US20040048783A1 - Acidic insulin preparations having improved stability - Google Patents

Acidic insulin preparations having improved stability Download PDF

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Publication number
US20040048783A1
US20040048783A1 US10/461,740 US46174003A US2004048783A1 US 20040048783 A1 US20040048783 A1 US 20040048783A1 US 46174003 A US46174003 A US 46174003A US 2004048783 A1 US2004048783 A1 US 2004048783A1
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Prior art keywords
insulin
pharmaceutical formulation
formulation according
human insulin
concentration
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Abandoned
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US10/461,740
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English (en)
Inventor
Anette Brunner-Schwarz
Norbert Lill
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Sanofi Aventis Deutschland GmbH
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Aventis Pharma Deutschland GmbH
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Application filed by Aventis Pharma Deutschland GmbH filed Critical Aventis Pharma Deutschland GmbH
Priority to US10/461,740 priority Critical patent/US20040048783A1/en
Assigned to AVENTIS PHARMA DEUTSCHLAND GMBH reassignment AVENTIS PHARMA DEUTSCHLAND GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRUNNER-SCHWARZ, ANETTE, LILL, NORBERT
Assigned to AVENTIS PHARMA DEUTSCHLAND GMBH reassignment AVENTIS PHARMA DEUTSCHLAND GMBH ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRUNNER-SCHWARZ, ANETTE, LILL, NORBERT
Publication of US20040048783A1 publication Critical patent/US20040048783A1/en
Priority to US11/089,777 priority patent/US7476652B2/en
Priority to US12/328,208 priority patent/US7713930B2/en
Priority to US12/773,356 priority patent/US20100216692A1/en
Abandoned legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7028—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages
    • A61K31/7032—Compounds having saccharide radicals attached to non-saccharide compounds by glycosidic linkages attached to a polyol, i.e. compounds having two or more free or esterified hydroxy groups, including the hydroxy group involved in the glycosidic linkage, e.g. monoglucosyldiacylglycerides, lactobionic acid, gangliosides
    • 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
    • A61K38/28—Insulins
    • 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
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A61P5/50—Drugs for disorders of the endocrine system of the pancreatic hormones for increasing or potentiating the activity of insulin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis

Definitions

  • the invention relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin metabolite, an insulin analog, an insulin derivative or combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffers or further excipients or combinations thereof, the pharmaceutical formulation having a pH in the acidic range.
  • These formulations can be employed for the treatment of diabetes, and are particularly suitable for preparations in which a high stability to thermal and/or physicomechanical stress is necessary.
  • the invention likewise relates to parenteral preparations which contain such formulations and can be used in diabetes and to methods for producing the preparations and for improving the stability of insulin preparations.
  • Diabetic late damage is microvascular and macrovascular damage which is manifested, under certain circumstances, as retinopathy, nephropathy or neuropathy and leads to loss of sight, kidney failure and the loss of extremities and is moreover accompanied by an increased risk of cardiovascular diseases.
  • an improved therapy of diabetes should be aimed at keeping the blood glucose as closely as possible in the physiological range.
  • intensified insulin therapy this should be achieved by repeated daily injections of rapid- and slow-acting insulin preparations.
  • Rapid-acting formulations are given at meals in order to level out the postprandial increase in the blood glucose.
  • Slow-acting basal insulins should ensure the basic supply with insulin, in particular during the night, without leading to hypoglycemia.
  • Insulin is a polypeptide of 51 amino acids, which are divided into 2 amino acid chains: the A chain having 21 amino acids and the B chain having 30 amino acids. The chains are connected to one another by means of 2 disulfide bridges. Insulin preparations have been employed for diabetes therapy for many years. Not only are naturally occurring insulins used, but recently also insulin derivatives and analogs.
  • Insulin analogs are analogs of naturally occurring insulins, namely human insulin or animal insulins, which differ by substitution of at least one naturally occurring amino acid residue with other amino acids and/or addition/removal of at least one amino acid residue from the corresponding, otherwise identical, naturally occurring insulin.
  • the amino acids can in this case also be those which do not occur naturally.
  • Insulin derivatives are derivatives of naturally occurring insulin or an insulin analog which are obtained by chemical modification.
  • This chemical modification can consist, for example, of the addition of one or more specific chemical groups to one or more amino acids.
  • insulin derivatives and insulin analogs have a somewhat modified action compared with human insulin.
  • Insulin analogs having an accelerated onset of action are described in EP 0 214 826, EP 0 375 437 and EP 0 678 522.
  • EP 0 124 826 relates, inter alia, to substitutions of B27 and B28.
  • EP 0 678 522 describes insulin analogs which in position B29 have various amino acids, preferably proline, but not glutamic acid.
  • EP 0 375 437 includes insulin analogs with lysine or arginine in B28, which can optionally be additionally modified in B3 and/or A21.
  • WO 92/00321 insulin analogs are described in which at least one amino acid of the positions B1-B6 is replaced by lysine or arginine. According to WO 92/00321, insulins of this type have a prolonged action. The insulin analogs described in EP-A 0 368 187 also have a delayed action.
  • the insulin preparations of naturally occurring insulins on the market for insulin substitution differ in the origin of the insulin (e.g. bovine, porcine, human insulin), and also the composition, whereby the profile of action (onset of action and duration of action) can be influenced.
  • the profile of action onset of action and duration of action
  • Recombinant DNA technology today makes possible the preparation of such modified insulins. These include insulin glargine (Gly(A21)-Arg(B31)-Arg(B32)-human insulin) with a prolonged duration of action.
  • Insulin glargine is injected as an acidic, clear solution and precipitates on account of its solution properties in the physiological pH range of the subcutaneous tissue as a stable hexamer associate. Insulin glargine is injected once daily and is distinguished compared with other long-acting insulins by its flat serum profile and the reduction of the danger of nightly hypoglycemia associated therewith (Schubert-Zsilavecz et al., 2:125-130(2001)).
  • the specific preparation of insulin glargine which leads to the prolonged duration of action, is characterized, in contrast to previously described preparations, by a clear solution having an acidic pH. Especially at acidic pH, insulins, however, show a decreased stability and an increased proneness to aggregation on thermal and physicomechanical stress, which can make itself felt in the form of turbidity and precipitation (particle formation) (Brange et al., J. Ph.Sci 86:517-525(1997)).
  • the proneness to aggregation can additionally be promoted by hydrophobic surfaces which are in contact with the solution (Sluzky et al., Proc.Natl.Acad.Sci. 88:9377-9381 (1991).
  • Surfaces which can be considered as hydrophobic are the glass vessels of the preparations, the stopper material of the sealing caps or the boundary surface of the solution with the air supernatant.
  • very fine silicone oil droplets can function as additional hydrophobic aggregation nuclei in the taking of the daily insulin dose by means of customary, siliconized insulin syringes and accelerate the process.
  • WO 01/43762 describes aqueous, parenteral pharmaceutical preparations comprising a polypeptide and glycerol, in which the stabilization of the preparation is to be achieved by purifying off destabilizing constituents of the glycerol.
  • WO 00/23098 describes insulin preparations stabilized using polysorbate 20 or poloxamer 188 for pulmonary administration, but does not describe the stabilization in an acidic solution against aggregation nuclei.
  • the present invention was thus based on the object of finding preparations for acid-soluble insulins containing surfactants, which are distinguished by a high long-term stability to stress due to temperature or physicomechanical stressing and tolerate a high stress with hydrophobic aggregation nuclei.
  • the pharmaceutical preparations of the present invention contain 60-6000 nmol/ml, preferably 240-3000 nmol/ml, of an insulin, an insulin metabolite, an insulin analog or an insulin derivative.
  • the surfactants which can be used are, inter alia, nonionic surfactants.
  • pharmaceutically customary surfactants are preferred, such as, for example: partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol, sorbitol and the like (Span®, Tween®, in particular Tween® 20 and Tween® 80, Myrj®, Brij®), Cremophor® or poloxamers.
  • the surfactants are present in the pharmaceutical composition in a concentration of 5-200 ⁇ g/ml, preferably of 5-120 ⁇ g/ml and particularly preferably of 20-75 ⁇ g/ml.
  • the preparation can additionally optionally contain preservatives (e.g. phenol, cresol, parabens), isotonicizing agents (e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol), buffer substances, salts, acids and alkalis and also further excipients. These substances can in each case be present individually or alternatively as mixtures. Glycerol, dextrose, lactose, sorbitol and mannitol are customarily present in the pharmaceutical preparation in a concentration of 100-250 mM, NaCl in a concentration of up to 150 mM.
  • preservatives e.g. phenol, cresol, parabens
  • isotonicizing agents e.g. mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, glycerol
  • buffer substances e.g. manni
  • Buffer substances such as, for example, phosphate, acetate, citrate, arginine, glycylglycine or TRIS (i.e. 2-amino-2-hydroxymethyl-1,3-propanediol) buffer and corresponding salts, are present in a concentration of 5-250 mM, preferably 10-100 mM. Further excipients can be, inter alia, salts or arginine.
  • the invention therefore relates to a pharmaceutical formulation
  • a pharmaceutical formulation comprising a polypeptide selected from the group consisting of insulin, an insulin analog, an insulin derivative, an active insulin metabolite and combinations thereof; a surfactant or combinations of two or more surfactants; optionally a preservative or combinations of two or more preservatives; and optionally an isotonicizing agent, buffer substances and/or further excipients or combinations thereof, the pharmaceutical formulation being a clear solution which has a pH in the acidic range (pH 1-6.8), preferably pH 3.5-6.8, very particularly preferably 3.5-4.5.
  • Preferred pharmaceutical formulations of the present invention are those wherein the surfactant is selected from the group consisting of partial and fatty acid esters and ethers of polyhydric alcohols such as of glycerol and sorbitol, and polyols; the partial and fatty acid esters and ethers of glycerol and sorbitol being selected from the group consisting of Span®, Tween®, Myrj®, Brij®, Cremophor®; the polyols being selected from the group consisting of polypropylene glycols, polyethylene glycols, poloxamers, Pluronics®, and Tetronics®; the preservative being selected from the group consisting of phenol, cresol, and parabens; the isotonicizing agent being selected from the group consisting of mannitol, sorbitol, sodium chloride, and glycerol; the excipients being selected from the group consisting of buffer substances, acids, and alkalis; the insulin
  • a further subject of the invention is a pharmaceutical formulation such as described above, in which the insulin, the insulin analog, the active insulin metabolite and/or the insulin derivative is present in a concentration of 60-6000 nmol/ml, preferably in a concentration of 240-3000 nmol/ml (this corresponds approximately to a concentration of 1.4-35 mg/ml or 40-500 units/ml); in which the surfactant is present in a concentration of 5-200 ⁇ g/ml, preferably of 5-120 ⁇ g/ml and particularly preferably of 20 75 ⁇ g/ml.
  • a further subject of the invention is a pharmaceutical formulation such as mentioned above, in which glycerol and/or mannitol is present in a concentration of 100-250 mM, and/or NaCl is preferably present in a concentration of up to 150 mM.
  • a further subject of the invention is a pharmaceutical formulation such as mentioned above, in which a buffer substance is present in a concentration of 5-250 mM.
  • a further subject of the invention is a pharmaceutical insulin formulation which contains further additives such as, for example, salts which delay the release of insulin. Mixtures of such delayed-release insulins with formulations described above are included therein.
  • a further subject of the invention is a method for the production of such pharmaceutical formulations.
  • a further subject of the invention is the use of such formulations for the treatment of diabetes mellitus.
  • a further subject of the invention is the use or the addition of surfactants as stabilizer during the process for the production of insulin, insulin analogs or insulin derivatives or their preparations.
  • a comparison solution is prepared identically, but first a suitable amount of surfactant (10-30 ppm of polysorbate 20) is suspended in water for injection.
  • Insulin glargine 10 10 10 10 10 10 10 Insulin glargine + 0 0 0 1 0.010 mg/ml of polysorbate 20 Insulin glargine + 0 0 1 0 0.015 mg/ml of polysorbate 20 Insulin glargine + 0 0 0 0 0.020 mg/ml of polysorbate 20 Insulin glargine + 0 0 0 0 0.030 mg/ml of polysorbate 20 Storage for 1 month at 37° C.
  • a comparison solution is prepared identically, but first a suitable amount of surfactant (0.010-0.030 mg/ml of polysorbate 20) is suspended in water for injection.
  • the samples are stored at +5° C., 25° C. und 37° C. for a fixed period of time. 5 samples in each case are then subjected to a shaking test. The results are shown in the table below, the limit 15 FNU corresponds to turbidities which are discernible in daylight. Number of vials > 15 FNU 0 0.5 1 2 3 4 6 8 10 Test sample days days day days days days days days Storage for 1 month at 5° C.
  • polysorbate 20 or of polysorbate 80 in a concentration of 0.001 mg/ml are equally able to stabilize the solution against particle formation during the in use period.

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  • Health & Medical Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
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  • Epidemiology (AREA)
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US10/461,740 2002-06-18 2003-06-13 Acidic insulin preparations having improved stability Abandoned US20040048783A1 (en)

Priority Applications (4)

Application Number Priority Date Filing Date Title
US10/461,740 US20040048783A1 (en) 2002-06-18 2003-06-13 Acidic insulin preparations having improved stability
US11/089,777 US7476652B2 (en) 2002-06-18 2005-03-25 Acidic insulin preparations having improved stability
US12/328,208 US7713930B2 (en) 2002-06-18 2008-12-04 Acidic insulin preparations having improved stability
US12/773,356 US20100216692A1 (en) 2002-06-18 2010-05-04 Acidic Insulin Preparations Having Improved Stability

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
DE10227232A DE10227232A1 (de) 2002-06-18 2002-06-18 Saure Insulinzubereitungen mit verbesserter Stabilität
DEDE10227232.8 2002-06-18
US40933802P 2002-09-09 2002-09-09
US10/461,740 US20040048783A1 (en) 2002-06-18 2003-06-13 Acidic insulin preparations having improved stability

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US10/461,740 Abandoned US20040048783A1 (en) 2002-06-18 2003-06-13 Acidic insulin preparations having improved stability
US11/089,777 Expired - Lifetime US7476652B2 (en) 2002-06-18 2005-03-25 Acidic insulin preparations having improved stability
US12/328,208 Expired - Lifetime US7713930B2 (en) 2002-06-18 2008-12-04 Acidic insulin preparations having improved stability
US12/773,356 Abandoned US20100216692A1 (en) 2002-06-18 2010-05-04 Acidic Insulin Preparations Having Improved Stability

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US12/328,208 Expired - Lifetime US7713930B2 (en) 2002-06-18 2008-12-04 Acidic insulin preparations having improved stability
US12/773,356 Abandoned US20100216692A1 (en) 2002-06-18 2010-05-04 Acidic Insulin Preparations Having Improved Stability

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US (4) US20040048783A1 (pt)
EP (2) EP2305288B1 (pt)
JP (2) JP5237522B2 (pt)
KR (1) KR101040029B1 (pt)
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UA (1) UA79477C2 (pt)
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Cited By (33)

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WO2005115303A1 (en) * 2004-05-24 2005-12-08 Wockhardt Limited Purification of insulin-like material by reverse phase chromatography
US20070235365A1 (en) * 2004-03-12 2007-10-11 Biodel Inc. Rapid Acting Drug Delivery Compositions
US20090175840A1 (en) * 2008-01-04 2009-07-09 Biodel, Inc. Insulin formulations for insulin release as a function of tissue glucose levels
US20100069292A1 (en) * 2008-09-02 2010-03-18 Biodel, Inc. Insulin with a basal release profile
US20100227795A1 (en) * 2009-03-03 2010-09-09 Biodel Inc. Insulin formulations for rapid uptake
CN102319422A (zh) * 2010-05-19 2012-01-18 赛诺菲-安万特 长效胰岛素制剂
US8637458B2 (en) 2010-05-12 2014-01-28 Biodel Inc. Insulin with a stable basal release profile
US20150246129A1 (en) * 2012-12-26 2015-09-03 Wockhardt Limited Pharmaceutical composition
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9670261B2 (en) 2012-12-21 2017-06-06 Sanofi Functionalized exendin-4 derivatives
US9694053B2 (en) 2013-12-13 2017-07-04 Sanofi Dual GLP-1/glucagon receptor agonists
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US9751926B2 (en) 2013-12-13 2017-09-05 Sanofi Dual GLP-1/GIP receptor agonists
US9750788B2 (en) 2013-12-13 2017-09-05 Sanofi Non-acylated exendin-4 peptide analogues
US9758561B2 (en) 2014-04-07 2017-09-12 Sanofi Dual GLP-1/glucagon receptor agonists derived from exendin-4
US9771406B2 (en) 2014-04-07 2017-09-26 Sanofi Peptidic dual GLP-1/glucagon receptor agonists derived from exendin-4
US9775904B2 (en) 2014-04-07 2017-10-03 Sanofi Exendin-4 derivatives as peptidic dual GLP-1/glucagon receptor agonists
US9789165B2 (en) 2013-12-13 2017-10-17 Sanofi Exendin-4 peptide analogues as dual GLP-1/GIP receptor agonists
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
US9932381B2 (en) 2014-06-18 2018-04-03 Sanofi Exendin-4 derivatives as selective glucagon receptor agonists
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US9982029B2 (en) 2015-07-10 2018-05-29 Sanofi Exendin-4 derivatives as selective peptidic dual GLP-1/glucagon receptor agonists
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10092513B2 (en) 2013-04-03 2018-10-09 Sanofi Treatment of diabetes mellitus by long-acting formulations of insulins
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
US10335489B2 (en) 2012-01-09 2019-07-02 Adocia Injectable solution at pH 7 comprising at least one basal insulin the pi of which is between 5.8 and 8.5 and a substituted co-polyamino acid
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10449256B2 (en) 2013-02-12 2019-10-22 Adocia Injectable solution at pH 7 comprising at least one basal insulin the isoelectric point of which is between 5.8 and 8.5 and a hydrophobized anionic polymer
US10758592B2 (en) 2012-10-09 2020-09-01 Sanofi Exendin-4 derivatives as dual GLP1/glucagon agonists
US10806797B2 (en) 2015-06-05 2020-10-20 Sanofi Prodrugs comprising an GLP-1/glucagon dual agonist linker hyaluronic acid conjugate

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