005-09-14 | 2007-03-22 | Takeda Pharmaceutical Company Limited | Dipeptidyl peptidase inhibitors for treating diabetis |
| GEP20135791B (en) * | 2005-09-14 | 2013-03-25 | Takeda Pharmaceutical | Use of dipeptidyl peptidase inhibitors |
| WO2007035629A2 (en) * | 2005-09-16 | 2007-03-29 | Takeda Pharmaceutical Company Limited | Process for the preparation of pyrimidinedione derivatives |
| TW200745079A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile and methods of use therefor |
| TW200745080A (en) * | 2005-09-16 | 2007-12-16 | Takeda Pharmaceuticals Co | Polymorphs of tartrate salt of 2-[2-(3-(R)-amino-piperidin-1-yl)-5-fluoro-6-oxo-6H-pyrimidin-1-ylmethyl]-benzonitrile and methods of use therefor |
| EP1943275B1 (en) * | 2005-11-01 | 2010-06-16 | Activotec SPP Limited | Insulinotropic compounds and uses thereof |
| BRPI0618379A2 (pt) | 2005-11-08 | 2011-08-30 | Ranbaxy Lab Ltd | processo para preparação do hemi-sal de cálcio do ácido (3r,5r) -7-[2-(4-fluorofenil)-5-isopropil-3-fenil-4-[(4-hidroxime tilfenilamino) carbonil]-pirrol-1-il] -3, 5-diidroxi heptanóico |
| US8039432B2 (en) | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
| US20080280328A1 (en) * | 2005-11-18 | 2008-11-13 | Novozymes A/S | Glucoamylase Variants |
| AU2006329215A1 (en) * | 2005-12-22 | 2007-06-28 | Conjuchem Biotechnologies Inc. | Process for the production of preformed conjugates of albumin and a therapeutic agent |
| EP1816201A1 (en) | 2006-02-06 | 2007-08-08 | CSL Behring GmbH | Modified coagulation factor VIIa with extended half-life |
| ATE507235T1 (de) * | 2006-02-08 | 2011-05-15 | Lonza Ag | Synthese von glucagon-ähnlichen peptiden |
| EP1999108A1 (en) * | 2006-03-28 | 2008-12-10 | Takeda Pharmaceutical Company Limited | Preparation of (r)-3-aminopiperidine dihydrochloride |
| CN103239773B (zh) | 2006-03-30 | 2015-08-26 | 瓦莱里塔斯公司 | 多筒式流体递送器械 |
| EP2020990B1 (en) | 2006-05-30 | 2010-09-22 | Intarcia Therapeutics, Inc | Two-piece, internal-channel osmotic delivery system flow modulator |
| KR100886783B1 (ko) | 2006-06-12 | 2009-03-04 | 성균관대학교산학협력단 | N-말단이 수식된 peg-trail 결합체, 이의 제조방법 및 이의 용도 |
| KR20090039787A (ko) | 2006-07-18 | 2009-04-22 | 센토코 인코포레이티드 | 인간 ｇｌｐ-1 모방체, 조성물, 방법 및 용도 |
| DK2046826T3 (da) | 2006-07-24 | 2011-10-24 | Biorexis Pharmaceutical Corp | Exendin-fusionsproteiner |
| PL2359808T3 (pl) | 2006-08-09 | 2013-10-31 | Intarcia Therapeutics Inc | Osmotyczne systemy dostawcze i zespoły tłokowe |
| PL2073810T3 (pl) * | 2006-09-13 | 2012-01-31 | Takeda Pharmaceuticals Co | Zastosowanie 2-6-(3-amino-piperydyn-1-ylo)-3-metylo-2,4-diokso-3,4-dihydro-2H-pirymidyn-1-ylometylo-4-fluoro-benzonitrylu do leczenia cukrzycy, raka, zaburzeń autoimmunizacyjnych i zakażeń HIV |
| US8324383B2 (en) | 2006-09-13 | 2012-12-04 | Takeda Pharmaceutical Company Limited | Methods of making polymorphs of benzoate salt of 2-[[6-[(3R)-3-amino-1-piperidinyl]-3,4-dihydro-3-methyl-2,4-dioxo-1(2H)-pyrimidinyl]methyl]-benzonitrile |
| JO2945B1 (en) * | 2006-09-13 | 2016-03-15 | سميث كلاين بيتشام كوربوريشن | Methods of giving prolonged hypoglycemic agents |
| TW200838536A (en) * | 2006-11-29 | 2008-10-01 | Takeda Pharmaceutical | Polymorphs of succinate salt of 2-[6-(3-amino-piperidin-1-yl)-3-methyl-2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-ylmethy]-4-fluor-benzonitrile and methods of use therefor |
| AU2011254001B2 (en) * | 2007-01-05 | 2012-08-02 | Covx Technologies Ireland Limited | Glucagon-like protein-1 receptor (GLP-1R) agonist compounds |
| US20090098130A1 (en) * | 2007-01-05 | 2009-04-16 | Bradshaw Curt W | Glucagon-like protein-1 receptor (glp-1r) agonist compounds |
| US20090099074A1 (en) * | 2007-01-10 | 2009-04-16 | Conjuchem Biotechnologies Inc. | Modulating food intake |
| NZ578948A (en) | 2007-02-15 | 2012-03-30 | Univ Indiana Res & Tech Corp | Glucagon/glp-1 receptor co-agonists |
| US8093236B2 (en) | 2007-03-13 | 2012-01-10 | Takeda Pharmaceuticals Company Limited | Weekly administration of dipeptidyl peptidase inhibitors |
| EP2157967B1 (en) | 2007-04-23 | 2013-01-16 | Intarcia Therapeutics, Inc | Suspension formulations of insulinotropic peptides and uses thereof |
| EP2171080A4 (en) * | 2007-06-12 | 2010-10-27 | Glaxosmithkline Llc | PROCESS FOR DETECTING PROTEIN IN PLASMA |
| WO2008157824A2 (en) * | 2007-06-21 | 2008-12-24 | Conjuchem Biotechnologies Inc. | Thrombopoietin peptide conjugates |
| US7960336B2 (en) * | 2007-08-03 | 2011-06-14 | Pharmain Corporation | Composition for long-acting peptide analogs |
| US20100292133A1 (en) | 2007-09-05 | 2010-11-18 | Novo Nordisk A/S | Truncated glp-1 derivaties and their therapeutical use |
| EP2190872B1 (en) | 2007-09-05 | 2018-03-14 | Novo Nordisk A/S | Glucagon-like peptide-1 derivatives and their pharmaceutical use |
| US20100261637A1 (en) | 2007-09-05 | 2010-10-14 | Novo Nordisk A/S | Peptides derivatized with a-b-c-d- and their therapeutical use |
| JP5473925B2 (ja) * | 2007-10-27 | 2014-04-16 | コーデン ファーマ コロラド インコーポレイテッド | 固相および溶液相の組み合わせ技法を使用するインスリン分泌性ペプチドの合成 |
| JP2011506442A (ja) * | 2007-12-11 | 2011-03-03 | コンジュケム バイオテクノロジーズ インコーポレイテッド | インスリン分泌性ペプチド結合体の製剤 |
| EP2240155B1 (en) | 2008-02-13 | 2012-06-06 | Intarcia Therapeutics, Inc | Devices, formulations, and methods for delivery of multiple beneficial agents |
| ES2552646T3 (es) | 2008-05-21 | 2015-12-01 | Amylin Pharmaceuticals, Inc. | Exendinas para disminuir el colesterol y los triglicéridos |
| ES2558842T3 (es) | 2008-06-17 | 2016-02-09 | Indiana University Research And Technology Corporation | Agonistas mixtos a base de GIP para el tratamiento de trastornos metabólicos y obesidad |
| CA2728284C (en) | 2008-06-17 | 2019-09-10 | Richard D. Dimarchi | Glucagon/glp-1 receptor co-agonists |
| CN105727261A (zh) | 2008-06-27 | 2016-07-06 | 杜克大学 | 包含弹性蛋白样肽的治疗剂 |
| WO2010015668A1 (en) | 2008-08-06 | 2010-02-11 | Novo Nordisk A/S | Conjugated proteins with prolonged in vivo efficacy |
| TW201012829A (en) * | 2008-09-22 | 2010-04-01 | Ipsen Mfg Ireland Ltd | Process for the synthesis of (Aib8,35)hGLP-1(7-36)-NH2 |
| WO2010043047A1 (en) | 2008-10-15 | 2010-04-22 | Angiochem Inc. | Conjugates of glp-1 agonists and uses thereof |
| PT3228320T (pt) | 2008-10-17 | 2020-03-26 | Sanofi Aventis Deutschland | Combinação de uma insulina e de um agonista do glp-1 |
| WO2010063122A1 (en) | 2008-12-05 | 2010-06-10 | Angiochem Inc. | Conjugates of neurotensin or neurotensin analogs and uses thereof |
| HUE031900T2 (en) | 2008-12-10 | 2017-08-28 | Glaxosmithkline Llc | Pharmaceutical compositions containing Albiglutide |
| JP5816097B2 (ja) | 2009-01-22 | 2015-11-18 | ノヴォ・ノルディスク・ヘルス・ケア・アーゲー | 安定な成長ホルモン化合物 |
| EP2401378B1 (en) | 2009-02-25 | 2013-08-14 | Merck Sharp & Dohme Corp. | Metabolic engineering of a galactose assimilation pathway in the glycoengineered yeast pichia pastoris |
| WO2010118384A2 (en) | 2009-04-10 | 2010-10-14 | Amylin Pharmaceuticals, Inc. | Amylin agonist compounds for estrogen-deficient mammals |
| WO2010148089A1 (en) | 2009-06-16 | 2010-12-23 | Indiana University Research And Technology Corporation | Gip receptor-active glucagon compounds |
| WO2011000095A1 (en) * | 2009-07-02 | 2011-01-06 | Angiochem Inc. | Multimeric peptide conjugates and uses thereof |
| PH12011502708B1 (en) | 2009-07-06 | 2017-11-10 | Sanofi Aventis Deutschland | Insulin preparations containing methionine |
| CN101987868B (zh) * | 2009-07-30 | 2013-09-04 | 江苏豪森医药集团有限公司 | Glp-1类似物的衍生物或其可药用盐和用途 |
| WO2011015649A1 (en) | 2009-08-06 | 2011-02-10 | Novo Nordisk Health Care Ag | Growth hormones with prolonged in-vivo efficacy |
| EP3323423B1 (en) | 2009-09-28 | 2020-06-17 | Intarcia Therapeutics, Inc | Rapid establishment and/or termination of substantial steady-state drug delivery |
| JP5608867B2 (ja) * | 2009-09-30 | 2014-10-15 | 国立大学法人京都大学 | 膵島イメージング用分子プローブ及びその使用 |
| WO2011048614A2 (en) | 2009-10-22 | 2011-04-28 | Cadila Healthcare Limited | Short chain peptidomimetics based orally active glp-1 agonist and glucagon receptor antagonist |
| SG10201500871TA (en) | 2009-11-13 | 2015-04-29 | Sanofi Aventis Deutschland | Pharmaceutical composition comprising a glp-1 agonist and methionine |
| JP5832439B2 (ja) | 2009-11-13 | 2015-12-16 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | Ｇｌｐ−１アゴニスト、インスリン及びメチオニンを含む薬学的組成物 |
| JP2013511287A (ja) | 2009-11-23 | 2013-04-04 | アミリン・ファーマシューティカルズ，リミテッド・ライアビリティ・カンパニー | ポリペプチド・コンジュゲート |
| PL2525834T3 (pl) | 2010-01-22 | 2020-10-19 | Novo Nordisk Health Care Ag | Hormony wzrostu o przedłużonej skuteczności in-vivo |
| RU2012134974A (ru) | 2010-01-22 | 2014-02-27 | Ново Нордиск Хелс Кеа Аг | Стабилизированное соединение гормона роста |
| KR20120123443A (ko) | 2010-01-27 | 2012-11-08 | 인디애나 유니버시티 리서치 앤드 테크놀로지 코퍼레이션 | 대사 장애 및 비만 치료용 글루카곤 길항제-ｇｉｐ 항진제 콘쥬게이트 |
| BR112012020882A2 (pt) | 2010-02-24 | 2015-11-03 | Merck Sharp & Dohme | métodos para produzir uma glicoproteína heteróloga e para produzir uma composição de glicoproteína, célula hospedeira, composição de glicoproteína, e, uso da pichia pastoris recombinante. |
| KR20130018410A (ko) * | 2010-03-26 | 2013-02-21 | 노보 노르디스크 에이/에스 | 새로운 글루카곤 유사체 |
| US9168288B2 (en) | 2010-04-09 | 2015-10-27 | Mount Sinai Hospital | Methods for treating disorders of the gastrointestinal tract using a GLP-1 agonist |
| CN103003300B (zh) | 2010-04-27 | 2017-06-09 | 西兰制药公司 | Glp‑1受体激动剂和胃泌素的肽缀合物及其用途 |
| EP2566502A4 (en) | 2010-05-04 | 2013-10-09 | Glaxosmithkline Llc | METHODS OF TREATING OR PREVENTING CARDIOVASCULAR DISORDERS AND PROVIDING CARDIOVASCULAR PROTECTION |
| ES2661228T3 (es) | 2010-05-13 | 2018-03-28 | Indiana University Research And Technology Corporation | Péptidos de la superfamilia de glucagón que muestran actividad de receptor nuclear de hormona |
| RU2012153753A (ru) | 2010-05-13 | 2014-06-20 | Индиана Юниверсити Рисерч Энд Текнолоджи Корпорейшн | Пептиды глюкагонового суперсемейства, обладающие активностью в отношении сопряженных с g-белком рецепторов |
| CN103179978A (zh) | 2010-08-30 | 2013-06-26 | 赛诺菲-安万特德国有限公司 | Ave0010用于制造供治疗2型糖尿病用的药物的用途 |
| MX377589B (es) | 2010-12-16 | 2025-03-10 | Novo Nordisk As | Composiciones sólidas que comprenden agonista de glp-1 y sal del ácido n-(8-(2-hidroxibenzoil)amino)caprílico. |
| NZ612297A (en) | 2010-12-22 | 2015-10-30 | Univ Indiana Res & Tech Corp | Glucagon analogs exhibiting gip receptor activity |
| US20120208755A1 (en) | 2011-02-16 | 2012-08-16 | Intarcia Therapeutics, Inc. | Compositions, Devices and Methods of Use Thereof for the Treatment of Cancers |
| EP2681327B1 (en) * | 2011-03-04 | 2018-11-21 | Intrexon Corporation | Vectors conditionally expressing protein |
| AU2012241894B2 (en) | 2011-04-12 | 2015-12-03 | Novo Nordisk A/S | Double-acylated GLP-1 derivatives |
| US9821032B2 (en) | 2011-05-13 | 2017-11-21 | Sanofi-Aventis Deutschland Gmbh | Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin |
| CN103857408B (zh) | 2011-06-22 | 2017-04-12 | 印第安那大学科技研究公司 | 胰高血糖素/glp‑1受体协同激动剂 |
| JP6184404B2 (ja) | 2011-06-22 | 2017-08-23 | インディアナ ユニヴァーシティ リサーチ アンド テクノロジー コーポレイション | グルカゴン／ｇｌｐ−１レセプターコアゴニスト |
| KR101357117B1 (ko) * | 2011-06-28 | 2014-02-06 | 비앤엘델리팜 주식회사 | 폴리에틸렌글라이콜 또는 이의 유도체로 페길화된 엑센딘-4 유사체, 이의 제조방법 및 이를 유효성분으로 함유하는 당뇨병 예방 또는 치료용 약학적 조성물 |
| JP6367115B2 (ja) | 2011-08-29 | 2018-08-01 | サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング | ２型糖尿病患者の血糖コントロールに使用する組合せ医薬 |
| TWI559929B (en) | 2011-09-01 | 2016-12-01 | Sanofi Aventis Deutschland | Pharmaceutical composition for use in the treatment of a neurodegenerative disease |
| CN103189389B (zh) * | 2011-09-03 | 2017-08-11 | 深圳市健元医药科技有限公司 | 新的glp‑ⅰ类似物及其制备方法和用途 |
| CN102286092B (zh) * | 2011-09-14 | 2014-01-01 | 深圳翰宇药业股份有限公司 | 利拉鲁肽的固相合成方法 |
| MX354705B (es) | 2011-09-23 | 2018-03-16 | Novo Nordisk As | Analogos de glucagon novedosos. |
| KR20140100947A (ko) | 2011-11-03 | 2014-08-18 | 질랜드 파마 에이/에스 | Ｇｌｐ-1 수용체 효능제 펩타이드 가스트린 접합체들 |
| WO2013112548A1 (en) | 2012-01-23 | 2013-08-01 | University Of South Florida | Gamma-aapeptides with potent and broad-spectrum antimicrobial activity |
| ES2715308T3 (es) | 2012-03-22 | 2019-06-03 | Novo Nordisk As | Composiciones que comprenden un agente de suministro y su preparación |
| KR102072202B1 (ko) | 2012-03-22 | 2020-01-31 | 노보 노르디스크 에이/에스 | Ｇｌｐ-1 펩티드의 조성물 및 그것의 제조 |
| WO2013163162A1 (en) * | 2012-04-24 | 2013-10-31 | Amylin Pharmaceuticals, Llc | Site-specific enzymatic modification of exendins and analogs thereof |
| MX349035B (es) | 2012-05-17 | 2017-07-07 | Extend Biosciences Inc | Portadores para el suministro mejorado de farmaco. |
| WO2013189988A1 (en) | 2012-06-20 | 2013-12-27 | Novo Nordisk A/S | Tablet formulation comprising a peptide and a delivery agent |
| MX2014015557A (es) | 2012-06-21 | 2015-02-24 | Univ Indiana Res & Tech Corp | Polipeptidos de fusion de region fc de polipeptido de ligando receptor de incretina y conjugados con función efectora fc alterada. |
| ES2602486T3 (es) | 2012-06-21 | 2017-02-21 | Indiana University Research And Technology Corporation | Análogos de glucagón que muestran actividad de receptor de GIP |
| NZ704043A (en) | 2012-07-23 | 2017-07-28 | Zealand Pharma As | Glucagon analogues |
| TWI608013B (zh) | 2012-09-17 | 2017-12-11 | 西蘭製藥公司 | 升糖素類似物 |
| UA116217C2 (uk) | 2012-10-09 | 2018-02-26 | Санофі | Пептидна сполука як подвійний агоніст рецепторів glp1-1 та глюкагону |
| HUE035803T2 (en) | 2012-12-21 | 2018-05-28 | Sanofi Sa | Dual GLP1 / GIP or trigonal GLP1 / GIP / glucagon agonists |
| TWI780236B (zh) | 2013-02-04 | 2022-10-11 | 法商賽諾菲公司 | 胰島素類似物及/或胰島素衍生物之穩定化醫藥調配物 |
| MY170528A (en) | 2013-02-18 | 2019-08-09 | Vegenics Pty Ltd | Vegfr-3 ligand binding molecules and uses thereof |
| JP6538645B2 (ja) | 2013-03-14 | 2019-07-03 | インディアナ ユニバーシティー リサーチ アンド テクノロジー コーポレーションＩｎｄｉａｎａ Ｕｎｉｖｅｒｓｉｔｙ Ｒｅｓｅａｒｃｈ Ａｎｄ Ｔｅｃｈｎｏｌｏｇｙ Ｃｏｒｐｏｒａｔｉｏｎ | インスリン‐インクレチン複合物 |
| US20160039877A1 (en) * | 2013-03-15 | 2016-02-11 | Shenzhen Hightide Biopharmaceutical, Ltd. | Compositions and methods of using islet neogenesis peptides and analogs thereof |
| AR095986A1 (es) * | 2013-04-03 | 2015-11-25 | Sanofi Sa | Proteínas modificadas que regulan glucosa en sangre con perfil alterado de actividad farmacológica y preparación de las mismas |
| ES2841123T3 (es) | 2013-04-05 | 2021-07-07 | Formulacion Del Compuesto De La Hormona De Crecimiento | Formulación del compuesto de la hormona de crecimiento |
| BR112015025464A2 (pt) | 2013-04-18 | 2017-10-10 | Novo Nordisk As | coagonistas do receptor de glp-1/glucagon estáveis, prolongados para uso médico |
| RS58039B1 (sr) | 2013-05-02 | 2019-02-28 | Novo Nordisk As | Oralno doziranje glp-1 jedinjenja |
| AR098065A1 (es) | 2013-10-17 | 2016-04-27 | Zealand Pharma As | Análogos de glucagón acilados |
| US9988429B2 (en) | 2013-10-17 | 2018-06-05 | Zealand Pharma A/S | Glucagon analogues |
| CA2929459C (en) | 2013-11-06 | 2022-05-03 | Zealand Pharma A/S | Gip-glp-1 dual agonist compounds and methods |
| AU2014345570B2 (en) | 2013-11-06 | 2019-01-24 | Zealand Pharma A/S | Glucagon-GLP-1-GIP triple agonist compounds |
| WO2015086730A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Non-acylated exendin-4 peptide analogues |
| WO2015086728A1 (en) | 2013-12-13 | 2015-06-18 | Sanofi | Exendin-4 peptide analogues as dual glp-1/gip receptor agonists |
| TW201609797A (zh) | 2013-12-13 | 2016-03-16 | 賽諾菲公司 | 雙重ｇｌｐ－１／升糖素受體促效劑 |
| EP3080154B1 (en) | 2013-12-13 | 2018-02-07 | Sanofi | Dual glp-1/gip receptor agonists |
| US10137170B2 (en) | 2013-12-20 | 2018-11-27 | Indiana University Research And Technology Corporation | Lipidated incretin receptor ligand human immunoglobulin Fc-region fusion polypeptides |
| JP6641280B2 (ja) | 2014-01-09 | 2020-02-05 | サノフイＳａｎｏｆｉ | インスリンアナログおよび／またはインスリン誘導体の安定化された医薬製剤 |
| KR20160104726A (ko) | 2014-01-09 | 2016-09-05 | 사노피 | 인슐린 유사체 및/또는 인슐린 유도체의 안정화된 무글리세롤 약제학적 제형 |
| CA2932873A1 (en) | 2014-01-09 | 2015-07-16 | Sanofi | Stabilized pharmaceutical formulations of insulin aspart |
| WO2015138638A1 (en) | 2014-03-11 | 2015-09-17 | Theraly Pharmaceuticals, Inc. | Long acting trail receptor agonists for treatment of autoimmune diseases |
| TW201625669A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑 |
| TW201625668A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物 |
| TW201625670A (zh) | 2014-04-07 | 2016-07-16 | 賽諾菲公司 | 衍生自ｅｘｅｎｄｉｎ－４之雙重ｇｌｐ－１／升糖素受體促效劑 |
| JP2017525656A (ja) | 2014-06-04 | 2017-09-07 | ノヴォ ノルディスク アー／エス | 医療用のｇｌｐ−１／グルカゴン受容体コアゴニスト |
| US9932381B2 (en) | 2014-06-18 | 2018-04-03 | Sanofi | Exendin-4 derivatives as selective glucagon receptor agonists |
| GB201415598D0 (en) | 2014-09-03 | 2014-10-15 | Univ Birmingham | Elavated Itercranial Pressure Treatment |
| CN108271356A (zh) | 2014-09-24 | 2018-07-10 | 印第安纳大学研究及科技有限公司 | 肠降血糖素-胰岛素缀合物 |
| US9889085B1 (en) | 2014-09-30 | 2018-02-13 | Intarcia Therapeutics, Inc. | Therapeutic methods for the treatment of diabetes and related conditions for patients with high baseline HbA1c |
| US9585934B2 (en) | 2014-10-22 | 2017-03-07 | Extend Biosciences, Inc. | Therapeutic vitamin D conjugates |
| 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 |
| EP3212218B1 (en) | 2014-10-29 | 2021-06-30 | Zealand Pharma A/S | Gip agonist compounds and methods |
| CN107206058A (zh) | 2014-12-12 | 2017-09-26 | 赛诺菲-安万特德国有限公司 | 甘精胰岛素/利西拉来固定比率配制剂 |
| TWI748945B (zh) | 2015-03-13 | 2021-12-11 | 德商賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患治療 |
| TW201705975A (zh) | 2015-03-18 | 2017-02-16 | 賽諾菲阿凡提斯德意志有限公司 | 第２型糖尿病病患之治療 |
| PL3283507T3 (pl) | 2015-04-16 | 2020-05-18 | Zealand Pharma A/S | Acylowany analog glukagonu |
| ES2968262T3 (es) | 2015-06-03 | 2024-05-08 | I2O Therapeutics Inc | Sistemas de colocación de implantes |
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| EP3307326B9 (en) | 2015-06-15 | 2021-02-24 | Angiochem Inc. | Methods for the treatment of leptomeningeal carcinomatosis |
| TW201706291A (zh) | 2015-07-10 | 2017-02-16 | 賽諾菲公司 | 作為選擇性肽雙重ｇｌｐ－１／升糖素受體促效劑之新毒蜥外泌肽（ｅｘｅｎｄｉｎ－４）衍生物 |
| US11007251B2 (en) | 2015-12-17 | 2021-05-18 | The Johns Hopkins University | Ameliorating systemic sclerosis with death receptor agonists |
| AU2016379403B2 (en) | 2015-12-23 | 2020-03-12 | The Johns Hopkins University | Long-acting GLP-1r agonist as a therapy of neurological and neurodegenerative conditions |
| CN109195620B (zh) | 2016-04-07 | 2022-06-28 | 约翰霍普金斯大学 | 用死亡受体激动剂治疗胰腺炎和疼痛的组合物和方法 |
| KR20240037175A (ko) | 2016-05-16 | 2024-03-21 | 인타르시아 세라퓨틱스 인코포레이티드 | 글루카곤-수용체 선택적 폴리펩티드 및 이들의 이용 방법 |
| USD860451S1 (en) | 2016-06-02 | 2019-09-17 | Intarcia Therapeutics, Inc. | Implant removal tool |
| USD840030S1 (en) | 2016-06-02 | 2019-02-05 | Intarcia Therapeutics, Inc. | Implant placement guide |
| CN108070030B (zh) * | 2016-11-17 | 2023-06-23 | 江苏豪森药业集团有限公司 | 洛塞那肽及其类似物的制备方法 |
| KR102502040B1 (ko) | 2016-12-09 | 2023-02-24 | 질랜드 파마 에이/에스 | 아실화 glp-1/glp-2 이중 효능제 |
| AU2018206539A1 (en) | 2017-01-03 | 2019-07-18 | Intarcia Therapeutics, Inc. | Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug |
| JOP20190211A1 (ar) | 2017-03-31 | 2019-09-15 | Takeda Pharmaceuticals Co | ببتيد منشط لمستقبل gip |
| CN109503700A (zh) * | 2017-09-14 | 2019-03-22 | 南京安吉生物科技有限公司 | 马来酰亚胺基团修饰的血管生成抑制剂hm-1及其应用 |
| US10905750B2 (en) | 2017-11-10 | 2021-02-02 | Donald J. Davidson | GRP78 antagonist that block binding of receptor tyrosine kinase orphan receptors as immunotherapy anticancer agents |
| AR114353A1 (es) | 2018-02-02 | 2020-08-26 | Novo Nordisk As | Composiciones sólidas que comprenden un agonista del glp-1 y una sal del ácido n-(8-(2-hidroxibenzoil)amino)caprílico |
| WO2019200594A1 (zh) | 2018-04-19 | 2019-10-24 | 杭州先为达生物科技有限公司 | 酰化的glp-1衍生物 |
| AU2019357621B2 (en) | 2018-10-11 | 2025-04-03 | Intarcia Therapeutics, Inc. | Human amylin analog polypeptides and methods of use |
| CN109400695B (zh) | 2018-10-31 | 2020-06-30 | 中南大学湘雅医院 | 一种多肽的修饰方法及应用 |
| CN110183531A (zh) * | 2019-05-17 | 2019-08-30 | 河北常山生化药业股份有限公司 | 一种艾本那肽前体的制备方法 |
| AU2020418207A1 (en) | 2019-12-30 | 2022-08-25 | Gan & Lee Pharmaceuticals Co., Ltd. | Long-acting GLP-1 compound |
| CN111333714A (zh) * | 2020-03-05 | 2020-06-26 | 成都奥达生物科技有限公司 | 一种长效glp-1化合物 |
| EP4126907A1 (en) * | 2020-03-27 | 2023-02-08 | Epivax, Inc. | Tregitope constructs useful in the prevention and treatment of type 1 diabetes |
| US12233115B2 (en) | 2022-09-30 | 2025-02-25 | Extend Biosciences, Inc. | Long-acting parathyroid hormone |
| CN115819493B (zh) * | 2022-11-16 | 2026-03-13 | 河北常山生化药业股份有限公司 | 一种多肽固相合成方法 |
| WO2024123812A1 (en) | 2022-12-05 | 2024-06-13 | Shattuck Labs, Inc. | Fusion proteins for the treatment of cardiometabolic diseases |
| CN121398836A (zh) | 2023-06-26 | 2026-01-23 | 阿尔布内克斯特有限责任公司 | 激活glp-1/gip/胰高血糖素受体的白蛋白结合的大分子三重激动剂 |
| KR102743491B1 (ko) | 2023-08-01 | 2024-12-17 | (주)인벤티지랩 | 세마글루타이드 또는 이의 약학적으로 허용 가능한 염을 포함하는 마이크로 입자 및 이의 제조 방법 |
| IL327385A (en) | 2023-09-29 | 2026-05-01 | Graviton Pharmaceuticals B V | ROCK2 inhibitors in the treatment of obesity |
Family Cites Families (86)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4206199A (en) * | 1977-07-22 | 1980-06-03 | Takeda Chemical Industries, Ltd. | Novel glucagon fragment and its derivatives |
| US4423034A (en) * | 1980-10-16 | 1983-12-27 | Toyo Jozo Kabushiki Kaisha | Process for the preparation of antibodies |
| US4462941A (en) * | 1982-06-10 | 1984-07-31 | The Regents Of The University Of California | Dynorphin amide analogs |
| US5614492A (en) | 1986-05-05 | 1997-03-25 | The General Hospital Corporation | Insulinotropic hormone GLP-1 (7-36) and uses thereof |
| US5120712A (en) | 1986-05-05 | 1992-06-09 | The General Hospital Corporation | Insulinotropic hormone |
| US5118666A (en) | 1986-05-05 | 1992-06-02 | The General Hospital Corporation | Insulinotropic hormone |
| DK608589D0 (da) | 1989-12-01 | 1989-12-01 | Holm Arne | Kemisk fremgangsmaade |
| US5116944A (en) * | 1989-12-29 | 1992-05-26 | Neorx Corporation | Conjugates having improved characteristics for in vivo administration |
| US5545618A (en) | 1990-01-24 | 1996-08-13 | Buckley; Douglas I. | GLP-1 analogs useful for diabetes treatment |
| ES2113879T3 (es) | 1990-01-24 | 1998-05-16 | Douglas I Buckley | Analogos de glp-1 utiles para el tratamiento de diabetes. |
| US5843440A (en) * | 1990-10-03 | 1998-12-01 | Redcell Canada, Inc. | Cellular and serum protein anchors for modulating pharmacokinetics |
| US5612034A (en) * | 1990-10-03 | 1997-03-18 | Redcell, Inc. | Super-globuling for in vivo extended lifetimes |
| DK0578728T3 (da) | 1991-04-05 | 1999-04-12 | Genentech Inc | Inhibitorer for aggregering af blodplader, hvilke inhibitorer har høj specificitet for GP IIbIIIa |
| BR9306551A (pt) | 1992-06-15 | 1998-09-15 | Pfizer | Derivados de peptídeo do tipo glucagona e de insulinotropina |
| EP0602290B1 (en) | 1992-12-04 | 1999-08-25 | ConjuChem, Inc. | Antibody-conjugated Hepatitis B surface antigen and use thereof |
| US5424286A (en) * | 1993-05-24 | 1995-06-13 | Eng; John | Exendin-3 and exendin-4 polypeptides, and pharmaceutical compositions comprising same |
| US5614487A (en) * | 1993-05-28 | 1997-03-25 | Genentech, Inc. | Sustained release pharmaceutical composition |
| US5705483A (en) | 1993-12-09 | 1998-01-06 | Eli Lilly And Company | Glucagon-like insulinotropic peptides, compositions and methods |
| US5580853A (en) * | 1994-03-22 | 1996-12-03 | New England Deaconess Hospital | Modified polypeptides with increased biological activity |
| US5945403A (en) * | 1997-05-30 | 1999-08-31 | The Children's Medical Center Corporation | Angiostatin fragments and method of use |
| US5837682A (en) * | 1996-03-08 | 1998-11-17 | The Children's Medical Center Corporation | Angiostatin fragments and method of use |
| CN1636594B (zh) * | 1994-04-26 | 2012-08-29 | 儿童医学中心公司 | 血管生成抑制素和用于抑制血管生成的方法 |
| US5639725A (en) * | 1994-04-26 | 1997-06-17 | Children's Hospital Medical Center Corp. | Angiostatin protein |
| US5574008A (en) | 1994-08-30 | 1996-11-12 | Eli Lilly And Company | Biologically active fragments of glucagon-like insulinotropic peptide |
| US5654276A (en) * | 1995-06-07 | 1997-08-05 | Affymax Technologies N.V. | Peptides and compounds that bind to the IL-5 receptor |
| ES2217340T3 (es) | 1995-12-13 | 2004-11-01 | The Children's Medical Center Corporation | Inhibidor de la proliferacion de celulas endoteliales y utilizacion de este. |
| US5854221A (en) * | 1996-12-12 | 1998-12-29 | The Children's Medical Center Corporation | Endothelial cell proliferation inhibitor and method of use |
| AU713616B2 (en) | 1996-01-12 | 1999-12-09 | Conjuchem, Inc. | Cellular and serum protein anchors for diagnostic imaging |
| US6277583B1 (en) * | 1996-02-07 | 2001-08-21 | Conjuchem, Inc. | Affinity labeling libraries and applications thereof |
| ID17252A (id) | 1996-04-29 | 1997-12-11 | Akzo Nobel Nv | Proses pembuatan obyek yang terbuat dari selulosa |
| JP4426650B2 (ja) | 1996-05-03 | 2010-03-03 | アボット・ラボラトリーズ | 新規な抗血管形成ペプチド、それをコードするポリヌクレオチド、および血管形成を阻害する方法 |
| US5801146A (en) * | 1996-05-03 | 1998-09-01 | Abbott Laboratories | Compound and method for inhibiting angiogenesis |
| AU723694B2 (en) * | 1996-06-05 | 2000-08-31 | Roche Diagnostics Gmbh | Exendin analogues, processes for their preparation and medicaments containing them |
| US5840733A (en) | 1996-07-01 | 1998-11-24 | Redcell, Canada, Inc. | Methods and compositions for producing novel conjugates of thrombin inhibitors and endogenous carriers resulting in anti-thrombins with extended lifetimes |
| DE69740096D1 (de) | 1996-08-08 | 2011-02-17 | Amylin Pharmaceuticals Inc | Pharmazeutische Zusammensetzung mit einem Exendin-4-Peptid |
| US6277819B1 (en) | 1996-08-30 | 2001-08-21 | Eli Lilly And Company | Use of GLP-1 or analogs in treatment of myocardial infarction |
| US6006753A (en) | 1996-08-30 | 1999-12-28 | Eli Lilly And Company | Use of GLP-1 or analogs to abolish catabolic changes after surgery |
| DE122009000079I2 (de) | 1996-08-30 | 2011-06-16 | Novo Nordisk As Novo Alle | Glp-1 derivate |
| WO1998011437A1 (en) | 1996-09-16 | 1998-03-19 | Conjuchem, Inc. | Affinity labeling libraries with tagged leaving groups |
| UA65549C2 (uk) * | 1996-11-05 | 2004-04-15 | Елі Ліллі Енд Компані | Спосіб регулювання ожиріння шляхом периферійного введення аналогів та похідних glp-1 (варіанти) та фармацевтична композиція |
| US5864372A (en) * | 1996-12-10 | 1999-01-26 | United Microelectronics Corporation | Apparatus for implementing a block matching algorithm for motion estimation in video image processing |
| US6723530B1 (en) * | 1997-02-05 | 2004-04-20 | Amylin Pharmaceuticals, Inc. | Polynucleotides encoding proexendin, and methods and uses thereof |
| US5981488A (en) | 1997-03-31 | 1999-11-09 | Eli Lillly And Company | Glucagon-like peptide-1 analogs |
| WO1998043658A1 (en) | 1997-03-31 | 1998-10-08 | Eli Lilly And Company | Glucagon-like peptide-1 analogs |
| EP1001985A1 (en) | 1997-06-26 | 2000-05-24 | Karolinska Innovations AB | Kringle domains 1-5 of plasminogen, capable of modulating angiogenesis in vivo |
| ES2293688T5 (es) | 1997-08-08 | 2011-05-04 | Amylin Pharmaceuticals, Inc. | Nuevos compuestos análogos de la exendina. |
| DE69812727D1 (de) | 1997-11-07 | 2003-04-30 | Conjuchem Inc | Opioid-konjugate mit endogenen Trägerproteinen |
| ATE406577T1 (de) | 1997-11-07 | 2008-09-15 | Conjuchem Biotechnologies Inc | Methoden zum screening von affinitätsmarker- bibliotheken |
| US6437092B1 (en) * | 1998-11-06 | 2002-08-20 | Conjuchem, Inc. | Conjugates of opioids and endogenous carriers |
| CA2309955A1 (en) | 1997-11-12 | 1999-05-20 | Alza Corporation | Method for decreasing self-association of polypeptides |
| CA2309356C (en) | 1997-11-14 | 2010-09-21 | Amylin Pharmaceuticals, Inc. | Novel exendin agonist compounds |
| NZ504258A (en) | 1997-11-14 | 2002-12-20 | Amylin Pharmaceuticals Inc | Exendin 3 and 4 agonist compounds for the treatment of diabetes |
| AU1617399A (en) | 1997-12-05 | 1999-06-28 | Eli Lilly And Company | Glp-1 formulations |
| AU757658B2 (en) | 1998-03-09 | 2003-02-27 | Zealand Pharma A/S | Pharmacologically active peptide conjugates having a reduced tendency towards enzymatic hydrolysis |
| US6107489A (en) * | 1998-03-17 | 2000-08-22 | Conjuchem, Inc. | Extended lifetimes in vivo renin inhibitors |
| US20030170250A1 (en) * | 1998-03-23 | 2003-09-11 | Ezrin Alan M. | Local delivery of long lasting therapeutic agents |
| IL133053A0 (en) * | 1998-03-23 | 2001-03-19 | Conjuchem Inc | Local delivery of long lasting therapeutic agents |
| GB9815505D0 (en) | 1998-07-16 | 1998-09-16 | Adprotech Plc | Polypeptide derivatives |
| JP2002524122A (ja) | 1998-09-09 | 2002-08-06 | ユー．エス． アーミー インスティテュート オブ サージカル リサーチ | 反射率パルスオキシメーターセンサーを備えた鼻咽腔気管エアウェイ |
| US6284725B1 (en) * | 1998-10-08 | 2001-09-04 | Bionebraska, Inc. | Metabolic intervention with GLP-1 to improve the function of ischemic and reperfused tissue |
| US6440417B1 (en) * | 1998-11-06 | 2002-08-27 | Conjuchem, Inc. | Antibodies to argatroban derivatives and their use in therapeutic and diagnostic treatments |
| AU2990300A (en) | 1999-02-10 | 2000-08-29 | Children's Medical Center Corporation | Deglycosylated kringle 1-5 region fragments of plasminogen and methods of use |
| US6465424B1 (en) | 1999-02-17 | 2002-10-15 | Bristol-Myers Squibb Company | Anti-angiogenic agent and method for inhibiting angiogenesis |
| US6451974B1 (en) * | 1999-03-17 | 2002-09-17 | Novo Nordisk A/S | Method of acylating peptides and novel acylating agents |
| JP2002538803A (ja) | 1999-03-18 | 2002-11-19 | チルドレンズ・メディカル・センター・コーポレイション | 新規の抗脈管形成ペプチド |
| WO2000061179A1 (en) | 1999-04-14 | 2000-10-19 | Karolinska Innovations Ab | Kringle domains of plasminogen, capable of modulating angiogenesis in vivo |
| PT1180121E (pt) * | 1999-05-17 | 2004-03-31 | Conjuchem Inc | Peptidos insulinotropicos de longa duracao |
| US7601691B2 (en) * | 1999-05-17 | 2009-10-13 | Conjuchem Biotechnologies Inc. | Anti-obesity agents |
| US20040266673A1 (en) * | 2002-07-31 | 2004-12-30 | Peter Bakis | Long lasting natriuretic peptide derivatives |
| US7144854B1 (en) * | 1999-09-10 | 2006-12-05 | Conjuchem, Inc. | Long lasting anti-angiogenic peptides |
| US6849714B1 (en) * | 1999-05-17 | 2005-02-01 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| EP1179012B2 (en) | 1999-05-17 | 2009-07-15 | ConjuChem Biotechnologies Inc. | Long lasting fusion peptide inhibitors of viral infection |
| AU765753B2 (en) | 1999-05-17 | 2003-09-25 | Conjuchem Biotechnologies Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US6887470B1 (en) * | 1999-09-10 | 2005-05-03 | Conjuchem, Inc. | Protection of endogenous therapeutic peptides from peptidase activity through conjugation to blood components |
| US6514500B1 (en) * | 1999-10-15 | 2003-02-04 | Conjuchem, Inc. | Long lasting synthetic glucagon like peptide {GLP-!} |
| DE19926154A1 (de) | 1999-06-09 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Verfahren zur Herstellung einer injizierbaren Arzneimittelzubereitung |
| DE19926475A1 (de) | 1999-06-10 | 2000-12-14 | Ktb Tumorforschungs Gmbh | Träger-Pharmaka-Konjugate |
| US6706892B1 (en) * | 1999-09-07 | 2004-03-16 | Conjuchem, Inc. | Pulmonary delivery for bioconjugation |
| US7090851B1 (en) * | 1999-09-10 | 2006-08-15 | Conjuchem Inc. | Long lasting fusion peptide inhibitors of viral infection |
| CA2435563A1 (en) * | 2001-02-02 | 2002-08-15 | Conjuchem Inc. | Long lasting growth hormone releasing factor derivatives |
| DK1360202T3 (da) * | 2001-02-16 | 2008-09-22 | Conjuchem Biotechnologies Inc | Langvarigt glucagon-lignende peptid 2 (GLP-2) til behandling af gastrointestinale sygdomme og lidelser |
| ES2242860T3 (es) * | 2001-05-31 | 2005-11-16 | Conjuchem, Inc. | Inhibidores peptidicos de fusion de larga vida contra infecciones por vih. |
| SI1648933T1 (sl) * | 2003-07-25 | 2010-01-29 | Conjuchem Biotechnologies Inc | Dolgo delujoäś inzulinski derivat in metoda zanj |
| ES2347902T3 (es) * | 2004-04-23 | 2010-11-22 | Conjuchem Biotechnologies Inc. Canadian Corporation 4528590 | Fase solida para uso en un procedimiento para la purificacion de conjugados de albumina. |
| US8039432B2 (en) * | 2005-11-09 | 2011-10-18 | Conjuchem, Llc | Method of treatment of diabetes and/or obesity with reduced nausea side effect |
| AU2006329215A1 (en) * | 2005-12-22 | 2007-06-28 | Conjuchem Biotechnologies Inc. | Process for the production of preformed conjugates of albumin and a therapeutic agent |
-
2000
- 2000-05-17 PT PT00930796T patent/PT1180121E/pt unknown
- 2000-05-17 EP EP00930796A patent/EP1180121B9/en not_active Expired - Lifetime
- 2000-05-17 EA EA200100939A patent/EA003922B1/ru not_active IP Right Cessation
- 2000-05-17 WO PCT/US2000/013563 patent/WO2000069911A1/en not_active Ceased
- 2000-05-17 US US09/623,618 patent/US6329336B1/en not_active Expired - Fee Related
- 2000-05-17 DE DE60006100T patent/DE60006100T2/de not_active Expired - Lifetime
- 2000-05-17 JP JP2000618327A patent/JP4115671B2/ja not_active Expired - Fee Related
- 2000-05-17 AU AU48555/00A patent/AU754770B2/en not_active Ceased
- 2000-05-17 ES ES00930796T patent/ES2209885T3/es not_active Expired - Lifetime
- 2000-05-17 DK DK00930796T patent/DK1180121T3/da active
- 2000-05-17 AT AT00930796T patent/ATE252601T1/de active
- 2000-05-17 CA CA2363712A patent/CA2363712C/en not_active Expired - Fee Related
- 2000-05-17 SI SI200030286T patent/SI1180121T1/xx unknown
- 2000-05-17 CN CNB008065489A patent/CN1191273C/zh not_active Expired - Lifetime
- 2000-05-17 CA CA002501421A patent/CA2501421A1/en not_active Abandoned
- 2000-05-17 BR BR0010750-6A patent/BR0010750A/pt not_active Application Discontinuation
-
2001
- 2001-06-06 US US09/876,388 patent/US6593295B2/en not_active Expired - Fee Related
- 2001-11-15 NO NO20015584A patent/NO20015584L/no not_active Application Discontinuation
-
2005
- 2005-05-24 JP JP2005151458A patent/JP4116016B2/ja not_active Expired - Fee Related
- 2005-12-14 JP JP2005361126A patent/JP2006151986A/ja not_active Withdrawn
-
2006
- 2006-02-08 US US11/350,703 patent/US7741286B2/en not_active Expired - Fee Related
-
2008
- 2008-07-18 JP JP2008187966A patent/JP2009007371A/ja active Pending
- 2008-07-18 JP JP2008187967A patent/JP2009001583A/ja active Pending
-
2010
- 2010-04-13 US US12/759,153 patent/US20110071082A1/en not_active Abandoned
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