WO2018210919A1 - Compositions de glp-1 et leurs utilisations - Google Patents

Compositions de glp-1 et leurs utilisations Download PDF

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WO2018210919A1
WO2018210919A1 PCT/EP2018/062698 EP2018062698W WO2018210919A1 WO 2018210919 A1 WO2018210919 A1 WO 2018210919A1 EP 2018062698 W EP2018062698 W EP 2018062698W WO 2018210919 A1 WO2018210919 A1 WO 2018210919A1
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composition
glp
peptide
thiol
composition according
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PCT/EP2018/062698
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English (en)
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Arne Staby
Møller EVA HORN
Ole Nordfang
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Novo Nordisk A/S
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    • 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
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids

Definitions

  • the present invention relates to compositions comprising the GLP-1 peptide liraglutide and uses thereof.
  • the GLP-1 peptide liraglutide has been marketed for use in, for example, treatment of type 2 diabetes.
  • compositions with even better stability are desired in order to improve e.g. storage stability and product economy.
  • the present invention relates to liquid pharmaceutical compositions comprising the GLP-1 peptide liraglutide and a thiol-containing excipient as well as their use in medicine.
  • composition of the invention comprises a thiol-containing excipient.
  • a "thiol-containing excipient” refers to an excipient comprising a free thiol (-SH) group.
  • the compositions of the invention have increased stability, a non-limiting examples hereof include improved storage stability.
  • the thiol-containing excipient may be selected from the group consisting of glutathione, cysteine, N-acetylcysteamine, or N-acetylcysteine.
  • the amino acids with a chiral carbon atom in glutathione may be in the L-form, the D-form, or a mixture hereof. In some embodiments all amino acids with a chiral carbon atom in glutathione are in the L-form.
  • Cysteine may be in the L-form, the D-form, or a mixture hereof.
  • cysteine is in the L-form.
  • N-acetylcysteine may be in the L-form, the D-form, or a mixture hereof.
  • the thiol-containing excipient used in the composition of the invention is in the form of a salt, such as a salt of the thiol-containing excipient selected from the group consisting of the zwitterion, acetate, chloride, and trifluoroacetic acid.
  • the composition comprises 0.1-50 mM, such as 1 -20 mM or 3-10 mM, of said thiol-containing excipient.
  • the composition of the invention is liquid and may be in the form of a solution or suspension.
  • the solution or suspension may comprise at least 90%(w/w) water, such as at least 95%(w/w) water.
  • composition of the invention comprises a GLP-1 peptide, such as liraglutide, and a thiol-containing excipient.
  • GLP-1 peptide such as liraglutide
  • composition a pharmaceutical composition.
  • composition of the invention may comprise one or more further ingredients
  • excipient broadly refers to any component other than the active therapeutic ingredient(s).
  • the excipient may be an inert substance, an inactive substance, and/or a not medicinally active substance.
  • the excipient may serve various purposes, non-limiting example include as a carrier, vehicle, diluent, tablet aid, and/or to improve administration, and/or absorption of the active substance.
  • the formulation of pharmaceutically active ingredients with various excipients is known in the art, see e.g. Remington: The Science and Practice of Pharmacy (e.g. 19th edition (1995), and any later editions).
  • Non-limiting examples of excipients are: Solvents, diluents, buffers, preservatives, tonicity regulating agents, chelating agents, and stabilisers.
  • pharmaceutical composition may have a pH in the range of 7.0-10.0, such as 7.4-9.0 or 7.8- 8.4.
  • pH of said pharmaceutical composition is in the range of 8.0-8.3, e.g. 8.15.
  • excipients are one or more selected from the group consisting of isotonic agent (e.g. propylene glycol), buffer (e.g. phosphate buffer, such as disodium phosphate dihydrate), and a preservative (e.g. phenol).
  • the methods of the present invention provides a stable pharmaceutical composition.
  • stable pharmaceutical composition when used herein refers to a composition, e.g. a solution or suspension, comprising GLP-1 peptide, and which composition following storage comprises at least 80%(w/v) of said GLP-1 peptide.
  • stability or “stable” as used interchangeably herein refers to stability following quiescent storage. Stability following quiescent storage may also be referred herein as “storage stability”.
  • stability is chemical stability of the GLP-1 peptide (e.g. determined by HPLC, such as Assay (I) herein), and optionally physical stability (e.g. determined by Thioflavin T assay, such as Assay (III) herein). Storage conditions for stability testing may be 2-8°C, such as 5°C or at least 2.5 years at 5°C.
  • storage conditions for stability testing may be 3 months, optionally at 25°C.
  • the conditions of storage for this stable pharmaceutical composition may be at 5°C for 1 or 2 years.
  • the conditions of this storage may be at 5°C for 24 hours or 1 week.
  • the conditions of this storage may room temperature for two months
  • chemical stability of the GLP-1 peptide requires at least 80%(w/v), such as at least 90%(w/v) or at least 95%(w/v), of said GLP-1 peptide remains in solution in said composition at the end of the storage period.
  • chemical stability of the GLP-1 peptide requires at least 95%(w/v), such as at least 97%(w/v) or at least 99%(w/v), of said GLP-1 peptide remains in solution in said composition at the end of the storage period.
  • the GLP-1 peptide is liraglutide.
  • Liraglutide is Arg34,Lys26- (N-epsilon-(gamma-L-glutamyl(N-alfa-hexadecanoyl)))-GLP-1 (7-37), also known as N 26 - (hexadecanoyl-Y-glutamyle)-[34-arginine]GLP-1 -(7-37)-peptide (WHO Drug Information Vol. 17, No. 2, 2003). Liraglutide may be prepared as described in Example 37 of WO98/08871.
  • the concentration of GLP-1 peptide may be determined using any suitable method.
  • LC-MS Liquid Chromatography Mass Spectroscopy
  • immunoassays such as RIA (Radio Immuno Assay), ELISA (Enzyme-Linked Immuno Sorbent Assay), and LOCI (Luminescence Oxygen Channeling Immunoasssay).
  • RIA Radio Immuno Assay
  • ELISA Enzyme-Linked Immuno Sorbent Assay
  • LOCI Luminescence Oxygen Channeling Immunoasssay
  • GLP-1 peptide refers to a compound comprising a peptide and which, when active, fully or partially activates the human GLP-1 receptor, e.g. with an EC50 on the human GLP-1 receptor below 5000 pM, such as below 1000 pM or below 500 pM.
  • the EC50 is determined in a medium containing membranes expressing the human GLP-1 receptor, and/or in an assay with whole cells expressing the human GLP-1 receptor.
  • the GLP-1 peptide comprises one or more substituents, such as one or more lipophilic moieties.
  • the GLP-1 peptide is a peptide wherein at least one amino acid residue of the peptide has been substituted with another amino acid residue and/or wherein at least one amino acid residue has been deleted from the peptide and/or wherein at least one amino acid residue has been added to the peptide and/or wherein at least one amino acid residue of the peptide has been modified, compared to e.g. GLP-1 (7-37).
  • Such addition or deletion of amino acid residues may take place at the N-terminal of the peptide and/or at the C-terminal of the peptide.
  • GLP-1 peptide designates GLP-1 (7-37) wherein the naturally occurring Lys in position 34 has been substituted with Arg.
  • the GLP-1 peptide comprises a maximum of twelve, such as a maximum of 10, 8 or 6, amino acids which have been altered, e.g., by substitution, deletion, insertion and/or modification, compared to e.g. GLP-1 (7-37).
  • the GLP-1 peptide comprises up to 10 substitutions, deletions, additions and/or insertions, such as up to 9 substitutions, deletions, additions and/or insertions, up to 8 substitutions, deletions, additions and/or insertions, up to 7 substitutions, deletions, additions and/or insertions, up to 6 substitutions, deletions, additions and/or insertions, up to 5 substitutions, deletions, additions and/or insertions, up to 4 substitutions, deletions, additions and/or insertions or up to 3 substitutions, deletions, additions and/or insertions, compared to e.g. GLP-1 (7-37). Unless otherwise stated the GLP-1 comprises only L-amino acids.
  • the GLP-1 peptide is human Glucagon-Like Peptide-1 (GLP- 1 (7-37)) comprising one or more amino acid substitutions, deletions, additions and/or insertions.
  • GLP-1 (7-37) has the sequence HAEGTFTSDV SSYLEGQAAKEFIAWLVKGRG (SEQ ID No: 1 ).
  • the GLP-1 peptide exhibits at least 60%, 65%, 70%, 80% or 90% sequence identity to GLP-1 (7-37) over the entire length of GLP-1 (7-37).
  • sequence identity As an example of a method for determination of sequence identity between the two peptides [Arg34]GLP- 1 (7-37) and GLP-1 (7-37) are aligned.
  • the sequence identity of [Arg34]GLP-1 (7-37) relative to GLP-1 (7-37) is given by the number of aligned identical residues minus the number of different residues divided by the total number of residues in GLP-1 (7-37). Accordingly, in said example the sequence identity is (31-1 )/31.
  • GLP-1 peptides are well-known in the art.
  • the amino acid sequence of the GLP-1 peptide (or fragments thereof), for example the unbranched amino acid sequence such as Arg34-GLP-1 (7-37) may for instance be produced by classical peptide synthesis, e.g., solid phase peptide synthesis using t-Boc or Fmoc chemistry or other well established techniques, see, e.g., Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999, Florencio Zaragoza Dorwald, Organic Synthesis on solid Phase", Wiley-VCH Verlag GmbH, 2000, and "Fmoc Solid Phase Peptide Synthesis", Edited by W.C.
  • host cells suitable for expression of these peptides are: Escherichia coli, Saccharomyces cerevisiae, as well as mammalian BHK or CHO cell lines.
  • the GLP-1 peptide may be in the form of a pharmaceutically acceptable salt, amide, or ester.
  • Salts are e.g. formed by a chemical reaction between a base and an acid, e.g.: 2NH 3 + H 2 S0 4 ⁇ (NH4)2S04.
  • the salt may be a basic salt, an acid salt, or it may be neither nor (i.e. a neutral salt).
  • Basic salts produce hydroxide ions and acid salts hydronium ions in water.
  • the salts of GLP-1 peptide may be formed with added cations or anions between anionic or cationic groups, respectively. These groups may be situated in the peptide moiety, and/or in the side chain of GLP-1 peptide.
  • Arg34-GLP-1 (7-37) may be regarded as the peptide moiety of GLP-1 peptide.
  • Gamma-L-glutamyl(N-alfa-hexadecanoyl) may be regarded as the side chain of GLP-1 peptide.
  • anionic groups of GLP-1 peptide include free carboxylic groups in the side chain as well as in the peptide moiety.
  • the peptide moiety of GLP-1 peptide includes a free carboxylic acid group at the C-terminus, and it may also include free carboxylic groups at internal acid amino acid residues, such as Asp and Glu.
  • Non-limiting examples of cationic groups in the peptide moiety include the free amino group at the N-terminus as well as any free amino group of internal basic amino acid residues, such as His, Arg, and Lys.
  • the ester of GLP-1 peptide may be formed by the reaction of a free carboxylic acid group with an alcohol or a phenol, which leads to replacement of at least one hydroxyl group by an alkoxy or aryloxy group. The ester formation may involve the free carboxylic group at the C-terminus of the peptide, and/or any free carboxylic group in the side chain.
  • the amide of GLP-1 peptide may be formed by the reaction of a free carboxylic acid group with an amine or a substituted amine, or by reaction of a free or substituted amino group with a carboxylic acid.
  • the amide formation may involve the free carboxylic group at the C-terminus of the peptide, any free carboxylic group in the side chain, the free amino group at the N-terminus of the peptide, and/or any free or substituted amino group of the peptide in the peptide and/or the side chain.
  • GLP-1 peptide is in the form of a pharmaceutically acceptable salt.
  • GLP-1 peptide is in the form of a pharmaceutically acceptable amide, preferably with an amide group at the C-terminus of the peptide. In some embodiment GLP-1 peptide is in the form a pharmaceutically acceptable ester. Medical use
  • the pharmaceutical composition of the invention may be for use in medicine.
  • the pharmaceutical composition of the invention may be for use in the treatment and/or prevention of type 2 diabetes or obesity.
  • the pharmaceutical composition of the invention is for use in prevention and/or treatment of diabetic
  • neuropathy including peripheral neuropathy
  • the pharmaceutical composition of the invention is for use in prevention and/or treatment of one or more cardiovascular diseases.
  • the pharmaceutical composition of the invention is for use in prevention and/or treatment of sleep apnoea.
  • the invention provides a method for prevention or treatment of diabetes or obesity comprising administering the composition as defined herein in an effective amount to a subject in need thereof.
  • the term “a” means “one or more”. In some embodiments, and unless otherwise indicated herein, terms presented in singular form also include the plural situation. In some embodiments, the term “about” means the value referred to ⁇ 10%.
  • a liquid pharmaceutical composition comprising a GLP-1 peptide, such as liraglutide, and a thiol-containing excipient.
  • composition according to embodiment 1 wherein said thiol-containing excipient is a peptide or an amino acid.
  • composition according to any of the preceding embodiments, wherein said thiol- containing excipient is glutathione, cysteine, N-acetylcysteamine, or N-acetylcysteine.
  • composition according to any of the preceding embodiments wherein said thiol- containing excipient is in the form of a salt before addition to said composition.
  • composition comprises 0.1-50 mM of said thiol-containing excipient.
  • composition comprises 1 -20 mM of said thiol-containing excipient.
  • composition comprises 3-10 mM of said thiol-containing excipient.
  • composition has a pH of 7-10.
  • composition has a pH of 7.5-9.0 or 7.8-8.4. 14. The composition according to any of the preceding embodiments, wherein said composition is for parenteral administration.
  • composition is for subcutaneous administration.
  • composition comprises one or more further pharmaceutically acceptable excipients.
  • composition comprises a preservative, such as phenol.
  • composition comprises 0.1 -100 mg/ml, such as 1-10 mg/ml, of said GLP-1 peptide.
  • composition is a stable pharmaceutical composition.
  • composition has stability of at least 2.5 years at 5°C.
  • a method for prevention or treatment of diabetes or obesity comprising administering the composition as defined in any one of the preceding claims in an effective amount to a subject in need thereof.
  • composition according to the preceding embodiment for use in the prevention or treatment of diabetes or obesity.
  • Liraglutide (Compound 1 ) may be prepared as described in Example 37 of
  • compositions comprising Compound 1 were prepared from Solution 1 and Solution 2:
  • Solution 1 preservative (phenol), isotonic agent (propylene glycol), buffer
  • SE-HPLC Waters Insulin HMWP column with a mobile phase of acetic acid and isopropanol using isocratic elution and detection at 276 nm.
  • HMWP is given in %, as the combined area of chromatographic peaks eluting earlier than the liraglutide peak (i.e. HMWP), relative to the total area of HMWP and liraglutide peaks.
  • the purpose of this assay is to assess the physical stability of a GLP-1 peptide in aqueous solutions.
  • Fibrils are structurally well-ordered, filamentous macromolecular structures formed by aggregation of soluble proteins and dominated by beta-sheet structure. Mature fibrils are insoluble and are resistant to degradation. For the sake of drug product quality and patient safety, it is desirable to minimize and control fibrillation events in pharmaceutical
  • compositions of therapeutic peptides and proteins can be assessed by visual inspection of a sample. Fibrillation can be assessed by the use of Thioflavin T (ThT), a small molecule indicator probe with a high specificity for fibrils. ThT has a distinct fluorescence signature when binding to fibrils compared to ThT in solution [Naiki et al. (1989) Anal. Biochem. 177, 244-249; LeVine (1999) Methods. Enzymol. 309, 274-284].
  • Thioflavin T Thioflavin T
  • the time course for fibril formation can be described by a sigmoidal curve with the following expression [Nielsen et al. (2001 ) Biochemistry 40, 6036-6046]: f f + m f t
  • F is the ThT fluorescence at the time t.
  • the constant to is the time needed to reach 50% of maximum fluorescence.
  • the two important parameters describing fibril formation are the lag-time calculated by to - 2 ⁇ and the apparent rate constant kapp 1/ ⁇ .
  • Formation of a partially folded intermediate of the peptide is suggested as a general initiating mechanism for fibrillation.
  • a small amount of these intermediates nucleates to form a template onto which further intermediates may assembly and the fibrillation proceeds.
  • the lag-time corresponds to the interval in which a critical amount of nuclei is generated and the apparent rate constant is the rate with which the fibril itself is formed.
  • Samples were prepared freshly before each assay. Each sample composition is described in the legends. ThT was added to the samples from a stock solution in H 2 0 to a final concentration of 20 ⁇ . Sample aliquots of 200 ⁇ of the composition comprising the GLP-1 peptide were placed in a 96 well microtiter plate (optical 0.4 ml. black Thermo Scientific Nunc) with a glass bead (2.8-3.2 mm, Whitehouse Scientific) placed in each well. Usually, eight replica of each sample were placed on the plate. The plate was sealed with sealing tape (Thermo Scientific Nunc).
  • ThT fluorescence emission were performed in a BMG FLUOStar Omega.
  • the plate was incubated at 40°C with double orbital shaking at 300 rpm with an amplitude of 2 mm. Fluorescence measurement was performed using excitation through a 450 nm filter and measurement of emission through a 480 nm filter. The plate was measured every 20 minutes for a desired period of time. Between each measurement, the plate was shaken and heated as described.
  • the threshold value was determined as the highest ThT fluorescence (in RFU) measured on the plate at time 1 h 13 min, plus 100 RFU. The threshold value was then used to calculate the lag time using the "time to threshold" method in the BMG FLUOstar software.
  • the tested compositions contained Compound 1 (6 mg/ml), phenol (5.5 mg/ml), propylene glycol (14 mg/ml), disodiumhydrogenphosphate dihydrate (1.42 mg/ml), and optionally the thiol-containing excipient (as specified in Table 1 ), at pH 8.15 in an aqueous solution; the composition without the thiol-containing excipient is referred to as Reference 1 .
  • Results of HMWP concentration, determined by Assay (I) herein, following storage of the tested compositions at 25°C or 37°C are shown in Table 2. The composition was prepared as described in the section General Methods of Preparation.
  • Example 2 Determined by Assay (I) herein.
  • the data obtained in Example 1 shows that addition of thiol-containing excipient cysteine, N- acetylcysteamine or glutathione reduces the development of HMWP in composition during storage at elevated temperatures.
  • Example 2 shows that addition of thiol-containing excipient cysteine, N- acetylcysteamine or glutathione reduces the development of HMWP in composition during storage at elevated temperatures.
  • the tested compositions contained Compound 1 (6 mg/ml), phenol (5.5 mg/ml), propylene glycol (14 mg/ml), disodiumhydrogenphosphate dihydrate (1.42 mg/ml) and optionally the thiol-containing excipient (as specified in Table 3), at pH 8.15 in an aqueous solution; the composition without the thiol-containing excipient is referred to as Reference 1 .
  • Results of HMWP concentration, determined by Assay (I) herein, following storage of the tested compositions at 25°C or 37°C are shown in Table 4. The composition was prepared as described in the section General Methods of Preparation.
  • composition 0 1 3 6 0 1 3 months months months months months months months months months months months months months months months
  • Example 2 shows that addition of thiol-containing excipient glutath reduces the development of HMWP in compositions during storage at elevated
  • the tested compositions contained Compound 1 (6 mg/ml), phenol (5.5 mg/ml), propylene glycol (14 mg/ml), disodiumhydrogenphosphate dihydrate (1.42 mg/ml), and optionally the thiol-containing excipient (as specified in Table 5), at pH 8.15 in an aqueous solution; the composition without the thiol-containing excipient is referred to as Reference 1 .
  • Results of HMWP concentration, determined by Assay (I) herein, following storage of the tested compositions at 25°C or 37°C are shown in Table 6. The composition was prepared as described in the section General Methods of Preparation.
  • Example 3 shows that addition of thiol-containing excipient glutathione reduces the development of HMWP in compositions during storage at elevated temperatures both at low (7.5) and high (9.0) composition pH.
  • the tested compositions contained Compound 1 (6 mg/ml), phenol (5.5 mg/ml), propylene glycol (14 mg/ml), disodiumhydrogenphosphate dihydrate (1.42 mg/ml), and optionally another excipient, at pH 8.15 in an aqueous solution; the composition without another excipient is referred to as "Reference 1 ", the composition comprising 10 mM citrate is referred to as "Citrate”, and the composition comprising 0.005% (w/v) butylated hydroxytoluene is referred to as "BHT”.
  • Results of HMWP concentration, determined by Assay (I) herein, following storage of the tested compositions at 25°C or 37°C are shown in Table 7. The composition was prepared as described in the section General Methods of Preparation.
  • Example 4 The data obtained in Example 4 shows that addition of other excipients does not reduce the development of HMWP in compositions.
  • compositions were assessed by Assay (II) (results shown in Table 8) and Assay (III) (results shown in Table 9). Table 8. Result of Assay (II) after 28 days of stress by incubation at elevated temperature (30°C) and handling (turning and syringe penetration of container once daily)
  • Example 5 shows that the physical stability of the compositions are comparable with the physical stability of the reference composition.

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Abstract

La présente invention concerne des compositions comprenant le peptide GLP-1 tel que le liraglutide et un excipient contenant un thiol.
PCT/EP2018/062698 2017-05-17 2018-05-16 Compositions de glp-1 et leurs utilisations WO2018210919A1 (fr)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021105393A1 (fr) * 2019-11-29 2021-06-03 Novo Nordisk A/S Procédés d'obtention de compositions de glp-1 stables

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US20080125361A1 (en) * 2004-11-12 2008-05-29 Novo Nordisk A/S Stable Formulations Of Peptides
WO2009030738A1 (fr) 2007-09-05 2009-03-12 Novo Nordisk A/S Dérivés de glucagon-like peptide-1 et leur utilisation pharmaceutique
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WO1998008871A1 (fr) 1996-08-30 1998-03-05 Novo Nordisk A/S Derives de glp-1
US20080125361A1 (en) * 2004-11-12 2008-05-29 Novo Nordisk A/S Stable Formulations Of Peptides
WO2009030738A1 (fr) 2007-09-05 2009-03-12 Novo Nordisk A/S Dérivés de glucagon-like peptide-1 et leur utilisation pharmaceutique
WO2016180353A1 (fr) * 2015-05-13 2016-11-17 杭州九源基因工程有限公司 Formulation pharmaceutique comprenant un analogue du glp-1 et son procédé de préparation

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WO2021105393A1 (fr) * 2019-11-29 2021-06-03 Novo Nordisk A/S Procédés d'obtention de compositions de glp-1 stables

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