Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/26—Glucagons
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
  • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
  • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
  • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
  • A61K47/645—Polycationic or polyanionic oligopeptides, polypeptides or polyamino acids, e.g. polylysine, polyarginine, polyglutamic acid or peptide TAT
  • A61K47/6455—Polycationic oligopeptides, polypeptides or polyamino acids, e.g. for complexing nucleic acids
• • 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
• • 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

Definitions

• the invention relates to therapies by injection of amylin, amylin receptor agonist or amylin analog to treat 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 agonist at the amylin receptor or a amylin analog and an amphiphilic compound comprising a hydrophilic HB skeleton carrying 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 amphiphilic compounds comprising a hydrophilic HB backbone carrying hydrophobic radicals according to the invention for stabilizing compositions of amylin, of amylin receptor agonist or analog of amylin as well as compositions of amylin, amylin receptor agonist or amylin analog further comprising an insulin.
• the composition according to the invention does not include basal insulin whose isoelectric point pi is between 5.8 and 8.5, and in particular no insulin glargine.
• Type 1 diabetes is an autoimmune disease leading to the destruction of beta cells in the pancreas. These cells are known to produce insulin, the main role of which is to regulate the use of glucose in peripheral tissues (Gerich 1993 Control of glycaemia). Consequently, patients with type 1 diabetes suffer from chronic hyperglycemia and must administer exogenous insulin in order to limit this hyperglycemia. Insulin therapy has drastically changed the life expectancy of these patients. However, the glycemic control provided by exogenous insulin is not optimal, especially after taking a meal. This is related to the fact that these patients produce glucagon after taking a meal, which leads to the destocking of part of the glucose stored in the liver, which is not the case in the healthy person. This glucagon-mediated glucose production exacerbates the problem of regulating blood sugar in these patients.
• Amylin another hormone produced by beta cells in the pancreas and therefore also deficient in type 1 diabetic patients, plays a key role in the regulation of postprandial blood sugar.
• Amylin also known as the "islet amyloid polypeptide" 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 the alpha cells of the pancreas.
• Human amylin has properties which are not compatible with pharmaceutical requirements in terms of solubility and stability (Goldsbury CS, Cooper GJ, Goldie KM, Muller SA, Saafi EL, Gruijters WT, Misur MP, Engel A , Aebi U, Kistler J: Polymorphie fibrillar assembly of human amylin. J Struct Biol 119: 17-27, 1997).
• Amylin is known to form amyloid fibers which lead to the formation of plaques which are insoluble in water. Although being the natural hormone, it was necessary to develop an analog in order to solve these solubility problems.
• amylin is only stable for about fifteen minutes at acidic pH, and less than a minute at neutral pH.
• Amylin has developed an analogue of amylin, pramlintide, to overcome the lack of stability of human amylin.
• This product marketed under the name of 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, within one hour before a meal. improve post-meal glucose control.
• This peptide is formulated at acidic pH and is described to fibrillate when the pH of the solution is above 5.5. Variants of analogs are described in US Patent 5,686,411.
• Patent application W02013067022 from the company XERIS provides a solution to the problem of the stability of amylin and its compatibility with insulin by using an organic solvent instead of water.
• the absence of water seems to solve the stability problems but the use of an organic solvent poses safety problems of chronic use for diabetic patients and also problems of compatibility with the usual medical devices, at the level of the tubes. , seals and plasticizers used.
• a conventional method for measuring the stability of proteins or peptides consists in measuring the formation of fibrils using Thioflavin T, also called ThT. This method makes it possible to measure, under temperature and stirring conditions which allow the phenomenon to accelerate, the lag time before the formation of fibrils by measuring the increase in fluorescence.
• the compositions according to the invention have a latency time before the formation of fibrils significantly greater than that of amylin, of an agonist at the amylin receptor or of an amylin analog at the pH of interest.
• the present invention aims to provide new amphiphilic compounds comprising a hydrophilic HB backbone comprising one or more hydrophobic grafts, said grafts comprising one or more imidazole radicals.
• modular association is meant that the association of said HB hydrophilic skeleton with amylin, an agonist at the amylin receptor or an amylin analog may be more or less strong depending on the environment of said amphiphilic compound.
• the invention thus relates to a composition, in the form of an injectable solution, comprising:
• amylin an amylin receptor agonist or an amylin analog, at least one ionic species, and
• amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I.
• the invention thus relates to a composition, in the form of an injectable solution, comprising:
• amylin an agonist at the amylin receptor or an amylin analog, at least one ionic species, in particular an at least divalent cation salt, and an amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I.
• the invention thus relates to a composition, in the form of an injectable solution, comprising:
• amylin an amylin receptor agonist or an amylin analog, at least one ionic species, and
• amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy of formula I below: in which,
• Gpl is a divalent radical, said radical comprising at least one imidazole Im unit of formula III:
• GpR is a radical of formulas II, IG or II ":
• GpC is a radical of formula IV:
• the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, IG, II ", III and IV) between them by amide functions;
• - a, b and g are identical or different integers equal to 0 or 1;
• b is an integer equal to 0 or 1;
• c is an integer equal to 0 or 1;
• d is an integer equal to 0, 1 or 2; and if c is equal to 0 then d is equal to 1 or 2;
• e is an integer equal to 0 or 1;
• i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 ⁇ i + i ' ⁇ 6,
• r and r ' are integers equal to 0, 1, 2 or 3;
• the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction d an amine function of the precursor of the hydrophilic backbone HB and an acid function carried by the precursor of the hydrophobic radical, and
• hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:
• t is an integer equal to 0 or 1;
• Cx is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and l l £ x ⁇ 25;
• G, I "and G”, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms, I is a trivalent radical, chosen from the group consisting of an linear or branched alkyl radical comprising from 1 to 12 carbon atoms,
• Im is an imidazolyl radical
• 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 branched alkyl radical from 1 to 8 carbon atoms, said alkyl radical carrying one or more acid function (s) free carboxylic, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions - CON H2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 carbon atoms oxygen, said free carboxylic acid functions being in the form of alkaline cation salts chosen from the group consisting of Na + and K + , and
• the invention relates to a stable composition as defined above, characterized in that the hydrophobic radical -Hy is chosen from the radicals of formula I:
• Gpl is a divalent radical, said radical comprising at least one imidazole Im unit of formula III:
• the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, IG, II ", III and IV) between them by amide functions;
• - a, b and g are identical or different integers equal to 0 or 1;
• c is an integer equal to 0 or 1;
• d is an integer equal to 0, 1 or 2; and if c is equal to 0 then d is equal to 1 or to
• e is an integer equal to 0 or 1;
• i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 ⁇ i + i ' ⁇ 6,
• r and r ' are integers equal to 0, 1, 2 or 3;
• the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction d an amine function of the precursor of the hydrophilic backbone HB and an acid function carried by the precursor of the hydrophobic radical, and
• hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:
• t is an integer equal to 0 or 1;
• B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen 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 ll £ x ⁇ 25;
• G, I "and G”, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms,
• Gpl is a divalent radical, said radical comprising at least one imidazole Im unit of formula III:
• GpR is a radical of formulas II, IG or II ":
• GpC is a radical of formula IV:
• the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, IG, II ", III and IV) between them by amide functions;
• - a, b and g are identical or different integers equal to 0 or 1;
• b is an integer equal to 0 or 1;
• c is an integer equal to 0 or 1;
• i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 ⁇ i + i ' ⁇ 6,
• r and r ' are integers equal to 0, 1, 2 or 3;
• the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction d an amine function of the precursor of the hydrophilic backbone HB and an acid function carried by the precursor of the hydrophobic radical, and
• hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:
• t is an integer equal to 0 or 1;
• B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen 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 l l £ x ⁇ 25;
• G, I "and G”, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms,
• I is a trivalent radical, chosen from the group consisting of an linear or branched alkyl radical comprising from 1 to 12 carbon atoms,
• Im is an imidazolyl radical
• R is a radical chosen from the group consisting of a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s), said free carboxylic acid functions being in the form of selected alkali cation salts in the group consisting of Na + and K + , and when several hydrophobic radicals are carried by a hydrophilic skeleton HB then they are identical or different.
• 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 50 and 60 carbon atoms.
• composition according to the invention is characterized in that Hy comprises between 20 and 40 carbon atoms. In one embodiment, the composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms.
• composition according to the invention is characterized in that Hy comprises between 30 and 40 carbon atoms.
• Hy comprises more than 15 carbon atoms.
• Hy comprises more than 30 carbon atoms.
• the composition is characterized in that the pH is between 6.0 and 8.0.
• 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 GpR group linked to the hydrophilic skeleton HB is chosen from the GpRs of formula II.
• the GpR group linked to the hydrophilic skeleton HB is chosen from the GpRs of formula II and the second GpR is chosen from the GpRs of formula II ".
• the GpR group linked to the hydrophilic skeleton HB is chosen from the GpRs of formula II ".
• GpR, Gpl, GpC, r and i have the definitions given above.
• GpR, Gpl, GpC, R and i have the definitions given above.
• GpRi is a radical of formula II ".
• GpR, Gpl, GpC, R and i have the definitions given above.
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Ilia formulas:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of formulas IIIc:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Illd formulas:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Illf formulas:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Illg formulas:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Illh formulas:
• said at least one hydrophobic radical -Hy is chosen from the radicals of formula I, la, Ib, le, Id, le or If in which the radical of formula III is chosen from the radicals of Illi formulas:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is an alkyl radical divalent comprising from 2 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is an alkyl radical divalent linear comprising from 2 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is a radical divalent alkyl comprising from 2 to 4 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is an alkyl radical divalent linear comprising from 2 to 4 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is an alkyl radical divalent comprising 2 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula IG.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula 11 in which R is an alkyl radical divalent linear comprising from 2 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula IG in which R is an alkyl radical divalent comprising from 2 to 4 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula IG in which R is an alkyl radical divalent comprising 2 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II ".
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a radical divalent linear alkyl comprising from 2 to 12 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a radical divalent alkyl comprising from 2 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a radical divalent linear alkyl comprising from 2 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a radical divalent linear alkyl comprising from 2 to 4 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II "in which R is a radical divalent alkyl comprising 2 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, IG or II ", in which R is a linear ether or unsubstituted 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 is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, IG or II ", in which R is an ether radical.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, IG or II ", in which R is an ether radical comprising from 4 to 6 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II, IG or II "in which R is an ether radical represented by the formula
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II or IG, in which R is a polyether radical.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II or IG, 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 formula I, la, Ib, Id or le in which GpR is a radical of formula II or IG, in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, Id or le in which GpR is a radical of formula II in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II "in which R is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II "in which R is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical branched alkyl of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical branched alkyl of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG in which R is a radical branched alkyl of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG in which R is a radical branched alkyl of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II "in which R is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II "in which R is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II "in which R is a branched alkyl radical of 1 to 6 carbon atoms, said alkyl radical carrying a free carboxylic acid function.
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II "in which R is a branched alkyl radical of 1 to 6 carbon atoms, said alkyl radical carrying a free carboxylic acid function.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical branched alkyl of 1 to 6 carbon atoms, said alkyl radical carrying a free carboxylic acid function.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG in which R is a radical branched alkyl of 1 to 6 carbon atoms, said alkyl radical carrying a free carboxylic acid function.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II "in which R is a branched alkyl radical of 1 to 6 carbon atoms, said alkyl radical carrying a free carboxylic acid function.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, in which R is an alkyl radical comprising 5 carbon atoms and carrying a free carboxylic acid function represented by the formula Z below:
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II in which R is a radical of formula Z whose precursor is lysine.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG, in which R is an alkyl radical comprising 3 carbon atoms and carrying a free carboxylic acid function represented by the formula Z 'below:
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG in which R is a radical of formula Z 'whose precursor is glutamic acid.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II ′, in which R is an alkyl radical comprising 2 carbon atoms and carrying a free carboxylic acid function represented by the formula Z "below:
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula IG in which R is a radical of formula Z "whose precursor is aspartic acid.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II ", in which R is an alkyl radical comprising 5 carbon atoms represented by - (CH2) 4-CH (COOH) -.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II ", in which R is an alkyl radical comprising 3 carbon atoms represented by - (CH 2 ) 2 -CH (COOH) -.
• the composition is characterized in that the hydrophobic radical of formula I, la, Ib, le, Id or le in which GpR is a radical of formula II, IG or II ", in which R is an alkyl radical comprising 2 carbon atoms represented by -CH2-CH (COOH).
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals of formulas IVe, IVf or IVg below represented:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical is of formula IVe.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals of formulas IVe, IVf or IVg in which b is equal to 0, corresponding respectively to the formulas
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of linear alkyl radicals.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals in which Cx is chosen from the group consisting of branched alkyl radicals.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of alkyl radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id, le or If in which the GpC radical of formula IV is chosen from the group consisting of the radicals in which Cx is chosen from the group consisting of alkyl radicals represented by the formulas below:
• the composition is characterized in that the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which a GpR is a radical of formula II, R is a radical of formula Z, Gpl is a radical of formula Ilia and GpC is a radical of formula IVh.
• the hydrophobic radical is a radical of formula I, la, Ib, le, Id or le in which a GpR is a radical of formula II, R is a radical of formula Z, Gpl is a radical of formula Ilia and GpC is a radical of formula IVh.
• Ri is a radical of Formula Z and R2 is a radical of formula Z 'or Z "
• i 2
• identical Gpli and Gph are radicals of formula Ilia
• GpC is a radical of formula IVh.
• GpRi is a radical of formula II
• Ri is a alkyl radical comprising 2 to 12 carbon atoms
• GpR ⁇ and GpR3 identical or different are radicals of formula IG
• R2 and R3 identical or different are radicals chosen from the formulas Z
• GpRi is a radical of formula II and Ri is a alkyl radical comprising 2 to 12 carbon atoms
• GpR2 and optionally GpR3 are radicals of formula IG
• identical Gpli and Gph are radicals
• the composition is characterized in that the precursor of the hydrophilic skeleton HB carrying at least one hydrophobic radical is a polymer whose repeating units are chosen from the group of lysine, the acid glutamic, aspartic acid, and ethers, including ethylene glycol and propylene glycol.
• - Ri is a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl, a unit " amino acid "terminal and a pyroglutamate,
• n> 1 - n + m represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 ⁇ n + m ⁇ 250 and
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe in which R2 is a radical hydrophobic -Hy, and Ri is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXe in which Ri and R2 are identical or different hydrophobic -Hy radicals.
• n, X, D, Ri and R2 have the definitions given above.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXf in which R2 is a radical hydrophobic -Hy, and Ri is not a hydrophobic radical -Hy.
• composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa below:
• Ra and R 'a are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of an H, a linear C2 to Cio acyl group, a branched C3 to Cio acyl group, a benzyl , a terminal "amino acid” unit and a pyroglutamate,
• Ra and R'a being a hydrophobic radical -Hy
• Q being a spacer linking at least two chains of glutamic or aspartic units
• k is 2, 3, 4, 5 or 6.
• F c , F c ⁇ and F C " are 1 -NH- and 2 -CO- then no conditions. In one embodiment, if Fc, F C ' and F C " are -CO- then at least one of v, v' and v" is different from 0.
• the at least two chains of PLG glutamic or aspartic units being linked to Q [- *] i ⁇ by a function F x or F y by a covalent bond to form an amide bond with a function -NH- or - CO- of PLG.
• At least one of the Q ' is a radical of formula
• t q 2 and the precursor of the radical of formula QUI is ethylenediamine.
• tq 4 and the precursor of the radical of formula QUI is butylenediamine.
• t q 6 and the precursor of the radical of formula QIII is hexylenediamine.
• the precursor of the radical of formula QUI is an amino acid.
• the precursor of the radical of formula QUI is an amino acid chosen from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.
• t q 2 and and the precursor of the radical of formula QUI is beta-alanine.
• III is aminohexanoic acid.
• t q 4 and the precursor of the radical of formula QUI is aminobutanoic acid
• the precursor of the radical of formula QUI is a diacid.
• t q 4 and the precursor of the radical of formula QUI is adipic acid.
• the precursor of the radical of formula QIV is a diamine chosen from the group consisting of diethylene glycol diamine, triethylene glycol diamine, 4,9-dioxa- l, 12-dodecanediamine and l-amino -4,7,10- trioxa-13-tridecanamine. In one embodiment, and the precursor of the radical of formula QIV is diethylene glycol diamine.
• precursor of the radical of formula QIV is 4.7, 10-trioxa-1,13-tridecanediamine.
• at least one of the Q ′ is a radical of formula QV,
• the precursor of the radical of formula QV is an amino acid chosen from the group consisting of lysine, ornithine, 2,3-diaminopropionic acid.
• the precursor of the radical of formula V is 2,3-diaminopropionic acid.
• the precursor of which is chosen from the group consisting of triacids.
• the precursor of the radical of formula QV is a triacid chosen from the group consisting of tricarballylic acid.
• At least one of the Q ' is a radical of formula
• w "a 0 and the precursor of the radical of formula QVI is a triamine chosen from the group consisting of spermidi ne, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.
• w 0 and the precursor of the radical of formula QVI is spermidine.
• w "2 0 and the precursor of the radical of formula QVI is norspermidine.
• At least one of the Q ' is a radical of formula
• w 1 and the precursor of the radical of formula QVI is a tetramine.
• ⁇ N "I 1 and the precursor of the radical of formula QVI is a tetramine chosen from the group consisting of spermine and triethylenetetramine.
• w 1 and the precursor of the radical of formula QVI is spermine.
• w 1 and the precursor of the radical of formula QVI is triethylenetetramine.
• the precursor of the radical or spacer Q [- *] k has 4 reactive functions, chosen from the group of amine functions and carboxylic acid functions.
• the precursor of the radical or spacer Q [- *] k has 4 reactive functions and the precursor of the radical or spacer Q [- *] k is 1,2,3,4-butanetetraic acid .
• At least one of the Q ' is a radical of formula
• ⁇ N "I 0 and the precursor of the radical of formula QVI 'is a triamine chosen from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.
• w "2 0 and the precursor of the radical of formula QVI 'is spermidine.
• w "2 0 and the precursor of the radical of formula QVI 'is norspermidine.
• w "2 0 and the precursor of the radical of formula
• At least one of the Q ' is a radical of formula QVI'
• w "2 1 and the precursor of the radical of formula QVI 'is a tetramine.
• w "2 1 and the precursor of the radical of formula
• QVI ' is a tetramine chosen from the group consisting of spermine and triethylenetetramine.
• w "2 1 and the precursor of the radical of formula QVI 'is spermine.
• w "i 1 and the precursor of the radical of formula
• one or more Fx are free, that is to say are not linked to the PLG, or to another F x , or to an F Y.
• an F x is free, that is to say is not linked to the PLG, or to another F x , or to an Fy.
• the (s) F x of -CO- type is free, it is in the form of the carboxylic acid salt.
• the free F x -CO- type is carried by a radical Q 'of Formula QV.
• the ( x ) F x -NH type is free, it is in the form of amine or ammonium.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R a and R ' a , identical are a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R a and R ' a, different are hydrophobic radicals -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R a is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa in which R'a is a hydrophobic radical -Hy, and R a is not a hydrophobic radical -Hy.
• composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'below:
• ni + mi represents the number of glutamic units or aspartic units of the chains of the co-polyamino acid carrying a radical -Hy,
• n2 + nri2 represents the number of glutamic units or aspartic units of the co-polyamino acid chains not carrying a -Hy radical
• n '+ m' represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 ⁇ n '+ m' ⁇ 250.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R 'a, identical are a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra and R 'a, different are hydrophobic radicals -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below:
• Rb and R'b are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid” unit and a pyroglutamate,
• Rb and R'b is a hydrophobic radical -Hy
• n + m has the same definition as given above.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb and R ' b, identical are a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb and R ' b, different are hydrophobic radicals -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which Rb is a radical hydrophobic -Hy and R'b is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'below:
• Rb and R'b are either a hydrophobic radical -Hy, or a radical chosen from the group consisting of -OH, an amine group, a unit
• Rb and R'b is a hydrophobic radical -Hy
• ni + mi represents the number of glutamic units or aspartic units of the chains of the co-polyamino acid carrying a radical -Hy,
• n2 + m2 represents the number of glutamic units or aspartic units of the co-polyamino acid chains not carrying a -Hy radical
• n '+ m' represents the degree of polymerization DP of the co-polyamino acid, that is to say the average number of monomeric units per chain of co-polyamino acid and 5 ⁇ n '+ m' ⁇ 250.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R 'b, identical are a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R 'b, different are hydrophobic radicals -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that the co-polyamino acid carrying at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
• the composition according to the invention is characterized in that when the co-polyamino acids comprises aspartate units, then the co-polyamino acids may also comprise monomeric units of formula VIII and / or VIII ' :
• the composition is characterized in that the co-polyamino acid carrying hydrophobic radicals is chosen from the co-polyamino acids of formulas XXX, XXXe, XXXf, XXXa, XXXb, XXXa 'or XXXb' in which group D is a group -CH2-CH2- (glutamic unit).
• the composition is characterized in that the co-polyamino acid carrying carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXX, XXXa, XXXb, XXXe, XXXf, XXXa ', XXXb 'in which group D is a group -CH2- (aspartic unit).
• composition according to the invention is characterized in that the hydrophilic skeleton HB is a polylysine carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polylysines of formula XXXX below:
• Ri is a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of a -H or a terminal "amino acid" unit,
• R2 is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of an -OH, an amine group or a terminal "amino acid" unit,
• said polylysine comprises at least one hydrophobic radical -Hy as defined above,
• - n + m represents the degree of polymerization DP of the polylysine, that is to say the average number of monomeric units per polylysine chain and 5 ⁇ n + m ⁇ 250 and
• the composition according to the invention is characterized in that the hydrophilic backbone HB is a polylysine carrying at least one radical hydrophobic and said hydrophilic skeleton is chosen from the polylysines of formula XXXXa below
• Ri, R, Hy, m and n have the meanings given above.
• composition according to the invention is characterized in that n + m is between 10 and 200.
• 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 65.
• composition according to the invention is characterized in that n + m is between 20 and 50.
• composition according to the invention is characterized in that n + m is between 20 and 40.
• Ri is a hydrophobic radical chosen from hydrophobic Hy radicals, or a radical chosen from the group consisting of -H or -OH,
• R2 is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical chosen from the group consisting of -OH or -H,
• Ri or R2 is a hydrophobic radical -Hy
• - pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 ⁇ n + m ⁇ 250.
• the composition according to the invention is characterized in that the hydrophilic skeleton HB is a polyalkylene glycol carrying hydrophobic radicals and said hydrophilic skeleton is chosen from the polyalkylene glycols of formula XXXXXb below
• Ri is a hydrophobic radical chosen from the hydrophobic radicals Hy, or a radical -OH,
• R2 is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical -H,
• Ri or R2 is a hydrophobic radical -Hy
• - pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per polyalkylene glycol chain and 5 ⁇ n + m
• the composition according to the invention is characterized in that the hydrophilic backbone HB is a polyalkylene glycol carrying radicals hydrophobic and said hydrophilic skeleton is chosen from the polyalkylene glycols of formula XXXXXc below
• - Ri is a hydrophobic radical chosen from hydrophobic radicals Hy, or a radical
• R.2 is either a hydrophobic radical chosen from hydrophobic radicals -Hy, or a radical -OH,
• - pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per chain of polyalkylene glycol and 5 ⁇ n + m ⁇ 250.
• the precursors of the polyalkylene glycols of formula XXXXa, XXXXXb or XXXXXc are chosen from the polyalkylene glycols of formulas XXXXX'a, XXXXX'b or XXXXX'c below:
• pn represents the degree of polymerization DP of the polyalkylene glycol, that is to say the average number of monomeric units per polyalkylene glycol chain and
• composition according to the invention is characterized in that pn is between 10 and 250.
• composition according to the invention is characterized in that pn is between 10 and 200.
• composition according to the invention is characterized in that pn is between 15 and 150.
• composition according to the invention is characterized in that pn is between 15 and 100.
• composition according to the invention is characterized in that pn is between 15 and 80.
• composition according to the invention is characterized in that pn is between 15 and 65.
• composition according to the invention is characterized in that pn is between 20 and 60.
• composition according to the invention is characterized in that pn is between 20 and 50.
• composition according to the invention is characterized in that pn is between 20 and 40.
• the invention also relates to said amphiphilic compounds comprising a hydrophilic backbone HB carrying hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.
• the invention also relates to amphiphilic compounds comprising a hydrophilic backbone HB, substituted by at least one hydrophobic -Hy radical of formula I:
• Gpl is a divalent radical, said radical comprising at least one imidazole Im unit of formula III:
• GpR is a radical of formulas II, IG or II ":
• GpC is a radical of formula IV:
• the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, IG, II ", III and IV) between them by amide functions;
• a, b and g are identical or different integers equal to 0 or 1;
• b is an integer equal to 0 or 1;
• c is an integer equal to 0 or 1;
• d is an integer equal to 0, 1 or 2; and if c is equal to 0 then d is equal to 1 or to
• e is an integer equal to 0 or 1;
• i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 ⁇ i + i ' ⁇ 6,
• r and r ' are integers equal to 0, 1, 2 or 3;
• the hydrophobic radical of formula I is linked to the hydrophilic backbone HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction of an amine function of the precursor of the hydrophilic skeleton HB and an acid function carried by the precursor of the hydrophobic radical, and
• hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:
• t is an integer equal to 0 or 1;
• B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen 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 ll £ x ⁇ 25;
• I "and Y”, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms,
• 1 is a trivalent radical, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms
• 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 branched alkyl radical from 1 to 8 carbon atoms, said alkyl radical carrying one or more acid function (s) free carboxylic, a divalent, linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -
• CONH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms, said acid functions free carboxylic being in the form of alkaline cation salts chosen from the group consisting of Na + and K + , and
• hydrophobic radicals when several hydrophobic radicals are carried by a hydrophilic HB backbone then they are identical or different.
• the invention also relates to the precusers Hy 'of hydrophobic radicals -Hy of formula G as defined below:
• - Gpl is a divalent radical, said radical comprising at least one imidazole Im unit of formula III:
• - GpR is a radical of formulas II, IG or II ":
• - GpC is a radical of formula IV:
• the * indicate the sites of attachment of the hydrophobic radical -Hy to the hydrophilic skeleton HB or the above radicals (I, II, IG, II ", III and IV) between them by amide functions;
• - a, b and y are identical or different integers equal to 0 or 1;
• - b is an integer equal to 0 or 1;
• - c is an integer equal to 0 or 1;
• - d is an integer equal to O, 1 or 2; and if c is equal to O then d is equal to 1 or to
• - e is an integer equal to 0 or 1;
• - i and i 'identical or different are integers less than or equal to 6 and i + i' is greater than or equal to 1 and less than or equal to 6, 1 ⁇ i + i ' ⁇ 6,
• the hydrophobic radical of formula I is linked to the hydrophilic skeleton HB via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom of the hydrophilic skeleton HB, thus forming an amide function resulting from the reaction an amine function of the precursor of the hydrophilic skeleton HB and an acid function carried by the precursor of the hydrophobic radical, and
• hydrophobic radical -Hy of formula I is linked to the hydrophilic skeleton HB:
• - t is an integer equal to 0 or 1;
• - B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen 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 ll £ x ⁇ 25;
• I "and G”, identical or different, are divalent radicals, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms,
• - I is a radical t riv, chosen from the group consisting of an alkyl radical, linear or branched comprising from 1 to 12 carbon atoms - Im is an imidazolyl radical,
• - 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 branched alkyl radical from 1 to 8 carbon atoms, said alkyl radical carrying one or more function (s) free carboxylic acid, 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 atoms oxygen, said free carboxylic acid functions being in the form of alkaline cation salts chosen from the group consisting of Na + and K + , and
• hydrophobic radicals when several hydrophobic radicals are carried by a hydrophilic HB backbone then they are identical or different.
• the invention also relates to the use of ionic species to improve the physico-chemical stability of the compositions.
• Amphiphilic compounds comprising a hydrophilic backbone HB carrying hydrophobic radicals of formula I are soluble in distilled water at a pH between 6 and 8, at a temperature of 25 ° C and at a concentration of less than 100 mg / ml.
• the invention further relates to a method for preparing stable injectable compositions.
• soluble is intended to make it possible to prepare a clear solution devoid of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
• solution is understood to mean a liquid composition devoid of visible particles, using the procedure in accordance with pharmacopoeias EP 8.0, in point 2.9.20, and US ⁇ 790>.
• compositions which, after a certain period of storage at a certain temperature, satisfy the criteria of visual inspection described in the European, American and international pharmacopoeia, that is to say, compositions which are clear and which contain no visible particles, but which are also colorless.
• compositions which, after storage for a certain time and at a certain temperature, have a minimum recovery of the active ingredients and comply with the specifications applicable to pharmaceutical products.
• a conventional method for measuring the stabilities of proteins or peptides consists in measuring the formation of fibrils using Thioflavin T, again called ThT. This method makes it possible to measure, under temperature and stirring conditions which allow the phenomenon to accelerate, the lag time before the formation of fibrils by measuring the increase in fluorescence.
• the compositions according to the invention have a latency time before the formation of fibrils significantly greater than that of gllucagon at the pH of interest.
• aqueous injectable solution is understood to mean water-based solutions which meet the conditions of the EP and US pharmacopoeias, and which are sufficiently liquid to be injected.
• co-polyamino acid consisting of glutamic or aspartic units is understood to mean non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a terminal C part, corresponding to the carboxylic acid at one end, and an N-terminal part, corresponding to the amine at the other end of the chain.
• alkyl radical means a carbon chain, linear or branched, which does not include a heteroatom.
• the co-polyamino acid is a statistical or block co-polyamino acid.
• the co-polyamino acid is a statistical co-polyamino acid in the chain of amino acid units, such as glutamic and / or aspartic units or lysine and / or ornithine.
• hydrophilic skeleton means a compound whose precursor (before grafting of the hydrophobic radical -Hy) has a LogP of less than 2 at pH 7.0.
• the logP of the hydrophilic skeleton precursor is less than 1 at pH 7.0.
• the logP of the hydrophilic skeleton precursor is less than 0 at pH 7.0.
• LogP or Log Kow or partition coefficient is a measure of distribution of a compound in a mixture of immiscible solvent n-octanol / water.
• LogP can be measured using the shake flask or shake fiask method, or when this is not possible using the H PLC method (OECD Guideline for the testing of Chemicals, 117, 30.03.89, Partition coefficient (n-octanol / water : HPLC method and 107, 27.07.95, Partition coefficient (n-octanol / water): Shake Fiask Method).
• Said LogP of a compound being defined by the following equation:
• Coct is the concentration of said compound in n-octanol and Ceau is the concentration of said compound in water.
• Ceau is the concentration of said compound in water.
• * indicate the sites of attachment of the various elements represented.
• the -Hy radicals are each independently identical or different from one monomer unit to another.
• radicals - GpR, Gpl, GpC, and D are each independently the same or different.
• the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of repeating 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 repeating units is between 0.01 and 0.3.
• the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.02 and 0.2.
• the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.007 and 0.15 .
• the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.01 and 0 1. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.02 and 0 08.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 9 and 10 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.03 and 0.15.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.015 and 0.1.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.02 and 0.08.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.01 and 0.1.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.01 and 0.06.
• the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.007 and 0.3 .
• the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.01 and 0 3.
• the composition is characterized in that the hydrophobic radical corresponds to formula I and the ratio M between the number of hydrophobic radicals and the number of repeating units is between 0.015 and 0.2 .
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 11 and 14 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.1 and 0.2.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 15 and 16 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of repeat units is between 0.04 and 0.15.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 17 and 18 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.02 and 0.06.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.01 and 0.06.
• the composition is characterized in that the hydrophobic radical corresponds to formula I in which the Cx radical comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number repeat units is between 0.01 and 0.05.
• Amylin, or amyloid polypeptide islet is a peptide hormone with 37 residues. It is co-secreted with insulin from the pancreatic beta cells in the ratio of approximately 100: 1. Amylin plays a role in glycemic regulation by stopping the secretion of endogenous glucagon and slowing gastric emptying and by promoting satiety, thereby reducing post-meal glycemic excursions in blood glucose levels.
• amyloid Proislet polypeptide proIAPP, proamyline, proislet protein
• pancreatic beta cells pancreatic beta cells
• pro-peptide of RSO 67 amino acids, 7404 Dalton undergoes post-translational modifications including cleavage of protease to produce amylin.
• amylin as mentioned refers to the compounds described in US patents 5,124,314 and US 5,234,906.
• analogue is understood to mean, when used with reference to a peptide or a protein, a peptide or a protein, in which one or more amino acid residues constituting the primary sequence have been substituted with d other amino acid residues and / or in which one or more constituent amino acid residues have been deleted and / or in which one or more constitutive amino acid residues have been added.
• the percentage of homology accepted for the present definition of an analogue is 50%.
• an analog may for example be derived from the primary amino acid sequence of amylin by substituting one or more natural or non-natural or peptidomimetic amino acids.
• derivative means, when used with reference to a peptide or a protein, a peptide or a protein or an analog chemically modified by a substituent which is not present in the peptide or the protein or the reference analog, that is to say a peptide or a protein which has been modified by creation of covalent bonds, to introduce substituents of the non-amino acid type.
• An agonist at the amylin receptor refers to a compound which mimics one or more characteristics of the activity of amylin.
• Amylin derivatives are described in the article Yan et al., PNAS, vol. 103, no 7, p 2046-2051, 2006.
• the substituent is chosen from the group consisting of fatty chains.
• amylin, the agonist at the amylin receptor or the amylin analog is amylin.
• the amylin, the agonist at the amylin receptor or the amylin analog is an analog of amylin.
• the composition is characterized in that the amylin analog is pramlintide (Symlin ® ) sold by the company ASTRAZENECA AB.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 1.5 and 75.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 2 and 35.
• amylin amylin receptor agonist or amylin analogue
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 3.5 and 30.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between
• amylin / amylin, amylin receptor agonist or amylin analogue are between
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amyl analog is only between 7 and 30.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 9 and 30.
• amphiphilic / amylin compound molar ratios are between 3 and 75.
• amphiphilic / amylin compound molar ratios are between 7 and 50.
• amphiphilic / amylin compound molar ratios are between 10 and 30.
• amphiphilic compound / pramlintide molar ratios are between 1.5 and 75.
• amphiphilic compound / pramlintide molar ratios are between 2 and 50.
• amphiphilic compound / pramlintide molar ratios are between 3 and 30.
• amphiphilic compound / pramlintide molar ratios are between 4 and 30.
• amphiphilic compound / pramlintide molar ratios are between 5 and 30. In one embodiment, the amphiphilic compound / pramlintide molar ratios are between 8 and 30.
• amphiphilic compound / pramlintide molar ratios are between 10 and 30.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 1.5 and 150.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 1.8 and 100.
• the hydrophobic Hy / amylin radical molar ratios, agonist at the amylin receptor or amylin analog are between 2 and 70.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 2.5 and 60.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 3 and 60.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 3.5 and 60.
• the hydrophobic Hy / amylin radical molar ratios, agonist at the amylin receptor or amylin analog are between 4 and 60.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 5 and 60.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amylin analog are between 7 and 60.
• the hydrophobic radical radicals Hy / amylin, agonist at the amylin receptor or amyl ine analog are between 9 and 60.
• the hydrophobic radical Hy / amylin molar ratios are between 5 and 60. In one embodiment, the hydrophobic Hy / amylin radical molar ratios are between 10 and 60.
• the hydrophobic radical Hy / amylin molar ratios are between 15 and 60.
• Hy / pramlintide 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.
• Hy / pramlintide are between 8 and 60.
• the hydrophobic Hy / pramlintide radical molar ratios are between 10 and 60. In one embodiment, the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or the like amylin range from 1.0 to 70.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 1.2 and 45.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 1.3 and 30.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 1.7 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 2.0 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 2.3 and 27. In one embodiment, the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 2.7 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 3.3 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 4.7 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist at the amylin receptor or amylin analog are between 6.0 and 27.
• amphiphilic compound / amylin mass ratios are between 2.0 and 67.
• amphiphilic compound / amylin mass ratios are between 4.7 and 27.
• amphiphilic compound / amylin mass ratios are between 6.7 and 27.
• amphiphilic compound / amylin mass ratios are between 10 and 27.
• amphiphilic / pramlintide compound mass ratios are between 1.0 and 67.
• amphiphilic compound / pramlintide mass ratios are between 1.3 and 45.
• amphiphilic compound / pramlintide mass ratios are between 2.7 and 27.
• amphiphilic compound / pramlintide mass ratios are between 3.3 and 27.
• amphiphilic compound / pramlintide mass ratios are between 5.3 and 27.
• amphiphilic compound / pramlintide mass ratios are between 6.7 and 27.
• the composition is characterized in that it also comprises insulin. In one embodiment, the composition is characterized in that the insulin is a mealtime insulin. Prandial insulins are soluble at pH 7.
• mealtime insulin is meant a so-called rapid or “regular” insulin.
• the so-called rapid meal insulins are insulins which must meet 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” mealtime insulin is human insulin.
• the meal insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
• the so-called fast prandial insulin are selected from the group consisting of insulin lispro (Humalog ®), insulin glulisine (Apidra ®) and insulin aspart (NovoLog ®) .
• the meal insulin is insulin lispro.
• the meal insulin is insulin glulisine.
• the meal insulin is insulin aspart.
• the insulin concentration is between 600 and 3000 mM (100 to 500 U / ml).
• the insulin concentration is between 600 and 2400 pM (100 to 400 U / mL).
• the insulin concentration is between 600 and 1800 pM (100 to 300 U / ml).
• the insulin concentration is between 600 and 1200 pM (100 to 200 U / ml).
• the insulin concentration is 600 pM (100 U / ml).
• the insulin concentration is 1200 pM (200 U / mL).
• the insulin concentration is 1800 pM (300 U / ml).
• the insulin concentration is 2400 pM (400 U / ml).
• the insulin concentration is 3000 pM (500 U / mL).
• the amphiphilic / amylin compound molar ratios, agonist at the amylin receptor or amylin analog are between 1.5 and 75.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 1.8 and 50. In one embodiment comprising prandial insulin, the amphiphilic compound / amylin, molar ratios at the amylin receptor or amylin analog receptor are between 2 and 35.
• the amphiphilic / amylin compound molar ratios, agonist at the amylin receptor or amylin analog are between 2.5 and 30.
• the amphiphilic compound / amylin, molar ratios at the amylin receptor or amylin analog receptor are between 3 and 30.
• the rat molar bones amphiphilic / amylin compound, agonist at the amylin receptor or amylin analog are between 3.5 and 30.
• the amphiphilic compound / amylin, agonist at the amylin receptor or amyli analog molar ratios are only between 4 and 30.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 5 and 30.
• the molar ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 7 and 30.
• the amphiphilic / amylin compound molar ratios, agonist at the amylin receptor or amylin analog are between 9 and 30.
• the amphiphilic / amylin compound molar ratios are between 5 and 75.
• the amphiphilic / amylin compound molar ratios are between 10 and 50.
• the amphiphilic / amylin compound molar ratios are between 15 and 30.
• the amphiphilic compound / pramlintide molar ratios are between 1.5 and 75.
• the amphiphilic compound / pramlintide molar ratios are between 2 and 50.
• the amphiphilic compound / pramlintide molar ratios are between 3 and 30. In one embodiment comprising prandial insulin, the amphiphilic compound / pramlintide molar ratios are between 4 and 30.
• the amphiphilic compound / pramlintide molar ratios are between 5 and 30.
• the amphiphilic compound / pramlintide molar ratios are between 8 and 30.
• the amphiphilic compound / pramlintide molar ratios are between 10 and 30.
• the hydrophobic radical molar ratios - Hy / amylin, agonist at the amylin receptor or amylin analog are between 1.5 and 150.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 1, 8 and 100.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 2 and 70.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 2.5 and 60.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 3 and 60.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 3.5 and 60.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 4 and 60.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 5 and 60.
• the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog are between 7 and 60. In one embodiment comprising prandial insulin, the hydrophobic radical -Hy / amylin molar ratios, agonist at the amylin receptor or amylin analog 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.
• 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 compound amphiphilic / amylin, amylin receptor agonist or amylin analog are between 1.0 and 70.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 1, 2 and 45.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 1.3 and 30.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 1, 7 and 27. In one embodiment comprising prandial insulin, the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 2.0 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 2.3 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 2.7 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 3.3 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 4.7 and 27.
• the mass ratios of amphiphilic compound / amylin, agonist to the amylin receptor or amylin analog are between 6.0 and 27.
• the amphiphilic / amylin compound mass ratios are between 3.3 and 67.
• the amphiphilic / amylin compound mass ratios are between 6.6 and 27.
• the amphiphilic / amylin compound mass ratios are between 10 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 1.0 and 67.
• the amphiphilic compound / pramlintide mass ratios are between 1.2 and 45.
• the amphiphilic compound / pramlintide mass ratios are between 1.3 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 1.7 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 2.0 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 2.3 and 27. In one embodiment comprising prandial insulin, the amphiphilic compound / pramlintide mass ratios are between 2.7 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 3.3 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 4.7 and 27.
• the amphiphilic compound / pramlintide mass ratios are between 6.0 and 27.
• the composition comprises amylin, an agonist to the amylin receptor or an amylin analog, in combination or not with a mealtime insulin, with GLP-1, GLP-1 analogs, GLP-1 receptor agonists, commonly called GLP-1 RA and an amphiphilic compound comprising a hydrophilic backbone HB, substituted by at least one hydrophobic radical -Hy.
• GLP-1 an agonist at the amylin receptor or an amylin analog
• GLP-1 receptor agonists these are commonly called GLP-1 RA. This allows in particular to potentiate the effect of insulin and is recommended in certain types of diabetes treatment.
• GLP-1, analogs of GLP-1, or GLP-1 RA are said to be "fast”.
• the term “rapid” means GLP-1, analogs of GLP-1, or GLP-1 RA, the apparent elimination half-life after subcutaneous injection in humans is less than 8 hours, in particular less 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 chosen from the group consisting of exenatide or Byetta ® (ASTRA-ZENECA), lixisenatide or Lyxumia ® (SANOFI), their analogs or derivatives and their pharmaceutically acceptable salts.
• GLP-1, analog of GLP-1, or GLP-1 RA is exenatide or Byetta ® , its analogs or derivatives and their pharmaceutically acceptable salts.
• GLP-1, analog of GLP-1, or GLP-1 RA is lixisenatide or Lyxumia ® , its analogs or derivatives and their pharmaceutically acceptable salts.
• concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range of 0.01 to 1.0 mg per 1 mg of agonist at the amylin receptor or an analog of amylin.
• the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.01 to 0.5 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.2 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.15 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in the range of 0.01 to 1 mg per 1 mg of amylin receptor agonist or the like amylin.
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.01 to 0.5 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.02 to 0.4 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.03 to 0.3 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is 0.04 to 0.2 mg per 1 mg of agonist at the amylin receptor or an amylin analog .
• the concentration of lixisenatide, its analogs or derivatives and their pharmaceutically acceptable salts is from 0.04 to 0.15 mg per 1 mg of amylin receptor agonist or an analogue of amylin.
• the compositions according to the invention are produced by mixing amylin solutions and commercial solutions of GLP-1, analog of GLP-1 or agonist of GLP receptors- 1 AR in volume ratios in the range 10/90 to 90/10 in the presence of an amphiphilic compound.
• said at least one ionic species makes it possible to improve the stability of the compositions.
• said at least one ionic species is chosen from at least divalent cations, anions, cations or zwitterions and their mixtures.
• the at least divalent cation salt is a cation salt of mineral origin chosen from the group of at least divalent cations derived from metals such as zinc or from alkaline earth metals such as magnesium or calcium.
• the at least divalent cation salt is a zinc salt.
• the at least divalent cation salt is a calcium salt.
• the at least divalent cation salt is a magnesium salt.
• the salts of at least divalent cations are provided in the composition in the form of salts chosen from chlorides, phosphates, sulfates or hydroxides.
• the at least divalent cation salts are present at a concentration of between 0.1 and 5 mM.
• the at least divalent cation salts are present at a concentration of between 0.2 and 4 mM.
• the at least divalent cation salts are present at a concentration of between 0.5 and 3 mM.
• the at least divalent cation salts are present at a concentration of between 0.1 and 5 mM for 1 mg / ml of amylin, agonist at the amylin receptor or the like. amylin.
• the at least divalent cation salts are present at a concentration of between 0.2 and 4 mM for 1 mg / ml of amylin, agonist at the amylin receptor or the like amylin.
• the at least divalent cation salts are present at a concentration of between 0.5 and 3 mM per 1 mg / m L of amylin, of agonist at the amylin receptor or of analogue of amylin.
• the zinc salts are present at a concentration of between 0.1 and 5 mM.
• the zinc salts are present at a concentration of between 0.2 and 4 mM.
• the zinc salts are present at a concentration of between 0.5 and 3 mM.
• the zinc salts are present at a concentration of between 0.1 and 5 mM for 1 mg / ml of amylin, agonist at the amylin receptor or the like. amylin.
• the zinc salts are present at a concentration of between 0.2 and 4 mM for 1 mg / ml of amylin, of amylin receptor agonist or of amylin analog .
• the zinc salts are present at a concentration of between 0.5 and 3 mM for 1 mg / ml of amylin, of amylin receptor agonist or of amylin analog.
• the ionic species comprise less than 10 carbon atoms.
• Said ionic species are chosen from the group of anions, cations and / or zwitterions.
• zwitterion is meant a species carrying at least one positive charge and at least one negative charge on two nonadjacent atoms.
• Said ionic species are used alone or in admixture and preferably in admixture.
• 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 sulfates, phosphates and halides, in particular chloride ions.
• the anions of mineral origin are chosen from chloride ions.
• the chloride ions are provided in the form of salt by sodium chloride.
• the composition comprises sodium chloride.
• 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 ammonium.
• the cations are chosen from cations of monovalent mineral origin.
• the cations of mineral origin are chosen from the group consisting of cations derived from 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 from the group consisting of cysteine, serine, threonine, and methionine.
• the amino acids are chosen from aromatic amino acids from the group consisting of phenylalanine, tyrosine and tryptophan.
• the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidified in the group consisting of asparagine and glutamine.
• the zwitterions of organic origin are chosen from the group consisting of amino acids having an uncharged side chain.
• the zwitterions of organic origin are chosen from the group consisting of aminodiacids or acidic amino acids.
• the aminodiacides are chosen from the group consisting of glutamic acid and aspartic acid, optionally in the form of salts.
• the zwitterions of organic origin are chosen from the group consisting of basic 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 include as many negative charges as there are positive charges and therefore an overall charge zero at the isoelectric point and / or at a pH of between 6 and 8.
• Said ionic species are introduced into the compositions in the form of salts.
• the introduction of these can be done in solid form before dissolving in the compositions, or in the form of solution, in particular of concentrated solution.
• cations of mineral origin are provided in the form of salts chosen from sodium chloride, sodium phosphate and sodium sulfate.
• the anions of organic origin are provided in the form of the salts chosen from sodium or potassium citrate, sodium acetate.
• amino acids are added in the form of salts chosen from arginine hydrochloride, histidine hydrochloride or in non-salified form such as, for example, histidine, arginine.
• said at least one ionic species is a combination of a divalent cation and an anion of mineral origin.
• said at least one ionic species is a combination of a divalent cation and chloride ions.
• said at least one ionic species is a combination of a zinc salt and chloride ions.
• said at least one ionic species is a combination of a zinc salt and sodium chloride. In one embodiment, 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 40 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 less than or equal to 250 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 150 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 less than or equal to 75 mM.
• the total molar concentration of ionic species in the composition is less than or equal to 50 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 10 and 250 mM.
• 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 25 and 150 mM.
• the total molar concentration of ionic species in the composition is between 50 and 100 mM.
• the molar concentration of chloride ions in the composition is greater than or equal to 10 mM.
• the molar concentration of chloride ions in the composition is greater than or equal to 20 mM.
• the molar concentration of chloride ions in the composition is greater than or equal to 40 mM.
• the molar concentration of chloride ions in the composition is greater than or equal to 50 mM.
• the molar concentration of chloride ions in the composition is less than or equal to 250 mM. In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 200 mM.
• the molar concentration of chloride ions in the composition is less than or equal to 150 mM. In one embodiment, the molar concentration of chloride ions in the composition is less than or equal to 100 mM.
• the molar concentration of chloride ions in the composition is less than or equal to 75 mM.
• the molar concentration of chloride ions in the composition is less than or equal to 50 mM.
• the molar concentration of chloride ions in the composition is between 10 and 250 mM.
• the molar concentration of chloride ions in the composition is between 20 and 200 mM.
• the molar concentration of chloride ions in the composition is between 25 and 150 mM.
• the molar concentration of chloride ions in the composition is between 50 and 100 mM.
• the molar concentration of chloride ions in the composition is between 30 and 300 mM.
• the molar concentration of chloride ions in the composition is between 50 and 250 mM.
• the molar concentration of chloride ions in the composition is between 80 and 220 mM.
• the molar concentration of chloride ions in the composition is between 100 and 200 mM.
• the composition comprises from 10 to 500 mM NaCl.
• the composition comprises from 15 to 400 mM NaCl.
• the composition comprises from 20 to 300 mM NaCl.
• the composition comprises from 25 to 200 mM NaCl.
• the composition comprises from 50 to 100 mM NaCl. In one embodiment, the compositions according to the invention also comprise buffers.
• compositions according to the invention comprise buffers at concentrations between 0 and 100 mM.
• compositions according to the invention comprise buffers at concentrations between 15 and 50 mM.
• compositions according to the invention comprise a buffer chosen from the group consisting of a phosphate buffer and Tris (trishydroxymethylaminomethane).
• the buffer is sodium phosphate.
• the buffer is the Tris
• 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 preservatives is between 10 and 50 mM.
• the concentration of preservatives is between 10 and 40 mM.
• compositions according to the invention further comprise a surfactant.
• the surfactant is chosen from the group consisting of propylene glycol and polysorbate.
• compositions according to the invention can also comprise additives such as tonicity agents.
• the tonicity agents are chosen from the group consisting of glycerin, mannitol and glycine.
• compositions according to the invention may also comprise all the excipients in accordance with the pharmacopoeias and compatible with the insulins used at the usual concentrations.
• 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 by the intravenous, subcutaneous, intradermal or intramuscular route.
• the transdermal, oral, nasal, vaginal, ocular, oral, pulmonary administration routes are also envisaged.
• 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 analog and an amphiphilic compound according to the invention .
• the invention also relates to single-dose formulations at pH between 6.0 and 8.0 comprising amylin, an agonist at the amylin receptor or amylin analog, an amphiphilic compound according to the invention and a GLP-1, an analog of GLP-1 or a GLP-1 RA, as defined above.
• the invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising amylin, an agonist at the amylin receptor or an amylin analog and an amphiphilic compound according to the invention .
• the invention also relates to single-dose formulations at pH between 6.6 and 7.6 comprising amylin, an agonist at the amylin receptor or an amylin analog, an amphiphilic compound according to the invention and a mealtime insulin, as defined above.
• the single-dose formulations further comprise an amphiphilic compound 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, of an agonist at the amylin receptor or of an analogue of amylin, and of an amphiphilic compound comprising a hydrophilic backbone HB carrier of at least one radical hydrophobic according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
• 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, of an agonist at the amylin receptor or of an analogue of amyline, prandial insulin, and an amphiphilic compound comprising a hydrophilic backbone HB carrying at least one hydrophobic radical according to the invention, in aqueous solution or in lyophilized form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
• the mixture of mealtime insulin and amphiphilic compound is concentrated by ultrafiltration.
• composition of the mixture is adjusted to excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ® ) by adding concentrated solutions of these excipients within the mixture.
• pH of the preparation is adjusted to pH between 6 and 8.
• compositions are characterized in that said compositions have a stability measured by ThT greater than that of a reference composition comprising amylin, an agonist at the amylin receptor or the like of amylin but not comprising an amphiphilic compound carrying 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 agonist at the amylin receptor or the like of amylin in combination with an insulin but not comprising an amphiphilic compound carrying 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 agonist at the amylin receptor or the like amylin in combination with insulin and GLP-1, a GLP-1 analogue or a GLP-1 receptor agonist, but not comprising an amphiphilic compound carrying hydrophobic radicals -Hy.
• the invention also relates to said amphiphilic compounds carrying hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.
• the invention also relates to the precursors of said hydrophobic radicals of formula I.
• the invention also relates to the use of an amphiphilic compound carrying hydrophobic radicals -Hy to stabilize a composition comprising amylin, an amylin receptor agonist or an amylin analog.
• the invention also relates to a use of an amphiphilic compound carrying hydrophobic radicals -Hy to stabilize a composition comprising amylin, an amylin receptor agonist or an amylin analog and a prandial insulin, and optionally a GLP-1, a GLP-1 analog or a GLP-1 receptor agonist.
• the invention relates to a composition stabilization method comprising amylin, an amylin receptor agonist or an amylin analog or a composition stabilization method comprising amylin, a receptor agonist amylin or an amylin analog and a mealtime insulin, and optionally a GLP-1, a GLP-1 analog or a GLP-1 receptor agonist.
• the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by polymerization.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid chosen from the group consisting by N-carboxyanhyd ride poly methyl glutamate (GluOMe-IMCA), N-carboxyanhydride poly benzyl glutamate (GluOBzl-NCA) and N-carboxyanhydride poly t-butyl glutamate (GluOtBu-NCA).
• the N-carboxyanhydride derivative of glutamic acid is N-carboxyanhydride poly-L-methyl glutamate (L-GluOMe-NCA).
• the derivative of N-ca rboxya n hyd ri of glutamic acid is N-carboxyanhydride poly-L-benzyl glutamate (L-GluOBzl-NCA).
• the composition according to the invention is characterized in that the co-polyamino acid is obtained from a polyamino acid obtained by polymerization of an N-carboxyanhydride derivative of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as an initiator an organometallic complex of a transition metal as described in the publication Deming, TJ., Nature 1997, 390, 386-389.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as initiator ammonia or a primary amine as described in patent FR 2,801, 226 and the references cited by this patent.
• the initiator can be a polyamine in order to obtain polyamino acid comprising several PLGs.
• Said polyamines can be chosen from diamines, triamines and tetramines. The amines of these polyamines can be primary amines.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid using as an initiator hexamethyldisilazane as described in the publication Lu H. ; et al., J. Am. Chem.
• the composition according to the invention is characterized in that the process for the synthesis of the polyamino acid obtained by polymerization of a derivative of N-carboxyanhydride of glutamic acid or of a derivative of N-carboxyanhydride of aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.
• this step of hydrolysis of ester functions can consist of a hydrolysis in an acid medium or a hydrolysis in a basic medium or be carried out by hydrogenation.
• this step of hydrolysis of ester groups is a hydrolysis in an acid medium.
• this step of hydrolysis of ester groups is carried out by hydrogenation.
• the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid comes from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight chosen from the group consisting of the polyglutamate sodium and sodium polyaspartate.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
• the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acid poly-L-glutamic acid or poly-L-aspartic acid using methods of amide bond formation well known to those of skill in the art.
• the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acid poly-L-glutamic acid or poly-L-aspartic acid using the methods of amide bond formation used for peptide synthesis. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group on an acid poly-L-glutamic acid or poly-L-aspartic acid as described in the patent FR 2,840,614.
• the one or more free carboxylic acid function (s) of Hy can be in protected form before grafting on P LG via an acid protecting group, this protection is carried out for example by esterification using methanol, ethanol, benzyl alcohol or t-Butanol.
• the functions are deprotected, that is to say that a deprotection reaction is carried out so that the carboxylic function (s) is (are) free or in the form of the cation salt alkaline chosen from the group consisting of Na + and K +.
• one or more amine function (s) can be in protected form before grafting onto the PLG via an amine protecting group, this protection is carried out for example by acid or basic hydrolysis under heat via the group phenylmethoxycarbonyl or the 1,1-dimethylethoxycarbonyl group.
• the functions are deprotected, that is to say that a deprotection reaction is carried out so that the function (s) amine is (are) free (s).
• one or more free amine function (s) of the Hyd imidazole can be in protected form before grafting onto the PLG via an amine protecting group, this protection is carried out for example by nucleophilic substitution in basic medium via the benzyloxymethyl (BOM) or trityl (Tr) group.
• BOM benzyloxymethyl
• Tr trityl
• Molecule 1 Product obtained by the reaction between N-Boc ethylenediamine and phthalic anhydride
• Phthalic anhydride is added to a solution of N-Boc ethylenediamine (BocEDA, 20.0 g, 124.83 mmol) in toluene (300 mL)
• Molecule 3 Product obtained by the reaction between proline and palmitoyl chloride
• Molecule 4 Product obtained by the reaction between Fmoc-His (CITrt) -OH and 2- chlorotrityl chloride resin
• the resin is filtered, washed successively with DCM (3 x 150 mL), N-methyl-2-pyrrolidone (NMP, 2 x 150 mL), DCM (2 x 150 mL) and methanol (3 x 150 mL).
• Molecule 5 Product obtained by the reaction between molecule 4 and an NMP / piperidine mixture 90: 10
• Molecule 6 Product obtained by the reaction between molecule 5 and molecule 3
• Molecule 7 Product obtained by the reaction between molecule 6 and a 1% TFA / DCM mixture
• Molecule 8 Product obtained by the reaction between molecule 7 and molecule 2
• the aqueous phase is extracted with DCM (2 x 50 mL).
• the combined organic phases are washed with a 5% aqueous solution of KHSCU (50 mL), a saturated aqueous solution of NaHCCh (50 mL) and a saturated aqueous solution of NaCl (2 x 50 mL).
• the organic phase is dried over Na2S0 4, filtered and concentrated under reduced pressure.
• Molecule 8 is obtained in the form of a white solid after purification by chromatography on silica gel (eluent: DCM, methanol).
• Molecule 9 Product obtained by peptide synthesis in solid phase
• the molecule 9 ([His (Trt)] 3ProC16) is obtained by the conventional method of peptide synthesis in solid phase on 2-chlorotrityl resin, successively using the Fmoc-protected amino acids Fmoc-L-His (Trt) -OH and Fmoc-Pro-OH " then palmitic acid (5 equivalents) and diisopropylcarbodiimide (5 equivalents) / cyano (hydroxyimino) ethyl acetate (5 equivalents) as coupling agents.
• a 20% piperidine solution in DMF is used for the steps of cleavage of the protective group Fmoc.
• the resin is washed with DCM, DMF and methanol after each coupling and deprotection step.
• the cleavage of the product from the resin is carried out using a DCM / HFIP 80:20 mixture.
• the molecule A3 is obtained by the solid phase peptide synthesis method (SPPS) on 2-chlorotrityl resin.
• a solution of 4.7, 10-trioxal, 13-tridecanediamine (TOTA, 68 mL, 310 mmol) in DCM (140 mL) is poured onto 2-chlorotrityl resin (13.60 g, 1.14 mmol / g, 15.5 mmol) previously washed with DCM in a reactor suitable for SPPS. After 2 h of stirring at room temperature, methanol (0.8 ml / g, 11 ml) is added and the medium is stirred for 15 min. The resin is filtered, washed successively with DCM, DMF, DCM, isopropanol and DCM.
• a 20% piperidine solution in DMF is used for the steps of cleavage of the protective group Fmoc.
• the resin is washed with DCM, DMF and isopropanol after each step of coupling and protection .
• the cleavage of the resin product is carried out using a mixture
• TFA / DCM 1 1. The solvents are evaporated under reduced pressure, the residue is dissolved in DCM (500 mL) and the organic phase is washed with a 1N aqueous NaOH solution (1 x 200 mL). After drying over Na 2 S0 4 , the organic phase is filtered, concentrated and dried under reduced pressure. The molecule A4 is obtained in the form of a yellow oil.

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