EP3740227A1 - Zusammensetzungen in form einer injizierbaren wässrigen lösung mit amylin, einem amylin-rezeptor-agonist oder einem amylin-analogon und einer copolyaminosäure - Google Patents

Zusammensetzungen in form einer injizierbaren wässrigen lösung mit amylin, einem amylin-rezeptor-agonist oder einem amylin-analogon und einer copolyaminosäure

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Publication number
EP3740227A1
EP3740227A1 EP18815677.2A EP18815677A EP3740227A1 EP 3740227 A1 EP3740227 A1 EP 3740227A1 EP 18815677 A EP18815677 A EP 18815677A EP 3740227 A1 EP3740227 A1 EP 3740227A1
Authority
EP
European Patent Office
Prior art keywords
radical
formula
hydrophobic
amylin
radicals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18815677.2A
Other languages
English (en)
French (fr)
Inventor
You-Ping Chan
Alexandre Geissler
Romain Noel
Richard Charvet
Nicolas Laurent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adocia SAS
Original Assignee
Adocia SAS
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 FR1761808A external-priority patent/FR3074682B1/fr
Priority claimed from FR1855943A external-priority patent/FR3083085B1/fr
Application filed by Adocia SAS filed Critical Adocia SAS
Priority claimed from PCT/EP2018/083943 external-priority patent/WO2019110788A1/fr
Publication of EP3740227A1 publication Critical patent/EP3740227A1/de
Pending 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • 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
    • 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
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • 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
    • A61P3/08—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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment

Definitions

  • the invention relates to amylin, amylin receptor agonist or amylin analogue therapy for the treatment of diabetes.
  • the invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least amylin, an amylin receptor agonist or a amylin analogue and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals according to the invention and compositions further comprising insulin (excluding basal insulins whose isoelectric point pi is between 5.8 and 8 , 5).
  • the invention also relates to pharmaceutical formulations comprising the compositions according to the invention.
  • the invention also relates to a use of the co-polyamino acids bearing carboxylate charges and hydrophobic radicals according to the invention for stabilizing amylin, agonist or amylin receptor agonist compositions.
  • amylin as well as amylin, amylin receptor agonist or amylin analogue compositions further comprising insulin.
  • Type 1 diabetes is an autoimmune disease leading to the destruction of beta cells in the pancreas. These cells are known to produce insulin whose main role is to regulate glucose utilization in peripheral tissues (Gerich 1993 Control of glycaemia). As a result, patients with type 1 diabetes have chronic hyperglycemia and must use exogenous insulin to limit this hyperglycaemia. Insulin therapy has drastically changed the life expectancy of these patients. However, the control of blood glucose provided by exogenous insulin is not optimal, especially after taking a meal. This is due to the fact that these patients produce glucagon after taking a meal, which leads to the destocking of some of the glucose stored in the liver, which is not the case in the healthy person. This glucagon-mediated glucagon production aggravates the problem of regulating blood sugar in these patients.
  • amylin another hormone produced by beta cells of the pancreas and therefore also deficient in type 1 diabetic patients, plays a key role in the regulation of postprandial blood glucose.
  • Amylin also known as "amyloid polypeptide islet" or IAPP, is a 37 amino acid peptide that is co-stored and co-secreted with insulin (Schmitz 2004 Amylin Agonists). This Peptide is described to block the production of glucagon by alpha cells of the pancreas.
  • insulin and amylin have complementary and synergistic roles, since insulin reduces blood glucose while amylin reduces endogenous glucose entry into the blood by inhibiting blood glucose levels. production (secretion) of endogenous glucagon.
  • Human amylin has properties that are not compatible with pharmaceutical requirements in terms of solubility and stability (Goldsbury CS, Cooper G3, Goldie KN, Muller SA, Saafi EL, WT Gruijters, Misur P, Engel A , Aebi U, Kistler 3: Polymorphic Fibrillar Assembly of Huan amylin J St ru and Biol 119: 17-27, 1997).
  • Amylin is known to form amyloid fibers which lead to the formation of plaques that are insoluble in water. Although being the natural hormone, it has been necessary to develop an analogue to solve these solubility problems.
  • amylin is stable for about fifteen minutes at acidic pH, and less than one minute at neutral pH.
  • Amylin company has developed an amylin analogue, pramlintide, to overcome the lack of stability of human amylin.
  • This product marketed as Symlin, was approved in 2005 by the FDA for the treatment of type 1 and type 2 diabetics. It must be administered subcutaneously three times a day, in the hour before the meal. to improve postprandial glucose control.
  • This peptide is formulated at acidic pH and is described to fibrillate when the pH of the solution is greater than 5.5. Analog variants are described in US Patent 5,686,411.
  • amylin an amylin analogue, or an amylin receptor agonist
  • a prandial insulin since these two products are to be administered before the meal.
  • the patent application WO2007104786 of NOVO NORDISK discloses a method for stabilizing a solution of pramlintide, which is an analogue of amylin, and insulin by adding a phospholipid, derivative of glycerophosphoglycerol, in particular dimyristoyl glycerophosphoglycerol (DMPG).
  • DMPG dimyristoyl glycerophosphoglycerol
  • this solution requires the use of large quantities of DMPG which can pose a local tolerance problem.
  • the DMPG leads to compositions having physical stabilities at 0-4 ° C quite low as described in the application WO2018122278.
  • the pH of acid formulation and rapid fibrillation are brakes to obtain a pH-neutral pharmaceutical formulation based on amylin and pramlintide, but also a brake to combine amylin or pramlintide with other ingredients.
  • active pharmaceutical agents in particular peptides or proteins.
  • the co-polyamino acids according to the invention stabilize amylin, amylin receptor agonist or amylin analogue compositions at a pH of between 6 and 6. , 0 and 8.0.
  • compositions comprising amylin, an amylin receptor agonist or an amylin analogue in combination with a co-polyamino acid according to the invention exhibit increased stability over time, which is great interest in pharmaceutical development.
  • co-polyamino acids according to the invention also make it possible to obtain a composition comprising prandial insulin and amylin, agonist at the receptor of amylin or amylin analogue. said composition being clear and having improved fibrillation stability.
  • a conventional method for measuring the stability of proteins or peptides is to measure the formation of fibrils using Thioflavin T, also called ThT.
  • ThT Thioflavin T
  • This method makes it possible to measure, under temperature and agitation conditions that allow an acceleration of the phenomenon, the latency time before the formation of fibrils by measuring the increase in fluorescence.
  • the compositions according to the invention have a lag time before fibril formation significantly greater than that of amylin, an amylin receptor agonist or an amylin analogue at the pH of interest.
  • compositions according to the invention have a physical stability, and possibly chemical, satisfactory at the desired pH.
  • the invention relates to a composition in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • GpA is chosen from the radicals of formula VIII
  • GpL is chosen from the radicals of formula XII Form XII,
  • GpC is a radical of formula IX:
  • Form IX * indicates the sites of attachment of the different groups linked by amide functions
  • a ' is an integer of 1, 2 or 3;
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g, h or
  • I is different from 0;
  • r is an integer equal to 0, 1 or 2
  • s' is an integer equal to 0 or 1;
  • A, Ai, A2 and A3 identical or different are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms
  • C x is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:
  • hydrophobic radical -Hy When the hydrophobic radical -Hy carries 4 -GpC, then 7 ⁇ x ⁇ 11, When the hydrophobic radical -Hy bears at least 5 -GpC then, 6 ⁇ x ⁇ 11,
  • G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • - R is a radical selected from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -CONH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms,
  • the hydrophobic radical (s) -Hy of formula X being bonded to PLG:
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • the composition is characterized in that the composition does not comprise basal insulin whose isoelectric point pi is between 5.8 and 8.5.
  • the composition is characterized in that the composition does not comprise GLP-1, GLP-1 analogue or GLP-1 receptor agonist, commonly called GLP-1 RA. .
  • the composition is characterized in that the composition does not comprise basal insulin whose isoelectric point pi is between 5.8 and 8.5 .mu.l of GLP-1, GLP-1 analogue, 1 or GLP-1 receptor agonist, commonly called GLP-1 RA.
  • the invention relates to a composition, free of basal insulin whose isoelectric point pi is between 5.8 and 8.5, in the form of an injectable aqueous solution, whose pH is between 6.0 and 8.0, comprising at least:
  • GpR is chosen from the radicals of formulas VII, VII 'or VII ;
  • GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': - NH - G - NH - Formula XI Formula CG
  • GpA is chosen from the radicals of formula VIII
  • a ' is selected from radicals of formula VIII', VIII "or VIII" '
  • GpC is a radical of formula IX: Form IX;
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2;
  • d is an integer equal to 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g, h or
  • I is different from 0;
  • r is an integer equal to 0, 1 or 2
  • s' is an integer equal to 0 or 1;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms
  • Cx is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:
  • G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions; CONHz or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms,
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • alkyl radical means a carbon chain, linear or branched, which does not include a heteroatom.
  • the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
  • Said co-polyamino acid bearing carboxylate charges and hydrophobic radicals Hy is soluble in aqueous solution at a pH of between 6.0 and 8.0, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. .
  • compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
  • the term "clear solution” means compositions which satisfy the criteria described in the American pharmacopoeias and European Commission on Injectable Solutions.
  • the solutions are defined in the ⁇ 1151> part referring to the injection ( ⁇ 1>) (referring to ⁇ 788> according to USP 35 and specified in ⁇ 788> according to USP 35 and in ⁇ 787> , ⁇ 788> and ⁇ 790> USP 38 (from 1 August 2014), according to USP 38).
  • injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
  • soluble capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
  • basal insulin whose isoelectric point is between 5.8 and 8.5 insoluble insulin at pH 7 and whose duration of action is between 8 and 24 hours or greater than 24 hours in the models diabetes standards.
  • Hy comprises more than 30 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 40 and 60 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms.
  • x is between 11 and 25 (11).
  • x is between 9 and 15 (9 ⁇ x ⁇ 15).
  • the composition is characterized in that the pH is between 6.6 and 7.8.
  • the composition is characterized in that the pH is between 7.0 and 7.8.
  • the composition is characterized in that the pH is between 6.8 and 7.4.
  • the group GpR linked to P LG is chosen from GpR of formula VIL
  • the group GpR linked to P LG is chosen from GpR of formula VII and the second GpR is chosen from GpR of formula VII.
  • At least one of the g, h or I is different from 0.
  • At most one of the g, h or I is different from 0.
  • At least one of g and h is equal to 1.
  • I 1, at least one of g or h is equal to 0.
  • GpA is a radical of
  • At least one of g and h is equal to 1.
  • a 0
  • g is greater than or equal to 2 (g> 2).
  • h is greater than or equal to 2 (h> 2).
  • g or h is greater than or equal to 2 (g> 2) and b is equal to 0.
  • GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • said hydrophobic radical-Hy is chosen from radicals of formula X in which
  • GpR is chosen from the radicals of formulas VII, VIF or VU ": ;
  • GpG is chosen from the radicals of formula XI or CG:
  • GpC is a radical of formula IX:
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g or h is other than 0;
  • r is an integer equal to 0, 1 or 2
  • s' is an integer equal to 0 or 1;
  • a 1 is a linear or branched alkyl radical comprising from 1 to 8 carbon atoms, and optionally substituted by a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms;
  • C x is an optionally branched or univalent monovalent alkyl radical comprising a ring moiety, wherein x is the number of carbon atoms and:
  • G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more -CONH 2 functions or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • GpR is chosen from the radicals of formulas VII, VII 'or VU ": ;
  • GpG is chosen from the radicals of formula XI or CG: * - NH - G - NH - *
  • GpA is chosen from the radicals of formulas, Ville or VUId:
  • GpC is a radical of formula IX:
  • GpA is a radical of formula Ville or VUId
  • b is an integer equal to 0 or 1;
  • - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
  • d is an integer equal to 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • ⁇ h is an integer equal to 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g or h is different from 0;
  • r is an integer equal to 0, 1 or 2
  • s' is an integer equal to 1;
  • A2 identical or different are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and optionally substituted by a radical derived from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms; ;
  • C x is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:
  • G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • - R is a radical selected from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -CONH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • r 0 and the hydrophobic radical of formula X is bonded to PLG via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by the PLG thus forming an amide function resulting from the reaction of an amine function carried by the precursor of PLG and an acid function carried by the precursor Hy 'of the hydrophobic radical.
  • r 1 and the hydrophobic radical of formula X is linked to PLG:
  • r 1 or 2
  • the GpCs are linked, directly or indirectly, to N "i and Npi, and the P LG is linked, directly or indirectly, via GpR to N a ; or the GpCs are linked, directly or indirectly, to N "2 and Npi, and the P LG is linked, directly or indirectly, via GpR to N ai .
  • GpC are directly or indirectly related to N ai and N a : and LG P is directly or indirectly related to Nri; or
  • GpC are directly or indirectly related to N ai and Npi, and LG L is directly or indirectly related to N a 2; or
  • N - GpCs are linked, directly or indirectly, to N "i, and Npi and P LG is linked, directly or indirectly, via GpR to Np; or
  • GpCs are linked, directly or indirectly, to N a i, N "2 and Np2 and the PLG, directly or indirectly, is linked via GpR to Npi; or
  • the GpCs are linked, directly or indirectly, to N "i, Npi and Np2 and the PLG, directly or indirectly, is linked via GpR to" 2; or
  • the GpCs are directly or indirectly linked to N H 2, Npi and p: and the PLG is linked, directly or indirectly, via GpR to N ai.
  • GpC are directly or indirectly related to N a i, N "2 and Npi and the PLG is directly or indirectly linked to Np2; or
  • the GpC are linked, directly or indirectly, to Mai, N H 2 and Np and the PLG is directly or indirectly linked to Npi; or
  • N - GpC are linked, directly or indirectly, to N "i, Npi and Np and the PLG is linked, directly or indirectly, to N K 2;
  • the GpCs are directly or indirectly linked to N U 2, Npi and Np2 and the PLG is directly or indirectly linked to IMai
  • GpR, GpG, GpL, GpH, GpC, Al, r, g, h, I and G have the definitions given above.
  • GpR, GpG, GpL, GpH, GpC, Al, a ', r, g, h, I and G have the definitions given above.
  • GpR, GpG, GpL, GpH, GpC, Al, A2, r, g, h, a ', I and G have the definitions given above.
  • GpR, GpG, GpL, GpH, GpC, Al, A2, A3, a ', r, g, h, I have the definitions given above.
  • GpG, GpA, GpL, GpH, GpC, R, a, g, h, I, a 'and G have the definitions given above.
  • VIF formula And GpG, GpA, GpL, GpH, GpC, R, a, g, h, I, a 'and G have the definitions given above.
  • GpG, GpA, GpL, GpH, GpC, R, a, g, h, I, a 'and G have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X as defined below: ,
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd 'as defined below. :
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd 'as defined below. :
  • GpR, GpG, GpA, GpH, GpC, r, g, h, and a have the definitions given above.
  • GpR, GpG, GpA, GpH, GpC, r, g and h have the definitions given above.
  • GpR, GpG, GpA, GpC, r, a and g have the definitions given above.
  • GpR, GpG, GpA, GpC, r and g have the definitions given above.
  • a 0,
  • GpR is a radical of formula VII '
  • r-0, and GpA is chosen from the radicals of formula Villa and VUIb.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising from 2 to 5 carbon atoms and bearing one or more amide functions (-CONH 2).
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent linear alkyl radical comprising from 2 to 5 carbon atoms and bearing one or more amide functions (-CONH 2).
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula XI.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X2.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is linked to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or in position 4 or 5) relative to the amide function (-CONH2).
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is an ether radical.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is an ether radical represented by the formula ./ ⁇ / ° ⁇ / ⁇ *.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the fo rmols below r
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X3.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a radical of formula X4.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by formulas X5 and X6 below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical of formula X5.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which R is a polyether radical of formula X6.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of CG form wherein G is an alkyl radical comprising 6 carbon atoms represented by the formula Z below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by the formula Z below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula XI wherein G is an alkyl radical having 4 carbon atoms represented by - (CH2) 2-CH (COOH) -.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula XI wherein G is an alkyl radical having 4 carbon atoms represented by -CH ((CH2) 2COOH) -.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula XI wherein G is an alkyl radical having 3 carbon atoms represented by -CH2-CH- (COOH).
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpG and / or GpH is of formula XI wherein G is an alkyl radical having 3 carbon atoms represented by -CH (CH2) COOH) -.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh and Xi is a radical in which the radical GpA is of formula VIII and wherein A 1, A 2 or A 3 is selected from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in wherein the GpC radical of formula IX is selected from the group consisting of the radicals of formulas IXe, IXf or IXg hereinafter represented:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in wherein the GpC radical of formula IX is selected from the group consisting of radicals of formulas IXe, IXf or IXg wherein b is 0, respectively corresponding to formulas IXh, IXi, and IXj hereinafter represented:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of linear alkyl radials.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of branched alkyl radicals.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of alkyl radicals comprising between 19 and 14 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of the radicals represented by the formulas below;
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of the radicals represented
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is chosen from the group consisting of the radicals represented
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi is a radical in which Cx is selected from the group consisting of the alkyl radicals represented by the formulas below
  • the composition is characterized in that the hydrophobic radical is a radical of formulas X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and Xi in wherein the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of alkyl radicals comprising 14 or 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula X, Xc ', Xd, Xa, Xb, Xd', Xc, Xe, Xf, Xg, Xh and in which the radical GpC of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
  • the copolyamino acid is a sodium poly-L-glutamate modified at one of its ends of the following formula shown below.
  • the copolyamino acid is a sodium poly-L-glutamate modified at one of its ends of formula shown below, described in Example B18.
  • the radicals Hy are attached to the PLG via amide functions.
  • composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula XXX below: ## STR2 ##
  • D represents, independently, either a -CH 2 - (aspartic unit) or a -CH 2 -CH 2 - (glutamic unit) group,
  • Hy is a hydrophobic radical chosen from hydrophobic radicals of formula X,
  • R2 is a hydrophobic radical chosen from hydrophobic radicals of formulas X or a radical -NR'R ", R 'and R", which may be identical or different, are chosen from the group consisting of H, linear or branched or cyclic C2 alkyls to CIO, benzyl and said R 'and R "alkyls capable of forming together one or more saturated, unsaturated and / or aromatic carbon rings and / or which may contain heteroatoms selected from the group consisting of O, N and S,
  • X represents a H or a cationic entity chosen in the group comprising the metal cations
  • n + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n + m ⁇ 250.
  • co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X may also be called "co-polyamino acid" in the present description.
  • random co-polyamino acid is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXa.
  • R 1 is a radical selected from the group consisting of H, linear C 2 -C 10 acyl group, branched C 3 -C 10 acyl group, benzyl, terminal amino acid unit and pyroglutamate,
  • R ' 2 is a radical -NR'R ", R' and R" identical or different being selected from the group consisting of H, linear or branched alkyls or C2-C10 cyclic, benzyl and said R 'and R "alkyl may together form one or more saturated carbon rings, saturated and / or aromatic and / or may contain heteroatoms, selected from the group consisting of O, N and S.
  • defined co-polyamino acid is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXb.
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen. among the co-polyamino acids of formulas XXXb in which R2 is a hydrophobic radical of formula X.
  • the composition is characterized in that R 1 is a radical selected from the group consisting of a C 2 to C 10 linear acyl group, a C 3 to C 10 acyl group, a benzyl group and Terminally "amino acid” and a pyroglutamate.
  • the composition is characterized in that R 1 is a radical selected from the group consisting of a C 2 to C 10 linear acyl group or a C 3 to C 10 branched acyl group.
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids of formulas XXX, XXXa or XXXb in which group D is a group -CH2- (aspartic unit).
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids of formulas XXX, XXXa or XXXb in which group D is a group -CH2-CH2- (glutamic unit).
  • the composition is characterized in that the ratio
  • Include the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2. [000191] In one embodiment, the composition according to the invention is characterized in that n + m is between 10 and 250.
  • the composition according to the invention is characterized in that n + m is between 10 and 200.
  • the composition according to the invention is characterized in that n + m is between 15 and 150.
  • the composition according to the invention is characterized in that n + m is between 15 and 100. In one embodiment, the composition according to the invention is characterized in that n + m is between 15 and 80.
  • composition according to the invention is characterized in that n + m is between 15 and 65.
  • composition according to the invention is characterized in that n + m is between 20 and 60.
  • composition according to the invention is characterized in that n + m is between 20 and 50.
  • the composition according to the invention is characterized in that n + m is between 20 and 40.
  • the invention also relates to the co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy, said co-polyamino acid being constituted by glutamic or aspartic units and said hydrophobic radicals Hy chosen from the radicals of formula X as defined above. below: Formula X in which
  • GpR is chosen from the radicals of formulas VII, VU 'or VU'
  • GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': - NH - G - NH -
  • GpA is chosen from the radicals of formula VIII
  • a ' is selected from radicals of formula VIII', VIII "or VIII"'
  • GpC is a radical of formula IX:
  • b is an integer equal to 0 or 1;
  • - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
  • d is an integer equal to 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g, h or
  • I is different from 0;
  • r is an integer equal to 0, 1 or 2
  • - s' is an integer equal to 0 or 1;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms
  • Cx is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:
  • G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • R is a radical selected from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more -CONH 2 functions or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms,
  • the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • the invention also relates to the precursor Hy 'of the hydrophobic radical -Hy of formula X' as defined below: Formula X 'in which
  • GpR is chosen from the radicals of formulas VII, VU 'or VU ":
  • GpG and GpH identical or different are chosen from the radicals of formulas
  • GpA is chosen from the radicals of formula VIII
  • a ' is selected from radicals of the formula HIV', VIII 'or HIV' "
  • GpC is a radical of formula IX Form IX;
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6, and at least one of g, h or
  • I is different from 0;
  • r is an integer equal to 0, 1 or 2
  • s' is an integer equal to 0 or 1;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms, and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms
  • Cx is a linear or branched monovalent alkyl radical optionally comprising a cyclic part, in which x indicates the number of carbon atoms and:
  • G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • - R is a radical selected from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -COIMH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms,
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • amylin or amyloid islet polypeptide (IAPP)
  • IAPP amylin, or amyloid islet polypeptide
  • the IAPP is processed from a coding sequence of 89 residues.
  • the Proislet amyloid polypeptide (proIAPP, proamyline, proislet protein) is produced in pancreatic beta cells (beta cells) in the form of a pro-peptide of SRO 67 amino acids, 7404 Dalton, and undergoes post-translational modifications including cleavage. of protease to produce amylin.
  • amylin refers to the compounds described in US Pat. Nos. 5,124,314 and 5,234,906.
  • the percentage of homology allowed for the present definition of an analogue is 50%.
  • an analogue may for example be derived from the primary amino acid sequence of amylin by substituting one or more natural or unnatural amino acids or peptidomimetics.
  • derivative when used by reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce non-amino acid substituents.
  • amylin receptor agonist refers to a compound that mimics one or more characteristics of amylin activity.
  • Amylin derivatives are described in the article Yan et al., PNAS Vol. 103, No. 7, p 2046-2051, 2006.
  • the substituent is selected from the group consisting of fatty chains.
  • Amyline analogues are described in US Pat. No. 5,686,411, US Pat. No. 6,114,304 or US Pat. No. 6,410,511.
  • the composition is characterized in that the amylin, the amylin receptor agonist or the amylin analogue is amylin.
  • the amylin receptor agonist is amylin.
  • the composition is characterized in that the amylin analogue or the amylin receptor agonist is pramlintide (Symlin ® ) marketed by ASTRAZENECA AB.
  • the amylin analogue or the amylin receptor agonist is pramlintide (Symlin ® ) marketed by ASTRAZENECA AB.
  • the co-polyamino acid / amylin, amylin receptor agonist, or amylin analogue molar ratios are greater than or equal to 1. [000214] In one embodiment, the molar ratios of polyamino acid / amylin, amylin receptor agonist or amylin analogue are between 1.5 and 75.
  • the co-polyamino acid / amyli ne, amylin receptor agonist or amylin analogue molar ratios are between 1.8 and 50.
  • the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 2 and 35.
  • the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 2.5 and 30. In one embodiment, the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 3 and 30.
  • the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 3.5 and 30.
  • the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 4 and 30.
  • the molar ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 5 and 30.
  • the co-polyamino acid / amylin molar ratios, agonist at the amylin receptor or amylin analogue are between 7 and 30.
  • the co-polyamino acid / amyli ne, amylin receptor agonist or amylin analogue molar ratios are between 9 and 30.
  • the co-polyamino acid / amylin molar ratios are between 3 and 75.
  • the co-polyamino acid / amylin molar ratios are between 7 and 50.
  • the co-polyamino acid / amylin molar ratios are between 10 and 30.
  • the co-polyamino acid / amylin molar ratios are between 15 and 30.
  • the polyamino acid / pramlintide molar ratios are between 1, 5 and 75.
  • the polyamino acid / pramlintide co molar ratios are between 2 and 50.
  • the polyamino acid / pramlintide co molar ratios are between 3 and 30.
  • the polyamino acid / pramlintide co molar ratios are between 4 and 30.
  • the polyamino acid / pramlintide molar ratios are between 5 and 30.
  • the polyamino acid / pramlintide co molar ratios are between 8 and 30.
  • the co-polyamino acid / pramlintide molar ratios are between 10 and 30.
  • the hydrophobic radical Hy / amylin, agonist at the amylin receptor or amylin analogue are between
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 1.8 and 100.
  • hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between
  • hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between
  • hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between
  • hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between
  • hydrophobic radical Hy / amylin, agonist at the amylin receptor or amyline analogue molar ratios are between
  • hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 7 and 60.
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 9 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 5 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 10 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 15 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 1.5 and 60. [000250] In one embodiment, the hydrophobic radical Hy / pramlintide molar ratios are between 2 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 3 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 4 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 5 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 8 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 10 and 60.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.0 and 70.
  • the mass ratios co-polyamino acid / amycin, amylin receptor agonist or amylin analogue are between 1.2 and 45.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.3 and 30.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.7 and 27.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amyli analogue are between 2.0 and 27.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.3 and 27.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.7 and 27.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 3.3 and 27. In one embodiment, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 4.7 and 27.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 6.0 and 27.
  • the co-polyamino acid / amylin mass ratios are between 2.0 and 67.
  • the co-polyamino acid / amylin mass ratios are between 4.7 and 27.
  • the co-polyamino acid / amylin mass ratios are between 6.7 and 27.
  • the co-polyamino acid / amylin mass ratios are between 10 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 1.0 and 67.
  • the co-polyamino acid / pramlintide mass ratios are between 1.3 and 45.
  • the co-polyamino acid / pramlintide mass ratios are between 2.7 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 3.3 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 5.3 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 6.7 and 27.
  • the composition is characterized in that it further comprises insulin.
  • the composition is characterized in that the insulin is a mealtime insulin. Prandial insulins are soluble at pH 7.
  • Prandial insulin is a so-called fast or "regular" insulin.
  • the so-called fast prandial insulins are insulins which must respond to the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes.
  • the so-called "regular" meal insulin is human insulin.
  • the prandial insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
  • Human insulin is for example marketed under the brands Humulin ® (ELI LILLY) and Novolin ® (NOVO NORDISK).
  • Fast-acting prandial insulins are insulins which are obtained by recombination and whose primary sequence has been modified to reduce their action time.
  • the prandial insulins called fast are selected from the group consisting of insulin lispro (Humalog ®), insulin glulisine (Apidra ®) and insulin aspart (NovoLog ®) .
  • the mealtime insulin is insulin lispro.
  • the mealtime insulin is insulin glulisine.
  • the mealtime insulin is insulin aspart.
  • the insulin concentration is between 240 and 3000 mM (40 to 500 U / mL).
  • it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 3000 ⁇ M (100 to 500 U / mL). In one embodiment, it relates to a pharmaceutical formulation characterized in that the insulin concentration is between 600 and 2400 m (100 to 400 U / mL).
  • the insulin concentration is between 600 and 1800 mM (100 to 300 U / mL).
  • the insulin concentration is between 600 and 1200 ⁇ M (100 to 200 U / mL).
  • the insulin concentration is 600 ⁇ M (100 U / mL).
  • the insulin concentration is 1200 ⁇ M (200 U / mL).
  • the insulin concentration is 1800 ⁇ M (300 U / mL).
  • the insulin concentration is 2400 ⁇ M (400 U / mL).
  • the insulin concentration is 3000 ⁇ M (500 U / mL).
  • the molar ratio of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue is greater than or equal to 1.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amyli analogue are between 1.5 and 75.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 1.8 and 50.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 2 and 35.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 2.5 and 30.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 3 and 30. In one embodiment comprising prandial insulin, the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 3.5 and 30.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 4 and 30.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 5 and 30.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 7 and 30.
  • the co-polyamino acid / amylin molar ratios, amylin receptor agonist or amylin analogue are between 9 and 30.
  • the co-polyamino acid / amylin molar ratios are between 5 and 75.
  • the co-polyamino acid / amylin molar ratios are between 10 and 50.
  • the co-polyamino acid / amylin molar ratios are between 15 and 30.
  • the co-polyamino acid / pramlintide molar ratio is greater than or equal to 1.
  • the co-polyamino acid / pramlintide molar ratios are between 1, 5 and 75.
  • the co-polyamino acid / pramlintide molar ratios are between 2 and 50.
  • the co-polyamino acid / pramlintide molar ratios are between 3 and 30.
  • the co-polyamino acid / pramlintide molar ratios are between 4 and 30.
  • the co-polyamino acid / pramlintide molar ratios are between 5 and 30.
  • the co-polyamino acid / pramlintide molar ratios are between 8 and 30.
  • the co-polyamino acid / pramlintide molar ratios are between 10 and 30.
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 1.5 and 150.
  • the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 1.8 and 100.
  • the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 2 and 70.
  • the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 2.5 and 60.
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 3 and 60.
  • the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 3.5 and 60.
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 4 and 60.
  • the hydrophobic radical Hy / amylin molar ratios, amylin receptor agonist or amyline analogue are between 5 and 60.
  • the hydrophobic radical Hy / amylin, amylin receptor agonist or amylin analogue molar ratios are between 7 and 60.
  • the hydrophilic radical molar ratios Hy / amylin, amylin receptor agonist or amylin analogue are between 9 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 5 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 10 and 60.
  • the hydrophobic radical Hy / amylin molar ratios are between 15 and 60. In one embodiment comprising prandial insulin, the hydrophobic radical Hy / pramlintide molar ratios are between 1, 5 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 2 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 3 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 4 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 5 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 8 and 60.
  • the hydrophobic radical Hy / pramlintide molar ratios are between 10 and 60.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.0 and 70.
  • the mass ratios co-polyamino acid / amylin, amylin receptor agonist or amylin analogue are between 1.2 and 45.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.3 and 30.
  • the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 1.7 and 27.
  • the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.0 and 27.
  • the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.3 and 27.
  • the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 2.7 and 27. In one embodiment comprising prandial insulin, the mass ratios of co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 3.3 and 27.
  • the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 4.7 and 27.
  • the mass ratios co-polyamino acid / amylin, agonist at the amylin receptor or amylin analogue are between 6.0 and 27.
  • the co-polyamino acid / amylin mass ratios are between 3.3 and 67.
  • the co-polyamino acid / amylin mass ratios are between 6.6 and 27.
  • the co-polyamino acid / amylin mass ratios are between 10 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 1.0 and 67.
  • the co-polyamino acid / pramlintide mass ratios are between 1.2 and 45.
  • the co-polyamino acid / pramlintide mass ratios are between 1.3 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 1.7 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 2.0 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 2.3 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 2.7 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 3.3 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 4.7 and 27.
  • the co-polyamino acid / pramlintide mass ratios are between 6.0 and 27.
  • GLP-1 an amylin receptor agonist or an amylin analogue
  • GLP-1 RA GLP-1 receptor agonists
  • GLP-1, GLP-1 analogs, or GLP-1 RA are said to be “fast”.
  • “Fast” is understood to mean GLP-1, GLP-1 analogs, or GLP-1 RA, whose apparent half-life after subcutaneous injection in humans is less than 8 hours, particularly inferior at 5 hours, preferably less than 4 hours or even less than 3 hours, such as exenatide and lixisenatide.
  • GLP-1, GLP-1 analogs, or GLP-1 RA are selected from the group consisting of exenatide or Byetta ® (AstraZeneca), or the lixisenatide Lyxumia ® (SANOFI), their analogues or derivatives and their pharmaceutically acceptable salts.
  • GLP-1, GLP-1 or GLP-1 RA is exenatide or Byetta ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • GLP-1, GLP-1 or GLP-1 RA is lixisenatide or Lyxumia ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1.0 mg per 100 U of insulin.
  • the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.01 to 0.5 mg per 100 U of insulin.
  • the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.
  • the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin. In one embodiment, the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 100 U of insulin.
  • the concentration of exenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.01 to 0.5 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 100 U of insulin.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 100 U of insulin.
  • compositions according to the invention are produced by mixing solutions of amylin and commercial solutions of GLP-1, GLP-1 analogue or GLP-1 receptor agonist. 1 RA in volume ratios ranging from 10/90 to 90/10 in the presence of a co-polyamino acid.
  • composition according to the invention is free from mealtime insulin.
  • composition according to the invention is free of GLP-1, GLP-1 analogue or GLP-1 receptor agonist, commonly called GLP-1 RA.
  • the invention also relates to compositions which further comprise ionic species, said ionic species making it possible to improve the stability of the compositions.
  • the invention also relates to the use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of the compositions.
  • the ionic species comprise less than 10 carbon atoms.
  • Said ionic species are chosen from the group of anions, cations and / or zwitterions.
  • Zwitterion means a species carrying at least one positive charge and at least one negative charge on two non-adjacent atoms.
  • Said ionic species are used alone or as a mixture and preferably in a mixture.
  • the anions are chosen from organic anions.
  • the organic anions comprise less than 10 carbon atoms.
  • the organic anions are chosen from the group consisting of acetate, citrate and succinate.
  • the anions are chosen from anions of mineral origin.
  • the anions of mineral origin are chosen from the group consisting of sulphates, phosphates and halides, especially chlorides.
  • the cations are chosen from organic cations.
  • the organic cations comprise less than 10 carbon atoms.
  • the organic cations are chosen from the group consisting of ammoniums, for example 2-amino-2- (hydroxymethyl) propane-1,3-diol, where the amine is in the form of amines. ammonium.
  • the cations are chosen from cations of mineral origin.
  • the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn 2+ and alkali metals, in particular Na + and K + ,
  • the zwitterions are chosen from zwitterions of organic origin.
  • the zwitterions of organic origin are chosen from amino acids.
  • the amino acids are chosen from aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.
  • the amino acids are chosen from cyclic amino acids in the group consisting of proline.
  • the amino acids are chosen from hydroxylated or sulfur-containing amino acids in the group consisting of cysteine, serine, threonine, and methionine.
  • the amino acids are chosen from aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.
  • the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidated in the group consisting of asparagine and glutamine.
  • the zwitterions of organic origin are selected from the group consisting of amino acids having an uncharged side chain.
  • the zwitterions of organic origin are chosen from the group consisting of aminodiacides or acidic amino acids.
  • the aminodiacides are selected from the group consisting of glutamic acid and aspartic acid, optionally in the form of salts.
  • the zwitterions of organic origin are selected from the group consisting of basic amino acids or so-called "cationic" amino acids.
  • the so-called "cationic" amino acids are chosen from arginine, histidine and lysine, in particular arginine and lysine.
  • the zwitterions comprise as many negative charges as positive charges and therefore a zero overall charge at the isoelectric point and / or at a pH between 6.0 and 8.0.
  • Said ionic species are introduced into the compositions in the form of salts.
  • the introduction of these can be in solid form before dissolution in the compositions, or in the form of a solution, in particular of concentrated solution.
  • the cations of mineral origin are provided in the form of salts chosen from sodium chloride, zinc chloride, sodium phosphate, sodium sulphate, and the like. '
  • anions of organic origin are provided in the form of salts selected from sodium or potassium citrate, sodium acetate.
  • the amino acids are added in the form of salts selected from arginine hydrochloride, histidine hydrochloride or non-salified form such as histidine, arginine.
  • the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 30 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 50 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 75 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 100 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 200 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 600 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1200 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM. [000435] In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 600 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 400 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 200 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 1000 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 500 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 1000 m.
  • the total molar concentration of ionic species in the composition is between 10 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 800 mM
  • the total molar concentration of ionic species in the composition is between 30 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 800 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 200 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 600 mM. [000491] In one embodiment, the total molar concentration of ionic species in the composition is between 50 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 300 m.
  • the total molar concentration of ionic species in the composition is between 100 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 200 m.
  • the total molar concentration of ionic species in the composition is between 20 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 100 mM. [000529] In one embodiment, the total molar concentration of ionic species in the composition is between 20 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 400 mM.
  • said ionic species are present in a concentration ranging from 5 to 300 mM.
  • said ionic species are present in a concentration ranging from 5 to 200 mM.
  • said ionic species are present in a concentration ranging from 5 to 100 mM.
  • said ionic species are present in a concentration ranging from 5 to 75 mM.
  • said ionic species are present in a concentration ranging from 5 to 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 25 mM. [000547] In one embodiment, said ionic species are present in a concentration ranging from 5 to 20 mM.
  • said ionic species are present in a concentration ranging from 5 to 10 mM.
  • said ionic species are present in a concentration ranging from 10 to 400 mM.
  • said ionic species are present in a concentration ranging from 10 to 300 mM.
  • said ionic species are present in a concentration ranging from 10 to 200 mM.
  • said ionic species are present in a concentration ranging from 10 to 100 mM.
  • said ionic species are present in a concentration ranging from 10 to 75 mM.
  • said ionic species are present in a concentration ranging from 10 to 50 mM.
  • said ionic species are present in a concentration ranging from 10 to 25 mM.
  • said ionic species are present in a concentration ranging from 10 to 20 mM.
  • said ionic species are present in a concentration ranging from 20 to 300 mM.
  • said ionic species are present in a concentration ranging from 20 to 200 mM.
  • said ionic species are present in a concentration ranging from 20 to 100 mM.
  • said ionic species are present in a concentration ranging from 20 to 75 mM.
  • said ionic species are present in a concentration ranging from 20 to 50 mM.
  • said ionic species are present in a concentration ranging from 20 to 25 mM.
  • said ionic species are present in a concentration ranging from 50 to 300 mM.
  • said ionic species are present in a concentration ranging from 50 to 200 mM.
  • said ionic species are present in a concentration ranging from 50 to 100 mM. In one embodiment, said ionic species are present in a concentration ranging from 50 to 75 mM.
  • its molar concentration within the composition may be between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.
  • the composition comprises zinc.
  • the composition comprises from 0.2 to 2 mM of zinc.
  • the composition comprises NaCl.
  • the composition comprises from 10 to 250 mM NaCl.
  • the composition comprises from 15 to 200 mM NaCl.
  • the composition comprises from 20 to 150 mM NaCl.
  • the composition comprises from 25 to 100 mM NaCl.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 500 mM per 100 U of insulin.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 400 mM per 100 U of insulin.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 300 ⁇ M per 100 U of insulin.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 200 ⁇ M per 100 U of insulin.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 100 ⁇ M per 100 U of insulin.
  • compositions according to the invention further comprise buffers.
  • compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM. In one embodiment, the compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
  • compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.
  • the buffer is sodium phosphate.
  • the buffer is Tris
  • the buffer is sodium citrate.
  • compositions according to the invention further comprise preservatives.
  • the preservatives are chosen from the group consisting of m-cresol and phenol, alone or as a mixture.
  • the concentration of the preservatives is between 10 and 50 mM
  • the concentration of the preservatives is between 10 and 40 mM.
  • compositions according to the invention further comprise a surfactant.
  • the surfactant is selected from the group consisting of propylene glycol and polysorbate.
  • compositions according to the invention may further comprise additives such as tonicity agents.
  • the tonicity agents are selected from the group consisting of glycerine, sodium chloride, mannitol and glycine.
  • compositions according to the invention may also comprise all the excipients compatible with the pharmacopoeia and compatible with the insulins used at the concentrations of use.
  • the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
  • the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
  • the transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
  • the invention also relates to a pump, implantable or transportable, comprising a composition according to the invention.
  • the invention also relates to the use of a composition according to the invention intended to be placed in a pump, implantable or transportable.
  • the invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention. invention.
  • the invention also relates to single-dose formulations having a pH of between 6.0 and 8.0, comprising amylin, an amylin receptor agonist or amylin analogue, a co-polyamino acid according to the invention. and a GLP-1, a GLP-1 analogue or a GLP-1 RA, as defined above.
  • the invention also relates to single-dose formulations at pH between
  • 6.6 and 7.8 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention.
  • the invention also relates to single-dose formulations at pH between
  • 6.6 and 7.8 comprising amylin, an amylin receptor agonist or an amylin analogue, a co-polyamino acid according to the invention and a mealtime insulin, as defined above.
  • the invention also relates to single-dose formulations at pH between
  • 6.6 and 7.6 comprising amylin, an amylin receptor agonist or an amylin analogue and a co-polyamino acid according to the invention.
  • the invention also relates to single-dose formulations at pH between
  • 6.6 and 7.6 comprising amylin, an amylin receptor agonist or an amylin analogue, a co-polyamino acid according to the invention and a prandial insulin, as defined above.
  • the single-dose formulations further comprise a co-polyamino acid as defined above.
  • the formulations are in the form of an injectable solution.
  • the preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of amylin, an agonist with the amylin receptor or a d-type analogue.
  • amylin, and a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6.0 and 8.0.
  • the preparation of a composition according to the invention has the advantage of being able to be carried out by simple mixing of an aqueous solution of amylin, a agonist at the receptor for amylin or an amylin analogue, prandial insulin, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6.0 and 8.0.
  • the mixture of prandial insulin and co-polyamino acid is concentrated by ultrafiltration.
  • composition of the mixture is adjusted by excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®) by addition of concentrated solutions of these excipients in the mixture.
  • excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®)
  • pH of the preparation is adjusted to pH between 6.0 and 8.0.
  • compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like. of amylin but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.
  • compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like.
  • compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like.
  • amylin in combination with GLP-1, GLP-1 analog or GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.
  • the compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an amylin receptor agonist or the like.
  • amylin in combination with insulin and GLP-1, GLP-1 analogue or GLP-1 receptor agonist, but not comprising a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy.
  • the invention also relates to a use of a co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy for stabilizing a composition comprising amylin, an amylin receptor agonist or an amylin analogue.
  • the invention also relates to a use of a co-polyamino acid bearing carboxylate charges and Hy hydrophobic radicals for stabilizing a composition comprising amylin, an amylin receptor agonist or an amylin analogue. and a mealtime insulin, and optionally a GLP-1, GLP-1 analogue, or GLP-1 receptor agonist.
  • the present invention relates to a composition stabilizing method comprising amylin, an amylin receptor agonist or an amylin analogue or a composition stabilizing method comprising amylin, an agonist at the receptor.
  • amylin or an amylin analogue and prandial insulin and optionally a GLP-1, GLP-1 analogue or GLP-1 receptor agonist
  • Molecule 2 Product obtained by the reaction between molecule 1 and a mixture of DMF / piperidine 80: 20.
  • Molecule 3 Product obtained by the reaction between molecule 2 and Fmoc-Glu (OtBu) -OH.
  • Fmoc-Glu (OtBu) -OH 10.55 g, 24.80 mmol
  • Molecule 4 Product obtained by the reaction between molecule 3 and a DMF / morpholine mixture 50:50.
  • the molecule 3 previously washed with DMF, is treated with a DMF / morpholine mixture 50:50 (60 mL). After stirring for 1 h at room temperature, the resin is filtered, washed successively with DM F (3 x 60 mL), isopropanol (1 x 60 mL) and dichloromethane (3 x 60 mL).
  • Molecule 5 Product obtained by the reaction between molecule 4 and molecule 11.
  • Molecule 6 Product obtained by the reaction between the molecule 5 and a mixture of dichloromethane / 1,1,3,3,3-hexafluoro-2-propanol (HFIP) 80: 20.
  • the molecule 5 is treated with a mixture of dichloromethane / 1, 1, 1,3, 3,3-hexafluoro-2-propanol (HFIP) 80: 20 (60 mL). After stirring for 20 minutes at room temperature, the resin is filtered and washed with dichloromethane (2 ⁇ 60 mL). The solvents are evaporated under reduced pressure. Two coevaporations are then carried out on the residue with dichloromethane (60 ml) and then diisopropyl ether (60 ml). The product is purified by chromatography on silica gel (dichloromethane, methanol). A white solid of molecule 6 is obtained.
  • HFIP 1, 1, 1,3, 3,3-hexafluoro-2-propanol
  • Molecule 7 Product obtained by the reaction between molecule 6 and N-Boc ethylenediamine.
  • the organic phase is diluted with dichloromethane (30 ml) and washed with a saturated aqueous solution of NH 4 Cl (2 ⁇ 20 ml), a saturated aqueous solution of NaHCO 3 (2 ⁇ 20 ml), and a saturated aqueous solution of NaCl. (2 x 20 mL).
  • the organic phase is dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • a white solid of the molecule 7 is obtained after recrystallization in acetonitrile.
  • Example A2 Molecule A2 Molecule 8 Product obtained by the coupling between myristic acid and methyl L-glutamate.
  • the medium is stirred for 48 h while raising the temperature to room temperature, filtered through sinter and then added to a solution of methyl L-glutamate (24.95 g, 154.79 mmol) and N, N- diisopropylethylamine (DIPEA, 99.0 g, 766.28 mmol) in water (30 mL).
  • DIPEA N, N- diisopropylethylamine
  • the reaction mixture is stirred at 20 ° C for 48 h and then concentrated under reduced pressure. Water (200 mL) is added and the resulting mixture is treated by successive addition of ethyl acetate (AcOEt, 100 mL) and then an aqueous solution of 5% CO 2 (5 mL) (50 mL).
  • aqueous phase is then washed once again with AcOEt (100 mL), acidified by adding 10% aqueous HCl solution and the product is extracted with dichloromethane (DCM, 3 x 150 mL).
  • DCM dichloromethane
  • the organic phase is dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. A white solid of molecule 8 is obtained.
  • Molecule 9 1 Product obtained by the coupling between molecule 8 and methyl L-glutamate.
  • Molecule 10 Product obtained by the coupling between the molecule 9 and N-Boc ethylenediamine.
  • the organic phase is washed with a saturated aqueous solution of NaHCOa (2 x 300 mL), an aqueous solution of 1N HCl (2 x 300 mL), a saturated aqueous solution of NaCl (500 mL). Methanol (40 mL) is added, the organic phase is dried over Na 2 SO 4 , filtered and concentrated under reduced pressure. A white solid of the molecule 10 is obtained after recrystallization from acetonitrile.
  • Molecule 1 1 Product obtained by the reaction between myristoyl chloride and L-proline.
  • Molecule 12 Product obtained by the coupling between molecule 11 and methyl L-glutamate.
  • Molecule 13 1 Product obtained by the coupling between molecule 12 and N-Boc ethylenediamine.
  • Molecule 15 Product obtained by the coupling between molecule 14 and methyl L-glutamate.
  • Molecule 16 Product obtained by the coupling between the molecule 15 and N-Boc ethylenediamine.
  • Molecule 17 i Product obtained by the reaction between 1-amino-4,7,10-trioxa-13-tridecane amine and tert-butylphenylcarbonate.
  • the aqueous phase is basified to pH 12.6 by addition of a 2N NaOH solution and extracted with DCM (3 x 250 mL).
  • the organic phase is washed with an aqueous solution of 1N NaOH (1 x 100 mL), a saturated aqueous solution of NaCl (100 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • a yellow oil of molecule 17 is obtained.
  • Molecule 18 Product obtained by the coupling between the molecule 12 and the molecule 17.
  • Molecule 21 Product obtained by coupling between the molecule 11 and L-lysine.
  • Molecule 22 Product obtained by coupling between the molecule 21 and methyl ⁇ -Boc-L-lysinate. [000646] By a method similar to that used for the preparation of the molecule 10 applied to molecule 21 (43.00 g, 56.50 mmol) in solution in THF and / V-Boc-L-lysinate hydrochloride of methyl (20.12 g, 67.79 mmol), a transparent solid of molecule 22 is obtained and used without further purification. Yield: 55.80 g (98%)
  • Molecule 23 Product obtained by saponification of the molecule 23.
  • a solution of molecule 22 (55.80 g, 55.61 mmol) in a 1: 1 THF / water mixture (370 mL) at 0 ° C. is treated by slow addition of a solution of LiOH (2, 00 g, 83.41 mmol) in water (185 mL). After stirring for 16 h at 0 ° C., the medium is concentrated under reduced pressure and the residue is taken up in water (500 mL). DCM (500 mL) is added, the heterogeneous mixture is cooled to 10 ° C and acidified by adding 10% aqueous HCl solution to pH 1.
  • aqueous phase is extracted with DCM (2 x 300 mL) the combined organic phases are washed with a saturated aqueous solution of NaCl (2 x 300 mL), dried over NaaSC, filtered and concentrated under reduced pressure.
  • a white solid of molecule 23 is obtained after crystallization in acetone.
  • Molecule 3a Product obtained by the reaction between Fmoc-Lys (Fmoc) -OH and 2-CI-trityl chloride resin.
  • Molecule 4a Product obtained by reaction between the molecule 3a and a mixture of DMF / piperidine 80: 20.
  • the molecule 3a previously washed with DMF, is treated with a mixture of DMF / piperidine 80:20 (60 mL). After 30 minutes stirring at room temperature, the resin is filtered, washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and DCM (3 x 60 mL).
  • Molecule 5a Product obtained by reaction between the molecule 4a and 8- (9-fluorenylmethyloxycarbonylamino) -3,6-dioxaoctanoic acid (Fmoc-020c-OH).
  • the molecule 6a is obtained.
  • Molecule 7a Product obtained by reaction between the molecule 6a and lauric acid.
  • Molecule Sa Product obtained by reaction between the molecule 7a and a mixture of dichloromethane / 1,1,3,3,3-hexafluoro-2-propanol (HFIP) 80: 20.
  • the molecule 7a is treated with a mixture of dichloromethane / 1, 1, 1,3, 3, 3-hexafluoro-2-propanol (HFIP) 80: 20 (60 mL). After stirring for 20 minutes at room temperature, the resin is filtered and washed with dichloromethane (2 ⁇ 60 mL). The solvents are evaporated under reduced pressure. Two coevaporations are then carried out on the residue with dichloromethane (60 ml) and then diisopropyl ether (60 ml). A white solid of molecule 8a is obtained after recrystallization in acetonitrile.
  • HFIP 1-hexafluoro-2-propanol

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EP18815677.2A 2017-12-07 2018-12-07 Zusammensetzungen in form einer injizierbaren wässrigen lösung mit amylin, einem amylin-rezeptor-agonist oder einem amylin-analogon und einer copolyaminosäure Pending EP3740227A1 (de)

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US201762606139P 2017-12-07 2017-12-07
FR1761808A FR3074682B1 (fr) 2017-12-07 2017-12-07 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 co-polyaminoacide
FR1855943A FR3083085B1 (fr) 2018-06-29 2018-06-29 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 co-polyaminoacide
PCT/EP2018/083943 WO2019110788A1 (fr) 2017-12-07 2018-12-07 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 co-polyaminoacide

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CN111836616B (zh) 2017-12-07 2024-01-16 阿道恰公司 包含至少一种pi在5.8与8.5之间的基础胰岛素和带有羧酸根电荷及疏水基的共聚氨基酸的ph 7为7的可注射溶液
MA51597A (fr) 2017-12-07 2020-11-25 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes
EP3858373A1 (de) 2020-01-31 2021-08-04 Adocia Zusammensetzungen mit mindestens einem amylin-rezeptor-agonisten und einem glp-1-rezeptor-agonisten
EP4129324A1 (de) 2021-08-02 2023-02-08 Adocia Zusammensetzungen mit mindestens einem amylin-rezeptor-agonisten und einem glp-1-rezeptor-agonisten

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BR112014016889A8 (pt) * 2012-01-09 2017-07-04 Adocia composição sob a forma de uma solução aquosa injetável, sujo ph está compreendido entre 6,0 e 8,0 e, formulação de dose unitária com ph compreendido entre 7 e 7,8
FR2985428B1 (fr) 2012-01-09 2016-05-27 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un polyaminoacide substitue
FR3001896B1 (fr) * 2013-02-12 2015-07-03 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le point isolectrique est compris entre 5,8 et 8,5 et un polymere anionique hydrophobise
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KR20190026748A (ko) 2016-06-07 2019-03-13 아도시아 인간 글루카곤 및 말단-그래프트된 코폴리아미노산을 포함하는 주사가능한 수용액 형태의 조성물
FR3052072A1 (fr) 2016-06-07 2017-12-08 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes
US10463717B2 (en) 2016-12-27 2019-11-05 Adocia Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog, and a co-polyamino acid
MA51597A (fr) * 2017-12-07 2020-11-25 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes

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