WO1995005848A1 - Protracted glp-1 - Google Patents

Protracted glp-1 Download PDF

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Publication number
WO1995005848A1
WO1995005848A1 PCT/DK1994/000317 DK9400317W WO9505848A1 WO 1995005848 A1 WO1995005848 A1 WO 1995005848A1 DK 9400317 W DK9400317 W DK 9400317W WO 9505848 A1 WO9505848 A1 WO 9505848A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
glp
zinc
compound
previous
Prior art date
Application number
PCT/DK1994/000317
Other languages
French (fr)
Inventor
Klavs Holger JØRGENSEN
Per Balschmidt
Hanne Agerbaek
Original Assignee
Novo Nordisk A/S
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Priority claimed from DK95593A external-priority patent/DK95593D0/en
Application filed by Novo Nordisk A/S filed Critical Novo Nordisk A/S
Priority to AU75310/94A priority Critical patent/AU7531094A/en
Publication of WO1995005848A1 publication Critical patent/WO1995005848A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • 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
    • A61K47/02—Inorganic compounds
    • 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
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles

Definitions

  • the present invention relates to a composition containing GLP-1 compounds and having protracted action and to a pro- cess for preparation thereof.
  • Type I diabetes also designated insulin demanding diabetes mellitus (IDDM)
  • IDDM insulin demanding diabetes mellitus
  • NIDDM non- insulin dependent diabetes mellitus
  • Type I diabetic patients are currently treated with insulin while the majority of type II diabetic patients are treated either with agents that stimulate ⁇ -cell func ⁇ tion or with agents that enhance the tissue sensitivity of the patients towards insulin.
  • Glucagon-like peptide-1 is a peptide sequence found as a constituent of mammalian pro- glucagon.
  • GLP-1 GLP-1 fragments
  • GLP-1 compounds GLP-1 compounds.
  • GLP-1 compounds such as GLP-1(7- 37) and GLP-l(7-36) amide have a too fast action when administered to human subjects. Therefore, there is a need for compositions containing GLP-1 compounds and having a protracted action. The availability of such protracted com ⁇ positions will spare the diabetics the chore and discomfort of multiple daily injections.
  • GLP-l(7-37) is desribed at the bottom of Page 6 in US patent specification No. 5,120,712.
  • the possibilities mentioned are the use of poly- mers to complex or adsorb GLP-l(7-37), the selection of appropriate macromolecules (for example, protamine sulphate is mentioned among other), the incorporation of GLP-l(7-37) into particles of a polymeric material or the entrapment of GLP-l(7-37) in microcapsules.
  • One object of this invention is to provide compositions containing GLP-1 compounds and having a protracted action.
  • a further object of this invention is to provide com ⁇ positions containing GLP-1 compounds and having a sufficient high stability.
  • compositions containing a GLP-1 compound are obtained if said com ⁇ positions contain protamine and/or a metal salt selected from the group consisting of cobalto and zinc salts. It is highly surprising that compositions of this invention release the same or almost the same amount of the active compound per time unit during a very long period of time, for example, during a period of a half to one day. In many cases, such a linear profile of release is the pre ⁇ ferred one.
  • GLP-1 compounds This invention deals with compounds having GLP-1 like activity herein referred to as GLP-1 compounds.
  • GLP-1 com ⁇ pounds bind to the GLP-1 receptor (vide Proc.Nat. Acad.Sci.USA 89 (1992) , 8641) .
  • GLP-1 receptor vide Proc.Nat. Acad.Sci.USA 89 (1992) , 8641
  • specific GLP-1 compounds are polypeptides comprising the 7 - 33 amino acid sequence of GLP-1, viz. formula I:
  • GLP-1 compound also comprises derivatives of said polypeptides such as acid addition salts, carboxylate salts, lower alkyl esters, amides, lower alkyl amides and lower dialkyl amides.
  • compositions of this invention always contain a GLP-1 compound.
  • said composition contains either protamine or a metal salt selected from the group consisting of cobalto and zinc salts.
  • the compositions of this invention contain both protamine and a metal salt selected from the group consisting of cobalto and zinc salts.
  • the GLP-1 compound present in the compositions of this invention is GLP-l(7-37) then said composition contains a metal salt selected from the group consisting of cobalto and zinc salts.
  • the compositions of this invention are prepared in a manner known per se. Being informed about the constituents of the composition, the skilled art worker knows how to prepare such compositions.
  • the cobalto or zinc salts can be the chloride or another pharmaceutically acceptable salt.
  • the cobalto or zinc may be present as free ions and, optionally, a proportion of cobalto or zinc may be bound to other co - pounds such as the GLP-1 compound and protamine, if present.
  • Protamine is known to be a mixture of basic polypep ⁇ tides. Protamine can be obtained from fishes of the family salmon such as Oncorhynchus keta. However, also protamine from other fish can be used. Normally, protamine is marketed as protamine sulphate. However, also other salts can be used. Preferably, protamine of high purity is used.
  • compositions of this invention may contain a micelle forming compound in order to stabilize the com ⁇ position of this invention.
  • said com ⁇ position usually also contains a lieguid diluent, preferably water, and, optionally, a pH buffering agent, an osmotic pressure controlling agent, a preservative or other an- ciliary agents may be added.
  • compositions of this invention can be in any form known by the skilled art worker for such compositions such as a solution or a suspension.
  • a suspension of this inven ⁇ tion may contain crystalline and/or amorphous material.
  • the compositions of this invention may, for example, be used as an insulinotropic agent in the treatment of diabetes.
  • the dosage to be administered to human subjects is conveniently determined by a physician.
  • the com ⁇ positions of this invention are administered subcutaneously or intramuscularly.
  • the features disclosed in the present description, examples and claims may, both separately and in any combination thereof, be material for realizing this invention in diverse forms thereof. This invention is further illustrated by the following examples which are not to be construed as limiting, but merely as an illustration of some preferred features of this invention. Additional preferred embodiments of this inven ⁇ tion are stated in the claims.
  • Preparation B GLP-l(7-36) amide (1 mg/ml), zinc chloride (0.9 mmol/1) , glycerol (16 mg/ml) and phenol (3 mg/ml) ; pH value: 7.4.
  • Preparation C GLP-l(7-36) amide (1 mg/ml), protamine sul- phate (500 ⁇ g/ml) , glycerol (16 mg/ml) and phenol (3 mg/ml) ; pH value: 7.3.
  • Preparation D GLP-l(7-36) amide (1 mg/ml) , zinc chloride (0.9 mmol/1) , protamine sulphate (500 ⁇ g/ml), glycerol (16 mg/ml) and phenol (3 mg/ml); pH value: 7.3.
  • preparation A 100 ⁇ l of preparation A was injected at one side of the neck and 100 ⁇ l of preparation B at the other side in each of 6 pigs.
  • preparations C and D were injected in the same way in the same pigs. The absorption was followed by external monitoring of the radioactivity remaining at the site of injection. Residual radioactivity was expressed as percentage of the radioactivity measured at the time of injection. The results obtained appear from table I.

Abstract

GLP-1 compounds containing certain protamine and/or metal ions such as zinc have protracted action.

Description

Protracted GLP-1
FIELD OF THIS INVENTION
The present invention relates to a composition containing GLP-1 compounds and having protracted action and to a pro- cess for preparation thereof.
BACKGROUND OF THIS INVENTION
Diabetes is characterized by an impaired glucose metabolism manifesting itself among other things by an elevated blood glucose level in the diabetic patients. Underlying defects lead to a classification of diabetes into two major groups, i.e., type I and type II diabetes. Type I diabetes, also designated insulin demanding diabetes mellitus (IDDM) , arises when patients lack β-cells producing insulin in their pancreatic glands. Type II diabetes, also designated non- insulin dependent diabetes mellitus (NIDDM) , occurs in patients with an impaired β-cell function besides a range of other abnormalities.
Type I diabetic patients are currently treated with insulin while the majority of type II diabetic patients are treated either with agents that stimulate β-cell func¬ tion or with agents that enhance the tissue sensitivity of the patients towards insulin.
Glucagon-like peptide-1, also designated GLP-1, is a peptide sequence found as a constituent of mammalian pro- glucagon. In 1985, it was demonstrated that GLP-l(l-36) amide stimulates insulin release from isolated precultured rat pancreatic islets in the presence of glucose in a dose- dependent manner. This finding suggests that GLP-l(l-36) amide and related peptides might be useful in the treatment of type II diabetes. In recent years, particular interest has focused on GLP-1 fragments such as GLP-l(7-37) and GLP- 1(7-36) amide and analogues and functional derivatives thereof. Hereinafter, these compounds are designated GLP-1 compounds.
It has been found that GLP-1 compounds such as GLP-1(7- 37) and GLP-l(7-36) amide have a too fast action when administered to human subjects. Therefore, there is a need for compositions containing GLP-1 compounds and having a protracted action. The availability of such protracted com¬ positions will spare the diabetics the chore and discomfort of multiple daily injections.
Apparently, some theoretical possibilities of con¬ trolling the duration of action of GLP-l(7-37) is desribed at the bottom of Page 6 in US patent specification No. 5,120,712. The possibilities mentioned are the use of poly- mers to complex or adsorb GLP-l(7-37), the selection of appropriate macromolecules (for example, protamine sulphate is mentioned among other), the incorporation of GLP-l(7-37) into particles of a polymeric material or the entrapment of GLP-l(7-37) in microcapsules. One object of this invention is to provide compositions containing GLP-1 compounds and having a protracted action.
A further object of this invention is to provide com¬ positions containing GLP-1 compounds and having a sufficient high stability.
BRIEF DESCRIPTION OF THIS INVENTION
Surprisingly, it has been found that protracted compositions containing a GLP-1 compound are obtained if said com¬ positions contain protamine and/or a metal salt selected from the group consisting of cobalto and zinc salts. It is highly surprising that compositions of this invention release the same or almost the same amount of the active compound per time unit during a very long period of time, for example, during a period of a half to one day. In many cases, such a linear profile of release is the pre¬ ferred one.
DETAILED DESCRIPTION OF THIS INVENTION
This invention deals with compounds having GLP-1 like activity herein referred to as GLP-1 compounds. GLP-1 com¬ pounds bind to the GLP-1 receptor (vide Proc.Nat. Acad.Sci.USA 89 (1992) , 8641) . Examples of specific GLP-1 compounds are polypeptides comprising the 7 - 33 amino acid sequence of GLP-1, viz. formula I:
His-Ala-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser-Ser-Tyr-Leu-Glu- Gly-Gln-Ala-Ala-Lys-Glu-Phe-Ile-Ala-Trp-Leu-Val
(I) or a peptide sequence derived from formula I by exchanging a few of the amino acid residues with other amino acid resi- dues which can be coded for by the nucleotide sequences. Preferably, not more than one, two or three of the amino acid residues have been exchanged. The term GLP-1 compound also comprises derivatives of said polypeptides such as acid addition salts, carboxylate salts, lower alkyl esters, amides, lower alkyl amides and lower dialkyl amides.
As appears from the above statement, the compositions of this invention always contain a GLP-1 compound. In addition to this, said composition contains either protamine or a metal salt selected from the group consisting of cobalto and zinc salts. Alternatively, the compositions of this invention contain both protamine and a metal salt selected from the group consisting of cobalto and zinc salts. If the GLP-1 compound present in the compositions of this invention is GLP-l(7-37) then said composition contains a metal salt selected from the group consisting of cobalto and zinc salts. The compositions of this invention are prepared in a manner known per se. Being informed about the constituents of the composition, the skilled art worker knows how to prepare such compositions. For example, the cobalto or zinc salts can be the chloride or another pharmaceutically acceptable salt. Obviously, in the composition of this invention, the cobalto or zinc may be present as free ions and, optionally, a proportion of cobalto or zinc may be bound to other co - pounds such as the GLP-1 compound and protamine, if present. Protamine is known to be a mixture of basic polypep¬ tides. Protamine can be obtained from fishes of the family salmon such as Oncorhynchus keta. However, also protamine from other fish can be used. Normally, protamine is marketed as protamine sulphate. However, also other salts can be used. Preferably, protamine of high purity is used.
The compositions of this invention may contain a micelle forming compound in order to stabilize the com¬ position of this invention. In addition to the specific ingredients which are to be present in the compositions of this invention, said com¬ position usually also contains a lieguid diluent, preferably water, and, optionally, a pH buffering agent, an osmotic pressure controlling agent, a preservative or other an- ciliary agents may be added.
The compositions of this invention can be in any form known by the skilled art worker for such compositions such as a solution or a suspension. A suspension of this inven¬ tion may contain crystalline and/or amorphous material. The compositions of this invention may, for example, be used as an insulinotropic agent in the treatment of diabetes. The dosage to be administered to human subjects is conveniently determined by a physician. Normally, the com¬ positions of this invention are administered subcutaneously or intramuscularly. The features disclosed in the present description, examples and claims may, both separately and in any combination thereof, be material for realizing this invention in diverse forms thereof. This invention is further illustrated by the following examples which are not to be construed as limiting, but merely as an illustration of some preferred features of this invention. Additional preferred embodiments of this inven¬ tion are stated in the claims.
Example 1
Trace concentrations of 125I-GLP-l(7-36) amide were added to GLP-l(7-36) amide in the following four preparations designated A, B, C and D:
Preparation A: GLP-l(7-36) amide (1 mg/ml), glycerol (16 mg/ml) and phenol (3 mg/ml); pH value: 7.4.
Preparation B: GLP-l(7-36) amide (1 mg/ml), zinc chloride (0.9 mmol/1) , glycerol (16 mg/ml) and phenol (3 mg/ml) ; pH value: 7.4.
Preparation C: GLP-l(7-36) amide (1 mg/ml), protamine sul- phate (500 μg/ml) , glycerol (16 mg/ml) and phenol (3 mg/ml) ; pH value: 7.3.
Preparation D: GLP-l(7-36) amide (1 mg/ml) , zinc chloride (0.9 mmol/1) , protamine sulphate (500 μg/ml), glycerol (16 mg/ml) and phenol (3 mg/ml); pH value: 7.3.
100 μl of preparation A was injected at one side of the neck and 100 μl of preparation B at the other side in each of 6 pigs. One week later, preparations C and D were injected in the same way in the same pigs. The absorption was followed by external monitoring of the radioactivity remaining at the site of injection. Residual radioactivity was expressed as percentage of the radioactivity measured at the time of injection. The results obtained appear from table I.
Table I
Time Percentage Residual Radioactivity
Hours after injection A B C D
0 100 100 100 100
1 61 96 - - 2 31 94 77 93
4 11 80 61 78
6 6 66 51 67
1\ - - 45 58
23 1 21 24 - 13 15
It appears from this table that the presence of zinc and, optionally, protamine surprisingly results in a prolonged absorption of the GLP-1 compound.

Claims

1. GLP-1 compositions containing, in addition to a GLP-1 compound, protamine and/or a metal salt selected from the group consisting of cobalto and zinc salt, with the proviso that if the GLP-1 compound is GLP-l(7-37) then said com¬ position contains a metal salt selected from the group con¬ sisting of cobalto and zinc salts.
2. A composition, according to Claim 1, characterized in that it does not contain protamine.
3. A composition, according to Claim 1, characterized in that it does not contain a cobalto or zinc salt.
4. A composition, according to Claim 1, characterized in that the content of the GLP-1 compound is in the range from about 0.1 through about 50 mg/ml.
5. A composition, according to Claim 1, 2 or 4, charac¬ terized in that it contains a cobalto salt.
6. A composition, according to Claim 1, 2 or 4, charac¬ terized in that it contains a zinc salt.
7. A composition, according to the previous claim, charac- terized in that the content of zinc is in the range from about 0.1 through about 10 atoms of zinc per molecule of GLP-1 compound.
8. A composition, according to the previous claim, charac¬ terized in that the content of zinc is in the range from about 0.3 through about 5 atoms of zinc per molecule of GLP- 1 compound.
9. A composition, according to the previous claim, charac¬ terized in that the content of zinc is in the range from about 0.3 through about 1 atom of zinc per molecule og GLP-1 compound.
5 10. A composition, according to Claim 9, characterized in that the content of zinc is in the range from about 2 through about 4 atoms of zinc per molecule of GLP-1 com¬ pound.
11. A composition, according to anyone of the previous 10 claims, characterized in that the GLP-1 compound is GLP-1(7-
37) .
12. A composition, according to anyone of the Claims 1 through 11, characterized in that the GLP-1 compound is GLP- 1(7-36) amide.
15 13. A composition, according to anyone of the Claims 1 and 3 through 12, characterized in that the composition contains protamine and a metal salt selected from the group con¬ sisting of cobalto and zinc salts.
14. A composition, according to the Claims 1 and 3 through 20 13, characterized in that the content of protamine is so that the molar ratio between protamine and the GLP-1 com¬ pound is in the range from about 1:1 through about 1:10.
15. A composition, according to anyone of the previous claims, characterized in that the composition contains a
25 micelle forming compound.
16. A composition, according to the previous claim, charac¬ terized in that the micelle forming compound is a phospholi- pid, preferably lechitin.
17. A composition, according to the previous claim, charac¬ terized in that the micelle forming compound is present in a concentration sufficiently high to form micelles.
18. A composition, according to any one of the previous 5 claims, characterized in the pH value thereof is in the range from about 3 through about 8.5.
19. A composition, according to the previous claim, charac¬ terized in that the pH value thereof is in the range from about 6 through about 8.
10 20. A composition, according to anyone of the preceding claims, for use as a pharmaceutical, preferably for sub¬ cutaneous or intramuscular administration.
21. The use of a composition described in anyone of the preceding claims as a medicament.
15 22. A method of treating diabetes which method comprises administering a composition described in anyone of the Claims 1 through 20 in an effective amount to a patient in need of such a treatment.
23. A process for preparing GLP-1 compositions described in 20 any one of the Claims 1 through 20, characterized in that protamine and/or a salt selected from the group consisting of a cobalto and zinc salt is mixed with the GLP-1 compound, optionally in an aςpieous medium.
PCT/DK1994/000317 1993-08-24 1994-08-23 Protracted glp-1 WO1995005848A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU75310/94A AU7531094A (en) 1993-08-24 1994-08-23 Protracted glp-1

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DK95593A DK95593D0 (en) 1993-08-24 1993-08-24 PREPARATION
DK0955/93 1993-08-24
US12207793A 1993-09-15 1993-09-15
US08/122,077 1993-09-15

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Cited By (38)

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EP0733644A1 (en) * 1995-03-21 1996-09-25 Eli Lilly And Company Glucagon-like insulinotropic complexes, compositions and methods
US5958909A (en) * 1986-05-05 1999-09-28 The General Hospital Corporation Insulinotropic hormones and uses thereof
US5981488A (en) * 1997-03-31 1999-11-09 Eli Lillly And Company Glucagon-like peptide-1 analogs
US6191102B1 (en) 1996-11-05 2001-02-20 Eli Lilly And Company Use of GLP-1 analogs and derivatives administered peripherally in regulation of obesity
US6277819B1 (en) 1996-08-30 2001-08-21 Eli Lilly And Company Use of GLP-1 or analogs in treatment of myocardial infarction
US6284727B1 (en) 1993-04-07 2001-09-04 Scios, Inc. Prolonged delivery of peptides
US6380357B2 (en) 1997-12-16 2002-04-30 Eli Lilly And Company Glucagon-like peptide-1 crystals
WO2002048183A2 (en) * 2000-12-13 2002-06-20 Eli Lilly And Company Compositions of peptide crystals
US6849708B1 (en) 1986-05-05 2005-02-01 The General Hospital Corporation Insulinotropic hormone and uses thereof
WO2005049061A2 (en) * 2003-11-20 2005-06-02 Novo Nordisk A/S Propylene glycol-containing peptide formulations which are optimal for production and for use in injection devices
US7138486B2 (en) 1986-05-05 2006-11-21 The General Hospital Corporation Insulinotropic hormone derivatives and uses thereof
EP2062593A2 (en) 2000-12-01 2009-05-27 Takeda Pharmaceutical Company Limited Method for producing preparation containing bioactive peptide
EP2111871A1 (en) * 2008-04-26 2009-10-28 Sandoz AG Stabilised fluid formula
US7847079B2 (en) 2001-12-21 2010-12-07 Human Genome Sciences, Inc. Albumin fusion proteins
US7939494B2 (en) 2002-02-20 2011-05-10 Emisphere Technologies, Inc. Method for administering GLP-1 molecules
WO2012098187A1 (en) * 2011-01-19 2012-07-26 Novo Nordisk A/S Glp-1 compositions
EP2665470A1 (en) * 2011-01-19 2013-11-27 Novo Nordisk A/S Glp-1 particles and compositions
WO2014010586A1 (en) 2012-07-10 2014-01-16 武田薬品工業株式会社 Pharmaceutical preparation for injection
US8748376B2 (en) 2004-11-12 2014-06-10 Novo Nordisk A/S Stable formulations of peptides
US8785381B2 (en) 2003-12-19 2014-07-22 Emisphere Technologies, Inc. Oral GLP-1 formulations
US8846618B2 (en) 2001-06-28 2014-09-30 Novo Nordisk A/S Stable formulation of modified GLP-1
US8901073B2 (en) 2011-01-27 2014-12-02 Imperial Innovations Limited Compounds and their effects on feeding behaviour
USRE45313E1 (en) 1999-07-12 2014-12-30 Zealand Pharma A/S Exendin variant peptides
US9018160B2 (en) 2010-01-27 2015-04-28 Imperial Innovations Limited Peptide tyrosine tyrosine analogues
US9089538B2 (en) 2010-04-27 2015-07-28 Zealand Pharma A/S Peptide conjugates of GLP-1 receptor agonists and gastrin and their use
US9259477B2 (en) 2011-11-03 2016-02-16 Zealand Pharma A/S GLP-1 receptor agonist peptide gastrin conjugates
US9944687B2 (en) 2011-07-04 2018-04-17 Imperial Innovations Limited Compounds and their effects on feeding behaviour
US9975939B2 (en) 2012-09-17 2018-05-22 Zealand Pharma A/S Glucagon analogues
US10093713B2 (en) 2013-11-06 2018-10-09 Zealand Pharma A/S GIP-GLP-1 dual agonist compounds and methods
US10131702B2 (en) 2013-11-06 2018-11-20 Zealand Pharma A/S Glucagon-GLP-1-GIP triple agonist compounds
US10253078B2 (en) 2014-10-29 2019-04-09 Zealand Pharma A/S GIP agonist compounds and methods
US10336802B2 (en) 2015-04-16 2019-07-02 Zealand Pharma A/S Acylated glucagon analogue
US10457714B2 (en) 2013-10-17 2019-10-29 Zealand Pharma A/S Acylated glucagon analogues
US10905745B2 (en) 2016-12-09 2021-02-02 Zealand Pharma A/S Acylated GLP-1/GLP-2 dual agonists
US11034747B2 (en) 2013-10-17 2021-06-15 Zealand Pharma A/S Glucagon analogues and methods of use
US11318191B2 (en) 2020-02-18 2022-05-03 Novo Nordisk A/S GLP-1 compositions and uses thereof
US11752198B2 (en) 2017-08-24 2023-09-12 Novo Nordisk A/S GLP-1 compositions and uses thereof
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Cited By (82)

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US6162907A (en) * 1986-05-05 2000-12-19 The General Hospital Corporation DNA encoding insulinotropic hormone
US7138486B2 (en) 1986-05-05 2006-11-21 The General Hospital Corporation Insulinotropic hormone derivatives and uses thereof
US6849708B1 (en) 1986-05-05 2005-02-01 The General Hospital Corporation Insulinotropic hormone and uses thereof
US5958909A (en) * 1986-05-05 1999-09-28 The General Hospital Corporation Insulinotropic hormones and uses thereof
US6828303B2 (en) 1993-04-07 2004-12-07 Scios, Inc. Prolonged delivery of peptides
US6284727B1 (en) 1993-04-07 2001-09-04 Scios, Inc. Prolonged delivery of peptides
US7232879B2 (en) 1993-12-09 2007-06-19 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5977071A (en) * 1993-12-09 1999-11-02 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US5705483A (en) * 1993-12-09 1998-01-06 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
US6133235A (en) * 1993-12-09 2000-10-17 Eli Lilly And Company Glucagon-like insulinotropic peptides compositions and methods
US6703365B2 (en) 1993-12-09 2004-03-09 Eli Lilly And Company Glucagon-like insulinotropic peptides, compositions and methods
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