ECSP19046865A - Conjugados que comprenden un agonista dual de glp-1/glucagón, un conector y ácido hialurónico - Google Patents
Conjugados que comprenden un agonista dual de glp-1/glucagón, un conector y ácido hialurónicoInfo
- Publication number
- ECSP19046865A ECSP19046865A ECSENADI201946865A ECDI201946865A ECSP19046865A EC SP19046865 A ECSP19046865 A EC SP19046865A EC SENADI201946865 A ECSENADI201946865 A EC SENADI201946865A EC DI201946865 A ECDI201946865 A EC DI201946865A EC SP19046865 A ECSP19046865 A EC SP19046865A
- Authority
- EC
- Ecuador
- Prior art keywords
- glp
- receptor agonist
- glucagon receptor
- hyaluronic acid
- connector
- Prior art date
Links
- 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 title abstract 5
- 102100040918 Pro-glucagon Human genes 0.000 title abstract 5
- KIUKXJAPPMFGSW-DNGZLQJQSA-N (2S,3S,4S,5R,6R)-6-[(2S,3R,4R,5S,6R)-3-Acetamido-2-[(2S,3S,4R,5R,6R)-6-[(2R,3R,4R,5S,6R)-3-acetamido-2,5-dihydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-2-carboxy-4,5-dihydroxyoxan-3-yl]oxy-5-hydroxy-6-(hydroxymethyl)oxan-4-yl]oxy-3,4,5-trihydroxyoxane-2-carboxylic acid Chemical compound CC(=O)N[C@H]1[C@H](O)O[C@H](CO)[C@@H](O)[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@H](O[C@H]2[C@@H]([C@@H](O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@H](O3)C(O)=O)O)[C@H](O)[C@@H](CO)O2)NC(C)=O)[C@@H](C(O)=O)O1 KIUKXJAPPMFGSW-DNGZLQJQSA-N 0.000 title abstract 2
- 229920002674 hyaluronan Polymers 0.000 title abstract 2
- 229960003160 hyaluronic acid Drugs 0.000 title abstract 2
- 101710198884 GATA-type zinc finger protein 1 Proteins 0.000 title 1
- 102000051325 Glucagon Human genes 0.000 title 1
- 108060003199 Glucagon Proteins 0.000 title 1
- 229940125542 dual agonist Drugs 0.000 title 1
- MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)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(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 title 1
- 229960004666 glucagon Drugs 0.000 title 1
- 229940123232 Glucagon receptor agonist Drugs 0.000 abstract 4
- 229940089838 Glucagon-like peptide 1 receptor agonist Drugs 0.000 abstract 4
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract 2
- 125000005647 linker group Chemical group 0.000 abstract 2
- 125000003277 amino group Chemical group 0.000 abstract 1
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 201000010099 disease Diseases 0.000 abstract 1
- 208000035475 disorder Diseases 0.000 abstract 1
- 239000003814 drug Substances 0.000 abstract 1
- 239000000017 hydrogel Substances 0.000 abstract 1
- 239000008194 pharmaceutical composition Substances 0.000 abstract 1
- 150000003839 salts Chemical class 0.000 abstract 1
Classifications
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- A—HUMAN NECESSITIES
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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
- A61K47/50—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
- A61K47/54—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 an organic compound
- A61K47/549—Sugars, nucleosides, nucleotides or nucleic acids
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- A—HUMAN NECESSITIES
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/715—Polysaccharides, i.e. having more than five saccharide radicals attached to each other by glycosidic linkages; Derivatives thereof, e.g. ethers, esters
- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
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- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- A61K38/1709—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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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
- A61K38/26—Glucagons
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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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
- A61K47/56—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
- A61K47/61—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 an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—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
- A61K47/69—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6903—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 conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit the form being semi-solid, e.g. an ointment, a gel, a hydrogel or a solidifying gel
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- 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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- A61K9/10—Dispersions; Emulsions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A61P3/06—Antihyperlipidemics
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- 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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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/1072—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups
- C07K1/1077—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides by covalent attachment of residues or functional groups by covalent attachment of residues other than amino acids or peptide residues, e.g. sugars, polyols, fatty acids
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
- C07K1/107—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides
- C07K1/113—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length by chemical modification of precursor peptides without change of the primary structure
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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
- C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
- C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
-
- 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
- C07K14/605—Glucagons
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Diabetes (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Gastroenterology & Hepatology (AREA)
- Zoology (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Endocrinology (AREA)
- Molecular Biology (AREA)
- Hematology (AREA)
- Obesity (AREA)
- Immunology (AREA)
- Biochemistry (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Dermatology (AREA)
- Child & Adolescent Psychology (AREA)
- Emergency Medicine (AREA)
- Marine Sciences & Fisheries (AREA)
- Toxicology (AREA)
- Inorganic Chemistry (AREA)
- Analytical Chemistry (AREA)
- Dispersion Chemistry (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
La presente invención se refiere a un conjugado, o una de sus sales farmacéuticamente aceptables, que comprende un agonista del receptor de GLP-1/glucagón, un conector y un hidrogel de ácido hialurónico que porta grupos -L1-L2-L-Y-R20 , en donde Y representa un resto agonista del receptor de GLP-1/glucagón; y -L es un resto conector de fórmula (Ia), en donde la línea discontinua indica la unión a uno de los grupos amino del agonista del receptor de GLP-1/glucagón a través de la formación de un enlace amida. La invención se refiere además a composiciones farmacéuticas que comprenden dicho conjugado, así como a su uso como medicamente para tratar o prevenir enfermedades o trastornos que pueden ser tratados mediante un agonista del receptor de GLP-1/glucagón. (ver documento de imágenes).
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| EP16306613 | 2016-12-02 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ECSP19046865A true ECSP19046865A (es) | 2019-07-31 |
Family
ID=57542941
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ECSENADI201946865A ECSP19046865A (es) | 2016-12-02 | 2019-07-01 | Conjugados que comprenden un agonista dual de glp-1/glucagón, un conector y ácido hialurónico |
Country Status (23)
| Country | Link |
|---|---|
| US (2) | US10792367B2 (es) |
| EP (1) | EP3548090A1 (es) |
| JP (1) | JP2020503278A (es) |
| KR (1) | KR20190091482A (es) |
| CN (1) | CN110022902A (es) |
| AR (1) | AR110299A1 (es) |
| AU (1) | AU2017369723A1 (es) |
| BR (1) | BR112019011139A8 (es) |
| CA (1) | CA3045483A1 (es) |
| CL (1) | CL2019001466A1 (es) |
| CO (1) | CO2019006912A2 (es) |
| CR (1) | CR20190312A (es) |
| DO (1) | DOP2019000038A (es) |
| EA (1) | EA201991316A1 (es) |
| EC (1) | ECSP19046865A (es) |
| IL (1) | IL266973A (es) |
| MA (1) | MA46996A (es) |
| MX (1) | MX2019006432A (es) |
| PE (1) | PE20191472A1 (es) |
| PH (1) | PH12019501215A1 (es) |
| TW (1) | TW201832783A (es) |
| UY (1) | UY37505A (es) |
| WO (1) | WO2018100174A1 (es) |
Families Citing this family (24)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| AR105319A1 (es) | 2015-06-05 | 2017-09-27 | Sanofi Sa | Profármacos que comprenden un conjugado agonista dual de glp-1 / glucagón conector ácido hialurónico |
| IL317744A (en) | 2016-03-01 | 2025-02-01 | Ascendis Pharma Bone Diseases As | PTH drug agonists |
| RS64440B1 (sr) | 2016-09-29 | 2023-09-29 | Ascendis Pharma Bone Diseases As | Režim doziranja za pth jedinjenje sa kontrolisanim oslobađanjem |
| PL3518961T3 (pl) | 2016-09-29 | 2023-08-14 | Ascendis Pharma Bone Diseases A/S | Związki pth o niskim stosunku wartości maksymalnej do minimalnej |
| FI3518982T3 (fi) | 2016-09-29 | 2025-02-11 | Ascendis Pharma Bone Diseases As | Säädellysti vapautuvia PTH-yhdisteitä |
| TW201832783A (zh) | 2016-12-02 | 2018-09-16 | 法商賽諾菲公司 | 包含glp-1/胰高血糖素雙重激動劑、連接子和透明質酸的接合物 |
| IL269506B2 (en) | 2017-03-22 | 2024-04-01 | Genentech Inc | Hydrogel cross-linked hyaluronic acid prodrug compositions and methods |
| CA3072118A1 (en) | 2017-08-09 | 2019-02-14 | Sanofi | Glp-1/glucagon receptor agonists in the treatment of fatty liver disease and steatohepatitis |
| TW202015735A (zh) | 2018-05-30 | 2020-05-01 | 法商賽諾菲公司 | 包含glp-1/升糖素/gip三重受體促效劑、連接子及透明質酸之接合物 |
| FR3084586B1 (fr) * | 2018-08-03 | 2020-11-06 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un compose amphiphile porteur de radicaux hydrophobes |
| US12403182B2 (en) | 2019-02-11 | 2025-09-02 | Ascendis Pharma Bone Diseases A/S | Liquid pharmaceutical formulations of PTH conjugates |
| ES3029282T3 (en) * | 2019-05-07 | 2025-06-23 | Genzyme Corp | Methods for quantifying drug concentration in a prodrug composition |
| ES2962935T3 (es) * | 2019-06-03 | 2024-03-21 | Symborg S L | Nueva cepa de Methylobacterium sp., composiciones que la comprenden, y su uso como bioestimulante y bacteria fijadora del nitrógeno endófito |
| KR20220117256A (ko) * | 2019-12-02 | 2022-08-23 | 엔리티사 (상하이) 파마슈티컬 컴퍼니 리미티드 | 펩타이드 및 염증 치료에서의 이의 용도 |
| KR20230005289A (ko) | 2020-04-24 | 2023-01-09 | 베링거 인겔하임 인터내셔날 게엠베하 | 지방 간 질환 및 지방간염의 치료에서 장시간-작용성 glp-1/글루카곤 수용체 작용제로서 글루카곤 유사체 |
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| US11141489B2 (en) | 2021-10-12 |
| MX2019006432A (es) | 2019-08-21 |
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| DOP2019000038A (es) | 2019-05-31 |
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| CR20190312A (es) | 2019-09-11 |
| IL266973A (en) | 2019-07-31 |
| CA3045483A1 (en) | 2018-06-07 |
| MA46996A (fr) | 2019-10-09 |
| PH12019501215A1 (en) | 2019-08-19 |
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| CL2019001466A1 (es) | 2019-10-11 |
| US10792367B2 (en) | 2020-10-06 |
| AU2017369723A1 (en) | 2019-07-18 |
| US20200155688A1 (en) | 2020-05-21 |
| JP2020503278A (ja) | 2020-01-30 |
| EP3548090A1 (en) | 2019-10-09 |
| CN110022902A (zh) | 2019-07-16 |
| US20180154005A1 (en) | 2018-06-07 |
| WO2018100174A1 (en) | 2018-06-07 |
| UY37505A (es) | 2018-06-29 |
| PE20191472A1 (es) | 2019-10-16 |
| BR112019011139A8 (pt) | 2020-03-24 |
| BR112019011139A2 (pt) | 2019-10-01 |
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