EP3723728A1 - Injektionslösung mit einem ph-wert von 7 mit mindestens einem basalinsulin mit einem pi zwischen 5,8 und 8,5 und einer copolyaminosäure mit carboxylatladungen und hydrophoben radikalen - Google Patents

Injektionslösung mit einem ph-wert von 7 mit mindestens einem basalinsulin mit einem pi zwischen 5,8 und 8,5 und einer copolyaminosäure mit carboxylatladungen und hydrophoben radikalen

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Publication number
EP3723728A1
EP3723728A1 EP18811570.3A EP18811570A EP3723728A1 EP 3723728 A1 EP3723728 A1 EP 3723728A1 EP 18811570 A EP18811570 A EP 18811570A EP 3723728 A1 EP3723728 A1 EP 3723728A1
Authority
EP
European Patent Office
Prior art keywords
radical
formula
hydrophobic
molecule
radicals
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18811570.3A
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English (en)
French (fr)
Inventor
You-Ping Chan
Romain NOËL
Alexandre Geissler
Walter ROGER
Richard Charvet
Nicolas Laurent
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Adocia SAS
Original Assignee
Adocia SAS
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Application filed by Adocia SAS filed Critical Adocia SAS
Publication of EP3723728A1 publication Critical patent/EP3723728A1/de
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/16—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/48—Polymers modified by chemical after-treatment
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08L—COMPOSITIONS OF MACROMOLECULAR COMPOUNDS
    • C08L77/00—Compositions of polyamides obtained by reactions forming a carboxylic amide link in the main chain; Compositions of derivatives of such polymers
    • C08L77/04—Polyamides derived from alpha-amino carboxylic acids

Definitions

  • the invention relates to insulin (s) injection therapies for treating diabetes.
  • the invention relates to physically stable compositions in the form of an injectable aqueous solution, whose pH is between 6.0 and 8.0, comprising at least one basal insulin whose isoelectric point (pi) is between 5.8 and 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals.
  • Insulin therapy or diabetes therapy by insulin injection, has seen remarkable progress in recent years thanks to the development of new insulins offering better correction of blood glucose in patients compared to insulin. human and which better simulate the physiological activity of the pancreas.
  • a type II diabetes When a type II diabetes is diagnosed in a patient, a gradual treatment is set up.
  • the patient initially takes oral antidiabetic drugs (OADs) such as etformine.
  • OADs oral antidiabetic drugs
  • ADOs alone are no longer sufficient to regulate glucose levels in the blood, a change in treatment must be made and, depending on the specificities of the patients, different combinations of treatments can be implemented.
  • the patient may be treated with basal insulin insulin glargine or insulin detemir in addition to ADOs, and then, depending on the course of the disease, treatment with basal insulin and insulin. prandial.
  • OAD when they are no longer able to control the level of glucose in the blood, to a basal insulin treatment / mealtime insulin, the injection of analogues of GLP-1 RA is recommended.
  • GLP-1 RA for Glucagon-Like Peptide-1 receptor agonists are insulinotropic or incretinic peptides, and belong to the family of gastrointestinal hormones (or Gut Hormones) that stimulate insulin secretion when the blood sugar is too high, for example after a meal.
  • the gastrointestinal hormones are also called satiety hormones. They include GLP-1 RA (Glucagon-like peptide- 1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin which have peptide or protein structures. They also stimulate insulin secretion in response to glucose and fatty acids and are therefore potential candidates for the treatment of diabetes.
  • GLP-1 RA Glucagon-like peptide- 1 receptor agonist
  • GIP Glucose-dependent insulinotropic peptide
  • oxyntomodulin a derivative of proglucagon
  • peptide YY amylin
  • cholecystokinin pancreatic polypeptide
  • enterostatin which have peptide or protein structures. They also stimulate insulin secretion in response to glucose
  • the GLP-1 RA are the ones that have brought the best results to date in the development of drugs. They allowed patients with type II diabetes to lose weight while having better control of their blood sugar.
  • a diabetic patient currently has, schematically, two types of insulins with complementary actions: the prandial insulins (or so-called insulins fast acting) and basal insulins (or so-called slow acting insulins).
  • Prandial insulins allow rapid management (metabolization and / or storage) glucose provided during meals and snacks.
  • the patient should inject a mealtime insulin before each food intake, approximately
  • the most widely used prandial insulins are: recombinant human insulin, NovoLog ® (insulin aspart of NOVO NORDISK), Humalog® (insulin lispro by ELI LILLY) and Apidra® (insulin glulisine from SANOFI).
  • the basal insulins ensure the maintenance of glycemic homeostasis of the patient, outside the periods of food intake. They act essentially to block the endogenous production of glucose (hepatic glucose).
  • the daily dose of basal insulin is usually 40-50% of the total daily insulin requirement. Depending on the basal insulin used, this dose is given in 1 or 2 injections, regularly distributed during the day.
  • the basal insulins are the most uti l Airbnbs Levemir® (insulin detemir from Novo Nordisk) and Lantus ® (insulin glargine SANOFI).
  • NPH NPH insulin for Neutral Protamine Hagedorn, Humulin NPH ® , Insulatard ®
  • This formulation is the result of a precipitation of human insulin (anionic at neutral pH) by a cationic protein, protamine.
  • the microcrystals thus formed are dispersed in an aqueous suspension and dissolve slowly after subcutaneous injection. This slow dissolution ensures prolonged release of insulin. However this release does not ensure a constant concentration of insulin during time.
  • the release profile is bell-shaped and lasts only 12 to 16 hours. It is injected twice a day.
  • This basal insulin NPH is less efficient than modern insulins basal Levemir and Lantus ®.
  • NPH is an intermediate-acting basal insulin.
  • basal insulins can be classified according to the technical solution that allows to obtain the prolonged action and to date two approaches are used.
  • insulin detemir is the binding to albumin in vivo. It is an analogue, soluble at pH 7, which comprises a fatty acid side chain (tetradecanoyl) attached to position B29 which, in vivo, allows this insulin to associate with albumin. Its prolonged action is mainly due to this affinity for albumin after subcutaneous injection.
  • Another soluble insulin at pH 7 is insulin degludec sold under the name Tresiba ®d . It also includes a fatty acid side chain attached to insulin (hexadecandioyl- ⁇ L-Glu).
  • Insulin glargine is an analogue of human insulin obtained by elongating the C-terminal part of the B chain of human insulin by two arginine residues, and by substituting the asparagine residue A21 for a glycine residue. (US 5,656,722).
  • the addition of two arginine residues was designed to adjust the pI (isoelectric point) of insulin glargine to physiological pH, and thus make this human insulin analog insoluble in a physiological medium.
  • the substitution of GA21 was designed to make insulin glargine stable at acidic pH and thus be able to formulate it as a pH injection solution.
  • acid During subcutaneous injection, the passage of insulin glargine from an acid pH (pH 4-4.5) to a physiological pH (neutral pH) causes its precipitation under the skin. The slow redissolution of insulin glargine micro-particles ensures a slow and prolonged action.
  • hypoglycemic effect of insulin glargine is almost constant over a period of 24 hours which allows most patients to be limited to a single injection per day.
  • Insulin glargine is considered today as the most widely used basal insulin.
  • the necessarily acidic pH of the basal insulin formulations, whose isoelectric point is between 5.8 and 8.5, insulin glargine type, can be a real drawback, because this acidic pH of the formulation of insulin glargine sometimes causes patients to experience pain during injection and especially prevents any formulation with other proteins and in particular with prandial insulins because they are not stable at acidic pH.
  • the impossibility of formulating a prandial insulin, at acid pH is due to the fact that a mealtime insulin undergoes, under these conditions, a secondary reaction of deamidation in position A21, which makes it impossible to meet the stability requirements applicable to the drugs. injectables.
  • compositions in the form of an aqueous solution for injection whose pH is between 6.0 and 8.0, comprising at least (a) a basal insulin whose the isoelectric point pi is between 5.8 and 8.5 and (b) a co-polyamino acid carrying carboxylate charges substituted with hydrophobic radicals.
  • compositions of the prior art do not allow satisfactorily meet the specifications applicable to pharmaceutical formulations.
  • the affinity of the co-polyamino acids according to the invention for insulin glargine has been increased in that it makes it possible to obtain solubilization and stabilization of insulin glargine solutions at a concentration of ratio [Hy] / [basal insulin] lower than that of the prior art; these results are moreover obtained without altering or even improving the propensity of insulin glargine to precipitate as demonstrated in the experimental part.
  • Co-polyamino acids bearing carboxylate charges and hydrophobic radicals Hy according to the invention have excellent resistance to hydrolysis. This can especially be verified under accelerated conditions, for example by hydrolysis tests at basic pH (pH 12).
  • the invention relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • compositions in the form of a injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least: a) a basal insulin whose isoelectric point (pi) is between 5.8 and 8.5,
  • the invention thus relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • the invention thus relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • the invention thus relates to physically stable compositions in the form of an injectable aqueous solution, the pH of which is between 6.0 and 8.0, comprising at least:
  • co-polyamino acid of formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and consisting of at least two chains of glutamic or aspartic units P LG linked together by a radical or spacer Q [- *] k linear or branched divalent at least consisting of an alkyl chain comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions,
  • said amide functions linking said radical or spacer Q [- *] k bonded to the at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,
  • k is 2, 3, 4, 5 or 6.
  • k 2.
  • k 3.
  • k 4.
  • k 5.
  • k 6.
  • j is 1, 2, 3, 4, 5 or 6.
  • j 1.
  • j 2.
  • j 3.
  • j 4.
  • j 5.
  • j 6.
  • g is greater than or equal to 2 (g> 2).
  • h is greater than or equal to 2 (h> 2).
  • the hydrophobic radical Hy is chosen from the group of hydrophobic radicals of formula X, in which h is greater than or equal to
  • the hydrophobic radical Hy is chosen from the group of hydrophobic radicals of formula X, in which g is greater than or equal to 2 and a, I and h are equal to 0 and GpC is of formula Ixe .
  • GpR is a radical of formula VII 'or VII ".
  • Said co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy is soluble in aqueous solution at pH between 6.0 and 8.0, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. ml.
  • Said co-polyamino acid bearing carboxylate charges and hydrophobic radicals -Hy is soluble in aqueous solution at a pH between 6.0 and 8.0, at a temperature of 25 ° C. and at a concentration of less than 60 mg / ml. ml.
  • alkyl radical is understood to mean a linear or branched carbon chain which does not comprise a heteroatom.
  • the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
  • compositions which satisfy the criteria of the visual inspection described in the European, American and international pharmacopoeia, that is to say compositions which are clear and which do not contain any visible particles, but also colorless.
  • aqueous solution for injection solutions whose solvent is water and which satisfy the conditions of EP and US pharmacopoeia.
  • compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
  • the term "clear solution” means compositions which satisfy the criteria described in the US and European pharmacopoeias concerning injectable solutions.
  • the solutions are defined in the ⁇ 1151> part referring to the injection ⁇ 1> (referring to ⁇ 788> according to USP 35 and specified in ⁇ 788> according to USP 35 and in ⁇ 787>, ⁇ 788> and ⁇ 790> USP 38 (from 1 August 2014), according to USP 38).
  • injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
  • co-polyamino acid consisting of glutamic or aspartic units non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a corresponding C-terminal portion, to the carboxylic acid of one end, and an N-terminal part, corresponding to the amine of the other end of the sequence.
  • soluble capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / ml in distilled water at 25 ° C.
  • soluble capable of allowing to prepare a clear solution and free of particles at a concentration of less than 60 mg / ml in distilled water at 25 ° C.
  • radicals -Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently identical or different from one residue to another.
  • the composition is characterized in that the pH is between 6.0 and 8.0. In one embodiment, 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.
  • composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 40 and 60 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms.
  • Hy comprises more than 15 carbon atoms.
  • Hy comprises more than 30 carbon atoms.
  • radical or spacer Q [- *] k is represented by a radical of formula II:
  • radicals Q ' being identical or different and selected from the group consisting of the following radicals of formulas III to VI', to form Q [- *] k:
  • ui 'and u 2 ' are the same or different and,
  • v, v 'and v "identical or different, are integers> 0, and
  • the at least two chains of glutamic or aspartic units P LG being bound to Q [- *] k by an Fx or Fy function by a covalent bond to form an amide bond with a function -NH- or -CO- PLG.
  • At least one of Q ' is a radical of formula
  • the precursor of the radical of formula III is a diamine selected from the group consisting of ethylene diamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diaminopropane. diaminopentane, propylene diamine, pentylene diamine.
  • t 2 and the precursor of the radical of formula III is ethylenediamine.
  • t 4 and the precursor of the radical of formula III is butylenediamine.
  • t 6 and the precursor of the radical of formula
  • III is hexylenediamine.
  • t 3 and the precursor of the radical of formula III is 1,3-diaminopropane.
  • t 5 and the precursor of the radical of formula III is 1,5-diaminopentane.
  • the precursor of the radical of formula III is an amino acid.
  • the precursor of the radical of formula III is an amino acid selected from the group consisting of aminobutanoic acid, aminohexanoic acid and beta-alanine.
  • III is beta-alanine.
  • t 6 and and the precursor of the radical of formula III is aminohexanoic acid.
  • t 4 and the precursor of the radical of formula
  • the precursor of the radical of formula III is a diacid.
  • the precursor of the radical of formula III is a diacid selected from the group consisting of succinic acid, glutaric acid and adipic acid.
  • t 2 and the precursor of the radical of formula III is succinic acid.
  • t 3 and the precursor of the radical of formula
  • III is glutaric acid.
  • t 4 and the precursor of the radical of formula III is adipic acid.
  • At least one of Q ' is a radical of formula
  • the precursor of the radical of formula IV is a diamine selected from the group consisting of diethyleneglycoldiamine, triethyleneglycol diamine, 1-amino-4,9-dioxa-12-dodecanamine and 1-amino-4,9-dioxa-12-dodecanamine. amino-4,7,10-trioxa-13-tridecanamine.
  • At least one of Q ' is a radical of formula
  • whose precursor is selected from the group consisting of amino acids.
  • the precursor of the radical of formula V is an amino acid selected from the group consisting of lysine, ornithine, 1,3-diaminopropionic acid.
  • At least one of Q ' is a radical of formula V
  • Formula V whose precursor is selected from the group consisting of triacids.
  • the precursor of the radical of formula V is a triacid selected from the group consisting of tricarballylic acid.
  • At least one of Q ' is a radical of formula
  • Formula V whose precursor is selected from the group consisting of triamines.
  • the precursor of the radical of formula V is a triamine selected from the group consisting of (2- (aminomethyl) propane-1,3-diamine).
  • Q ' is a radical of formula
  • w " 2 0 and the precursor of the radical of formula
  • VI is a triamine selected from the group consisting of spermidine, norspermidine, and diethylenetriamine and bis (hexamethylene) triamine.
  • w " 2 0 and the precursor of the radical of formula VI is spermidine.
  • w " 2 0 and the precursor of the radical of formula
  • VI is norspermidine.
  • w " 2 0 and the precursor of the radical of formula VI is diethylenetriamine.
  • w " 2 0 and the precursor of the radical of formula VI is bis (hexamethylene) triamine.
  • At least one of Q ' is a radical of formula VI
  • w " 2 1 and the precursor of the radical of formula VI is a tetramine.
  • w " 2 1 and the precursor of the radical of formula VI is spermine.
  • w " 2 1 and the precursor of the radical of formula VI is triethylenetetramine.
  • the precursor of the radical or spacer Q [- *] k has 4 reactive functional groups, chosen from amine and carboxylic acid functions.
  • Such a precursor may be 1,2,3,4-butanetratoic acid.
  • At least one of Q ' is a radical of formula
  • w "2 0 and the precursor of the radical of formula VI 'is spermidine.
  • w "2 0 and the precursor of the radical of formula VI 'is norspermidine.
  • w "2 0 and the precursor of the radical of formula VI 'is diethylenetriamine.
  • w "2 0 and the precursor of the radical of formula VI is bis (hexamethylene) triamine.
  • At least one of Q ' is a radical of formula
  • w "2 1 and the precursor of the radical of formula VI 'is a tetramine.
  • w "2 1 and the precursor of the radical of formula VI 'is spermine.
  • w "2 1 and the precursor of the radical of formula VI 'is triethylenetetramine.
  • the precursor of the radical or spacer Q [- *] k has 4 reactive functions, chosen from the amine and carboxylic acid functional groups.
  • 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-butanetrathoic acid. .
  • all the Fx's are linked to the PLG or other Fx or Fy.
  • one or more Fx are free, that is to say are not related to the PLG, or another Fx or Fy.
  • an Fx is free, that is to say is not linked to
  • the (s) Fx of the -CO- type is free, it is in the form of a carboxylic acid salt.
  • the free -CO- type Fx is carried by a radical Q 'of Formula V.
  • the (s) Fx of -NH- type is free, it is in the form of amine or ammonium.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa below:
  • D is, independently, either -CH2- (aspartic unit) or -CH 2 -CH 2 - (glutamic unit),
  • X represents a cationic entity selected from the group comprising alkaline cations
  • Ra and R'a which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of an H, a linear acyl group of C2 to C10, a branched acyl group of C3 to C10, a benzyl group. , a terminal "amino acid” unit and a pyroglutamate,
  • Ra and R'a being a hydrophobic radical -Hy
  • n + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n + m ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and 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 P LG chains of the co-polyamino acid bearing a radical -Hy,
  • n2 + nri2 represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid not bearing a -Hy radical
  • n '+ m' represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n '+ m' ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb below:
  • Rb and R'b which are identical or different, 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
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and from at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula
  • Rb and Rb ' which may be identical or different, 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
  • nl + ml represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid bearing a -Hy radical
  • n2 + m2 represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid which does not carry a -Hy radical
  • n '+ m' represents the degree of DP polymerization of the co-polyamino acid, that is the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n '+ m' ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which Rb and R'b are different hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from 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 carboxylate charges and 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 is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXa, XXXb, XXXa 'or XXXb' in which the group D is -CH2-CH2- (glutamic unit).
  • the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXa, XXXa ', XXXb' in which group D is a group -CH2- (aspartic unit).
  • co-polyamino acid comprises one or more aspartic unit (s), that (s) can (s) undergo structural rearrangements.
  • the composition according to the invention is characterized in that when the co-polyamino acid comprises aspartate units, then the co-polyamino acid may further comprise monomeric units of formula XXXX and / or XXXX ' :
  • a "co-polyamino acid with random grafting” is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical represented by a co-polyamino acid of formula XXXa 'and XXXb'.
  • a "co-polyamino acid with defined grafting” is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical represented by a co-polyamino acid of formula XXXa and XXXb.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 60 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 40 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
  • the composition according to the invention is characterized in that n + m is between 10 and 250.
  • the composition according to the invention is characterized in that n + m is between 10 and 200.
  • composition according to the invention is characterized in that n + m is between 15 and 150.
  • composition according to the invention is characterized in that n + m is between 15 and 100.
  • composition according to the invention is characterized in that n + m is between 15 and 80.
  • composition according to the invention is characterized in that n + m is between 15 and 65.
  • composition according to the invention is characterized in that n + m is between 20 and 60.
  • composition according to the invention is characterized in that n + m is between 20 and 50.
  • the composition according to the invention is characterized in that n + m is between 20 and 40.
  • the invention 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: • a basal insulin whose isoelectric point pi is between 5.8 and 8.5;
  • a co-polyamino acid of formula I defined above bearing carboxylate charges and hydrophobic radicals -Hy and said at least one hydrophobic radical Hy is chosen from the radicals of formula X: Formula X in which
  • GpR is chosen from the radicals of formulas VII, VII 'or VU ":
  • GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': Formula XI * - NH- G- NH- * Formula CG
  • GpA is chosen from the radicals of formula VIII
  • GpC is a radical of formula IX: Form IX; the * indicate the sites of attachment of the different groups linked by amide functions;
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
  • C x is a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and 6 ⁇ x ⁇ 25:
  • G is a divalent linear or branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
  • R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms bearing one or more functions - CONH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • x is between 9 and 15 (9 ⁇ x ⁇ 15).
  • the GpR group bonded to PLG is chosen from GpR of formula VII.
  • the GpR group linked to the PLG is chosen from the GpRs of the formula VII and the second GpR is chosen from the GpRs of the formula VU ".
  • the GpR group bonded to the PLG is chosen from the GpR of formula VU ".
  • the group GpR linked to the PLG is chosen from the GpRs of the formula VII and the second GpR is chosen from the GpRs of the formula VII.
  • GpR, GpG, GpA, GpL, GpH, GpC, a, a ', g, h, I have the definitions given above.
  • GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula Xc as defined below: Formula Xc
  • GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula Xc as defined below: Formula Xc
  • GpR is a radical of formula VII ".
  • GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and G have the definitions given above.
  • GpRi is a radical of formula VII.
  • GpR, GpA, GpH, GpC, r and h have the definitions given above.
  • GpA is a radical chosen from radicals of formula VUId and GpR, GpC, r are as defined above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below: Formula Xo
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below:
  • GpR, GpG, GpL, GpH, GpC, r, g, h, I and G have the definitions given above.
  • Formula Xb in which GpA, GpR, GpG, GpL, GpH, GpC, r, g, h, I and G have the definitions given above.
  • GpR, GpG, GpL, GpH, GpC, Al, A2, r, g, h, I and G have the definitions given above.
  • GpR, GpH, GpG, GpC, Al, B, Cx, G, H, R are as previously defined;
  • GpR, GpG, GpA, GpH, GpC, r, g and h have the definitions given above.
  • GpR, GpG, GpA, GpC, r, a and g have the definitions given above.
  • GpR, GpG, GpA, GpC, r and g have the definitions given above.
  • GpR, GpG, GpA, GpL, GpC, r, g, a, I, and a ' have the definitions given above.
  • GpR, GpA, GpL, GpC and r have the definitions given above.
  • GpR, GpA, GpL and GpC have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formulas X, Xa to Xu:
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which
  • GpC are directly or indirectly related to N ai and N a 2 and PLG is directly or indirectly linked via GpR to Npi, or
  • the GpCs are directly or indirectly related to N ai and Npi, and the PLG is linked directly or indirectly via GpR to N; or
  • GpCs are directly or indirectly related to "2 and Npi, and PLG is directly or indirectly linked via -GpR to May.
  • GpCs are directly or indirectly related to N ai and and the PLG is directly or indirectly related to Npi; or
  • the GpCs are directly or indirectly related to N ai and Npi, and the PLG is directly or indirectly linked to N 02; or
  • GpCs are directly or indirectly related to Na ⁇ , N a 2 and Npi and PLG is directly or indirectly linked via GpR to IM b 2; or
  • the GpCs are directly or indirectly related to N "i, N ai and Np2 and the PLG is linked directly or indirectly via GpR to Npi; or
  • the GpCs are directly or indirectly related to N "i, Npi and Np2 and the PLG is directly or indirectly linked via -GpR- to N"2; or the GpCs are directly or indirectly related to N a , Npi and Npz and the P LG is linked directly or indirectly via GpR to N ai .
  • the GpCs are directly or indirectly related to N "i, N and Npi and the LG P is directly or indirectly related to Np; or
  • the GpC are directly or indirectly related to N 'i, N and N b and the LG P is linked directly or indirectly to Nj ";
  • N - GpC are directly or indirectly related to N a i, Npi and Np and the PLG is directly or indirectly related to Na;
  • the GpCs are directly or indirectly related to N U , Npi and p and the PLG is directly or indirectly linked to Mai.
  • the * indicate the sites of attachment of the hydrophobic radicals to the PLG or between the different groups GpR, GpG, GpA, GpL, GpH and GpC to form amide functions.
  • radicals -Hy are attached to the PLG via amide functions.
  • g is greater than or equal to 2 (g32).
  • h is greater than or equal to 2 (h> 2).
  • g or h is greater than or equal to 2 (g> 2) and b is equal to 0.
  • h is greater than or equal to 2 (g> 2)
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 5 carbon atoms and bearing one or more amide functional groups ( -CONH2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 5 carbon atoms and carrying one or more amide functional groups. (-CONH2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is bonded to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or position 4 or 5) relative to the amide function (-CONH2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 carbon atoms. oxygen atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical represented by the formula
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms. .
  • the composition is characterized in that the hydrophobic radical of formula X is a radical 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 X is a radical in which R is a radical of formula X3.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X4.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X5.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X6.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by formulas x5 and X6 below. :
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpG and / or GpH radical is of formula CG wherein G is an alkyl radical comprising 6 carbon atoms represented by the formula Z below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 4 carbon atoms. represented by the formula Z 'below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by - (CH2) 2-CH (COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by -CH ((CH2) 2COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH 2 -CH- (COOH).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH (CH2) (COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpA is of formula VIII and wherein A 1 , A 2 or As is selected from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXe, IXf or IXg ci- after represented:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXe, IXf or IXg in which b is equal to 0, respectively corresponding to formulas IXh, IXi, and IXj hereinafter represented:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of branched alkyl radicals.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 9 and 14 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical 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 of formula X is a radical 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 of formula X is a radical 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 of formula X is a radical 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 of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical 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 of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical is a radical of formula X 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 by alkyl radicals comprising 14 or 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula X 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 by the radicals represented by the formulas below i
  • x is between 9 and
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.35. [000367] In one embodiment, the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.03 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the Cx radical comprises between 11 and and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.05.
  • the basal insulin hydrophobic radical ratio is defined as being the ratio of their respective molar concentrations: [Hy] / [basal insulin] (mol / mol) to obtain the expected performances, namely the solubilization of insulin. Basal pH at pH 6.0 to 8.0, the precipitation of basal insulin and the stability of the compositions according to the invention.
  • the minimum value of the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin], measured is the value at which the basal insulin is solubilized, since solubilization is the minimum effect to obtain; this solubilization conditions all the other technical effects that can only be observed if the basal insulin is solubilized at pH between 6.0 and 8.0.
  • the hydrophobic radical ratio by basal insulin [Hy] / [basal insulin] may be greater than the minimum value determined by the solubilization limit.
  • the hydrophobic radical ratio by basal insulin is the hydrophobic radical ratio by basal insulin
  • the hydrophobic radical ratio by basal insulin is the hydrophobic radical ratio by basal insulin
  • the hydrophobic radical ratio by basal insulin is the hydrophobic radical ratio by basal insulin
  • the invention also relates to a method for preparing stable injectable compositions.
  • the invention also relates to said co-polyamino acids I, carrying carboxylate charges and hydrophobic radicals of formula X and the precursors of said hydrophobic radicals.
  • the invention also relates to a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula X, said copolyamino acid being chosen from the copolyamino acids of formula I:
  • said co-polyamino acid of formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and consisting of at least two chains of glutamic or aspartic units P LG linked together by a radical or spacer Q [ - *] k linear or branched at least divalent consisting of an alkyl chain comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions,
  • radical or spacer Q [- *] K being linked to the at least two chains of P glutamic or aspartic units LG by an amide function
  • said amide functions linking said radical or spacer Q [- *] k bonded to the at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,
  • Co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I are soluble in distilled water at a pH between 6.0 and 8.0, at a temperature of 25 ° C. and at a lower concentration. at 100 mg / ml.
  • the invention also relates to the precursors Hy 'of said hydrophobic radicals of formula X' as defined below: Formula X 'in which
  • GpR is chosen from the radicals of formulas VII, VU 'or VU ": ;
  • GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': * - NH- G- NH- *
  • GpA is chosen from the radicals of formula VIII
  • Formula VIII 'Formula VIII' Formula VIII '-GpL is chosen from the radicals of formula XII Form XII,
  • GpC is a radical of formula IX: Form IX; the * indicate the sites of attachment of the different groups linked by amide functions;
  • a ' is an integer equal to 1, to 2 or to 3
  • b is an integer equal to 0 or 1;
  • - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
  • s' is an integer equal to 0 or 1;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
  • C x is a radical selected from the group consisting of a linear or branched monovalent alkyl radical, optionally comprising a cyclic moiety, wherein x denotes the number of carbon atoms and 6 ⁇ x ⁇ 25:
  • G is a divalent linear or branched alkyl radical comprising from 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
  • R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more -CONH 2 functions or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • the co-polyamino acid is selected from the group of copolyamino acids of formula I, wherein Q [- *] k is a radical of formula III.
  • the co-polyamino acid is a sodium poly-L-glutamate modified at two of its ends, of formula ci -a as shown, described in Example B14.
  • the co-polyamino acid is a sodium poly-L-glutamate modified at two of its ends, of the formula shown below, described in FIG.
  • the co-polyamino acid is a sodium poly-L-glutamate modified at two of its ends, of formula represented below, described in Example B23,
  • the composition according to the invention is characterized in that the co-polyamino acid is derived 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 ring opening polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative.
  • 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 glutamic acid N-carboxyanhydride derivative or a derivative thereof. of aspartic acid N-carboxyanhydride as described in Adv. Polym. Sci. 2006, 202, 1-18 (Deming, T.J.).
  • 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 glutamic acid N-carboxyanhydride derivative.
  • 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 glutamic acid N-carboxyanhydride derivative chosen from group consisting of methyl N-carboxyanhydride polyglutamate (GluOMe-IMCA), benzyl N-carboxyanhydride polyglutamate (GluOBzl-NCA) and t-butyl polyglutamate N-carboxyanhydride (GluOtBu-NCA).
  • a glutamic acid N-carboxyanhydride derivative chosen from group consisting of methyl N-carboxyanhydride polyglutamate (GluOMe-IMCA), benzyl N-carboxyanhydride polyglutamate (GluOBzl-NCA) and t-butyl polyglutamate N-carboxyanhydride (GluOtBu-NCA).
  • the glutamic acid N-carboxyanhydride derivative is methyl poly-L-glutamate N-carboxyanhydride (L-GluOMe-NCA).
  • the glutamic acid N-carboxyanhydride derivative is benzyl poly-L-glutamate N-carboxyanhydride (L-GluOBzl-NCA).
  • 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 glutamic acid N-carboxyanhydride derivative or a derivative thereof. of aspartic acid N-carboxyanhydride using as initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386-389 (Deming, TJ.).
  • 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 glutamic acid N-carboxyanhydride derivative or a derivative thereof. of aspartic acid N-carboxyanhydride using as initiator ammonia or a primary amine as described in patent FR 2,801,226 (Touraud, F. et al.) and references cited therein.
  • the initiator may be a polyamine to obtain polyamino acid comprising several PLG.
  • 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 glutamic acid N-carboxyanhydride derivative or a derivative thereof aspartic acid N-carboxyanhydride using hexamethyldisilazane as initiator as described in J. Am. Chem. Soc. 2007, 129, 14114-14115 (Lu H .; et al.) Or a silylated amine as described in J. Am. Chem. Soc. 2008, 130, 12562-12563 (Lu H. et al.).
  • the composition according to the invention is characterized in that the process for synthesizing the polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or an N-carboxyanhydride derivative 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 may consist of hydrolysis in an acidic medium or hydrolysis in a basic medium or may be carried out by hydrogenation. In one embodiment, this step of hydrolysis of ester groups is a hydrolysis in an acidic 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 is derived 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 is derived 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 selected from the group consisting of polyglutamate. of 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 onto a poly-L-glutamic acid or poly-L-aspartic acid using amide bond forming processes well known to those skilled 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 a poly-L-glutamic acid or poly-L-aspartic acid using the amide bond formation processes used for peptide synthesis.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a group hydrophobic on an acidic poly-L-glutamic or poly-L-aspartic acid as described in FR 2,840,614 (Chan, YP et al).
  • the one or more free carboxylic acid function (s) of Hy may be in protected form before the grafting on LG P via an acid-protecting group, this protection is carried out for example by esterification with using ethanol, 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 a salt.
  • alkaline cation selected from the group consisting of IMa + and K +.
  • the one or more amine function (s) can be in protected form before the grafting on LG P via an amine protecting group, this protection is carried out for example by an acidic or basic hydrolysis under heat via phenylmethoxycarbonyl group or 1,1-dimethylethoxycarbonyl group.
  • the functions are deprotected, that is to say that a deprotection reaction is performed so that the function (s) amine (s) free (s).
  • the units used for insulins are those recommended by pharmacopoeia whose correspondences in mg / ml are given in the table below:
  • 8.5 are recombinant insulins whose primary structure has been modified mainly by introduction of basic amino acids such as Arginine or Lysine. They are described for example in patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the contents of which are incorporated by reference.
  • the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine.
  • Insulin glargine is marketed under the trademark Lantus® (100 U / ml) or Toujeo® (300 U / ml) by SANOFI.
  • the basal insulin whose isoelectric point is between 5.8 and 8.5 is a biosimilar insulin glargine.
  • a biosimilar insulin glargine is being commercialized under the brand Abasaglar® or Basaglar ® by Eli Lilly.
  • compositions according to the invention comprise between 40 and 500 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 40 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 100 U / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 150 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 200 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 225 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 250 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 500 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5.
  • the mass ratio between the basal insulin, whose isoelectric point is between 5.8 and 8.5, and the co-polyamino acid, or co-polyamino acid / basal insulin is between 0.2 and 8.
  • the mass ratio is between 0.2 and 6.
  • the mass ratio is between 0.2 and 5.
  • the mass ratio is between 0.2 and 3.
  • the mass ratio is between 0.2 and 2.
  • the mass ratio is between 0.2 and 1.
  • compositions according to the invention further comprise a mealtime insulin.
  • Prandial insulins are soluble at pH 7.
  • Meal insulin means a so-called fast insulin or "regu la r”.
  • fast prandial insulins are insulins that 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” meal insulin is human insulin.
  • the prandial insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
  • Human insulin is for example marketed under the trademarks Humuiin ® (ELI LILLY) and Novolin ® (NOVO NORDISK).
  • the so-called fast acting prandial insulins are insulins which are obtained by recombination and whose primary structure has been modified to reduce their time of action.
  • the prandial insulins say very fast (fast acting) are selected from the group consisting of insulin lispro (Humalog ®), insulin glulisine (Apidra ®) and insulin aspart (NovoLog ® ).
  • the prandial insulin is insulin lispro.
  • the mealtime insulin is insulin glulisine.
  • the mealtime insulin is insulin aspart.
  • the compositions according to the invention comprise in total between 60 and 800 U / mL of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8. and 8.5.
  • compositions according to the invention comprise in total between 100 and 500 U / mL of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8. and 8.5.
  • compositions according to the invention comprise a total of 800 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 700 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 600 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 500 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 400 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 300 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 266 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • compositions according to the invention comprise a total of 200 U / ml of insulin with a combination of prandial insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • the compositions according to the invention comprise a total of 100 U / ml of insulin with a combination of mealtime insulin and basal insulin whose isoelectric point is between 5.8 and 8, 5.
  • the proportions between the basal insulin whose isoelectric point is between 5.8 and 8.5 and the prandial insulin are for example in the percentage of 25/75, 30/70, 40/60, 50/50. , 60/40, 63/37, 70/30, 75/25, 80/20, 83/17, 90/10 for formulations as described above comprising from 60 to 800 U / mL.
  • any other proportion can be realized.
  • the basal insulin whose isoelectric point is between 5.8 and 8.5 and the prandial insulin are respectively present in the following concentrations (in U / ml) 75/25.
  • the basal insulin whose isoelectric point is between 5.8 and 8.5 and the prandial insulin are respectively present in the following concentrations (in U / ml) 150/50.
  • compositions according to the invention further comprise a gastrointestinal hormone.
  • gastrointestinal hormones the hormones selected from the group consisting of GLP-1 RA (glucagon like peptide-1 receptor agonist) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin, their analogs or derivatives and / or their pharmaceutically acceptable salts.
  • GLP-1 RA glucagon like peptide-1 receptor agonist
  • GIP Glucose-dependent insulinotropic peptide
  • oxyntomodulin a derivative proglucagon
  • peptide YY amylin
  • cholecystokinin pancreatic polypeptide
  • enterostatin their analogs or derivatives and / or their pharmaceutically acceptable salts.
  • the gastrointestinal hormones are analogs or derivatives of GLP-1 RA selected from the group consisting of exenatide or Byetta ® (AstraZeneca), liraglutide or Victoza® (NOVO NORDISK ), or the lixisenatide Lyxumia ® (SAIMOFI), the albiglutide or Tanzeum® (GSK) or Dulaglutide or Trulicity ® (ELI LILLY & CO), analogues or derivatives thereof and their pharmaceutically acceptable salts.
  • GLP-1 RA GLP-1 RA selected from the group consisting of exenatide or Byetta ® (AstraZeneca), liraglutide or Victoza® (NOVO NORDISK ), or the lixisenatide Lyxumia ® (SAIMOFI), the albiglutide or Tanzeum® (GSK) or Dulaglutide or Trulicity ® (ELI LILLY & CO), analogues or derivatives thereof and their pharmaceutically acceptable
  • the gastrointestinal hormone is pramlintide or Symlin ® ® (ASTRA-ZENECA).
  • the gastrointestinal hormone is exenatide or Byetta®, its analogues or derivatives and their pharmaceutically acceptable salts.
  • gastrointestinal hormone is liraglutide or Victoza ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is lixisenatide or Lyxumia®, its analogues or derivatives and their pharmaceutically acceptable salts.
  • the gastrointestinal hormone is albiglutide or Tanzeum®, its analogues or derivatives and their pharmaceutically acceptable salts.
  • gastrointestinal hormone is Dulaglutide or Trulicity ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • gastrointestinal hormone is pramlintide or Symlin ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • analogue is meant, when used with reference to a peptide or protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted by other residues of amino acid and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added.
  • the percentage of homology allowed for the present definition of an analogue is 50%.
  • derivative when used with reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or the protein or the reference analogue, i.e., a peptide or protein that has been modified by creation of covalent bonds, to introduce substituents.
  • the substituent is selected from the group consisting of fatty chains.
  • the concentration of gastrointestinal hormone is in a range of 0.01 to 100 mg / mL.
  • the concentration of exenatide, its analogs or derivatives and their pharmaceutically acceptable salts is in a range of 0.04 to 0.5 mg / mL.
  • the concentration of liraglutide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 1 to 10 mg / mL.
  • the concentration of lixisenatide, its analogues or derivatives and their pharmaceutically acceptable salts is in a range of 0.01 to 1 mg / mL.
  • the concentration of albiglutide, its analogs or derivatives and their pharmaceutically acceptable salts is between 5 to 100 mg / ml.
  • the concentration of dulaglutide, its analogues or derivatives and their pharmaceutically acceptable salts is between 0.1 to 10 mg / ml.
  • the concentration of pramlintide, its analogues or derivatives and their pharmaceutically acceptable salts is between 0.1 to 5 mg / ml.
  • the compositions according to the invention are produced by mixing commercial solutions of basal insulin whose isoelectric point is between 5.8 and 8.5 and commercial solutions of GLP-1 RA. of analog or derivative of GLP-1 RA in volume ratios ranging from 10/90 to 90/10.
  • the composition according to the invention comprises a daily dose of basal insulin and a daily dose of gastrointestinal hormone.
  • compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and, between 0.05 and and 0.5 mg / mL exenatide.
  • compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and, from 1 to 10 mg / mL liraglutide.
  • compositions according to the invention comprise between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.01. at 1 mg / mL lixisenatide.
  • compositions according to the invention comprise between 40 U / ml and 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 5 to 100. mg / mL albiglutide.
  • compositions according to the invention comprise between 40 U / mL and 500 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and of 0.1 at 10 mg / mL dulaglutide.
  • compositions according to the invention comprise 500 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 500 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 500 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 500 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 5 to 100 mg / ml of albiglutide. .
  • compositions according to the invention comprise 500 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg. / mL of exenatide.
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide.
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.01 to 1 mg / ml of lixisenatide.
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 5 to 100 mg / ml of albiglutide. .
  • compositions according to the invention comprise 400 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.1 to 10 mg / ml of Dulaglutide.
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg / ml. mL of exenatide.
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide.
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.01 to 1 mg / ml of lixisenatide.
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 5 to 100 mg / ml of albiglutide. .
  • compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.1 to 10 mg / ml of Dulaglutide.
  • compositions according to the invention comprise 225 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg / ml. mL of exenatide.
  • compositions according to the invention comprise 225 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide. In one embodiment, the compositions according to the invention comprise 225 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide. In one embodiment, the compositions according to the invention comprise 225 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 225 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 225 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 200 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg / ml. mL of exenatide.
  • compositions according to the invention comprise 200 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide.
  • compositions according to the invention comprise 200 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 200 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 200 U / ml of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 100 U / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg / mL of exenatide.
  • compositions according to the invention comprise 100 U / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / mL of liraglutide.
  • compositions according to the invention comprise 100 U / ml (ie approximately 3.6 mg / ml) of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.01 to 1 mg / mL of lixisenatide.
  • compositions according to the invention comprise 100 U / mL of basal insulin whose isoelectric point is between
  • compositions according to the invention comprise 100 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.1 to 10 mg / ml of Dulaglutide.
  • compositions according to the invention comprise 40 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.04 to 0.5 mg / ml. mL of exenatide.
  • compositions according to the invention comprise 40 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 1 to 10 mg / ml of liraglutide.
  • compositions according to the invention comprise 40 U / mL of basal insulin whose isoelectric point is between 5.8 and 8.5 and 0.01 to 1 mg / mL of lixisenatide.
  • compositions according to the invention comprise 40 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 5 to 100 mg / ml of albiglutide. .
  • compositions according to the invention comprise 40 U / ml of basal insulin whose isoelectric point is between 5.8 and 8.5 and from 0.1 to 10 mg / ml of Dulaglutide.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 5000 mM.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 4000 mM.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 3000 ⁇ M.
  • compositions according to the invention further comprise zinc salts at a concentration of between 0 and 2000 ⁇ M.
  • compositions according to the invention also comprise zinc salts at a concentration of between 0 and 1000 .mu.M.
  • compositions according to the invention also comprise zinc salts at a concentration of between 50 and 600 .mu.M. [000547] In one embodiment, the compositions according to the invention also comprise zinc salts at a concentration of between 100 and 500 mM.
  • compositions according to the invention further comprise zinc salts at a concentration of between 200 and 500 ⁇ M.
  • compositions according to the invention further comprise buffers.
  • compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM.
  • compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
  • compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, Tris (trishydroxymethylaminomethane) and sodium citrate.
  • the buffer is sodium phosphate.
  • the invention also relates to compositions which further comprise ionic species, said ionic species making it possible to improve the physicochemical stability of the compositions.
  • the invention also relates to the use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of the compositions.
  • the ionic species comprise less than 10 carbon atoms.
  • Said ionic species are chosen from the group of anions, cations and / or zwitterions.
  • Zwitterion means a species carrying at least one positive charge and at least one negative charge on two non-adjacent atoms.
  • Said ionic species are used alone or as a mixture and preferably in a mixture.
  • the anions are chosen from organic anions.
  • the organic anions comprise less than 10 carbon atoms.
  • the organic anions are chosen from the group consisting of acetate, citrate and succinate.
  • the anions are chosen from anions of mineral origin.
  • the anions of mineral origin are chosen from the group consisting of sulphates, phosphates and halides, especially chlorides.
  • the cations are chosen from organic cations.
  • the organic cations comprise less than 10 carbon atoms.
  • the organic cations are chosen from the group consisting of ammoniums, for example 2-amino-2- (hydroxymethyl) propane-1,3-diol, where the amine is in the form of amines. ammonium.
  • the cations are chosen from cations of mineral origin.
  • the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn 2+ and alkali metals, in particular Na + and K +,
  • the zwitterions are chosen from zwitterions of organic origin.
  • the zwitterions of organic origin are chosen from amino acids.
  • the amino acids are chosen from aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.
  • the amino acids are chosen from cyclic amino acids in the group consisting of proline.
  • the amino acids are chosen from hydroxylated or sulfur-containing amino acids in the group consisting of cysteine, serine, threonine, and methionine.
  • the amino acids are chosen from aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.
  • the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidated in the group consisting of asparagine and glutamine.
  • the zwitterions of organic origin are selected from the group consisting of amino acids having an uncharged side chain. In one embodiment, the zwitterions of organic origin are chosen from the group consisting of aminodiacides or acidic amino acids.
  • 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 comprise as many negative charges as positive charges and therefore a zero overall charge at the isoelectric point and / or at a pH between 6 and 8.
  • Said ionic species are introduced into the compositions in the form of salts.
  • the introduction of these can be in solid form before dissolution in the compositions, or in the form of a solution, in particular of concentrated solution.
  • the cations of mineral origin are provided in the form of salts selected from sodium chloride, zinc chloride, sodium phosphate, sodium sulfate, etc.
  • anions of organic origin are provided in the form of salts selected from sodium or potassium citrate, sodium acetate.
  • amino acids are added in the form of salts selected from arginine hydrochloride, histidine hydrochloride or non-salified form such as histidine, arginine.
  • the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 30 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 50 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 75 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 100 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 200 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 600 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1200 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 600 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 400 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 200 mM. In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 600 M.
  • the total molar concentration of ionic species in the composition is between 30 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 500 mM. [000667] In one embodiment, the total molar concentration of ionic species in the composition is between 20 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 300 mM. In one embodiment, the total molar concentration of ionic species in the composition is between 50 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 200 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 30 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 400 mM.
  • said ionic species are present in a concentration ranging from 5 to 300 mM.
  • said ionic species are present in a concentration ranging from 5 to 200 mM.
  • said ionic species are present in a concentration ranging from 5 to 100 mM.
  • said ionic species are present in a concentration ranging from 5 to 75 mM.
  • said ionic species are present in a concentration ranging from 5 to 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 25 mM.
  • said ionic species are present in a concentration ranging from 5 to 20 mM.
  • said ionic species are present in a concentration ranging from 5 to 10 mM.
  • said ionic species are present in a concentration ranging from 10 to 400 mM.
  • said ionic species are present in a concentration ranging from 10 to 300 mM.
  • said ionic species are present in a concentration ranging from 10 to 200 mM.
  • said ionic species are present in a concentration ranging from 10 to 100 mM.
  • said ionic species are present in a concentration ranging from 10 to 75 mM.
  • said ionic species are present in a concentration ranging from 10 to 50 mM. In one embodiment, said ionic species are present in a concentration ranging from 10 to 25 mM.
  • said ionic species are present in a concentration ranging from 10 to 20 mM.
  • said ionic species are present in a concentration ranging from 20 to 300 mM.
  • said ionic species are present in a concentration ranging from 20 to 200 mM.
  • said ionic species are present in a concentration ranging from 20 to 100 mM.
  • said ionic species are present in a concentration ranging from 20 to 75 mM.
  • said ionic species are present in a concentration ranging from 20 to 50 mM.
  • said ionic species are present in a concentration ranging from 20 to 25 mM.
  • said ionic species are present in a concentration ranging from 50 to 300 mM.
  • said ionic species are present in a concentration ranging from 50 to 200 mM.
  • said ionic species are present in a concentration ranging from 50 to 100 mM.
  • said ionic species are present in a concentration ranging from 50 to 75 mM.
  • its molar concentration within the composition may be between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.
  • the composition comprises zinc.
  • the composition comprises from 0.2 to 2 mM of zinc.
  • the composition comprises NaCl.
  • the NaCl is present in a concentration ranging from 2 to 25 mM.
  • the NaCl is present in a concentration ranging from 2.5 to 20 mM.
  • the NaCl is present in a concentration ranging from 4 to 15 mM. In one embodiment, the NaCl is present in a concentration ranging from 5 to 10 mM.
  • the buffer is Tris (trishydroxymethylaminomethane).
  • the buffer is sodium citrate.
  • compositions according to the invention further comprise preservatives.
  • the preservatives are selected from the group consisting of m-cresol and phenol, alone or as a mixture.
  • the concentration of the preservatives is between 10 and 50 mM.
  • the concentration of the preservatives is between 10 and 40 mM.
  • compositions according to the invention further comprise a surfactant.
  • the surfactant is selected from the group consisting of propylene glycol and polysorbate.
  • compositions according to the invention may further comprise additives such as tonicity agents.
  • the tonicity agents are selected from the group consisting of glycerine, sodium chloride, mannitol and glycine.
  • compositions according to the invention may further comprise all the excipients according to the pharmacopoeia and compatible with the insulins used at the concentrations of use.
  • the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
  • the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
  • transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
  • the invention also relates to single-dose formulations with a pH of between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.
  • the invention also relates to single-dose formulations having a pH of between 6.0 and 8.0 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin.
  • the invention also relates to single-dose formulations having a pH of between 6.0 and 8.0, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.
  • the invention also relates to single-dose formulations having a pH of between 6.0 and 8.0, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as than previously defined.
  • the invention also relates to single-dose formulations with a pH of between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a prandial insulin.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as than previously defined.
  • the invention also relates to single-dose formulations with a pH of between 6.6 and 7.6 comprising a basal insulin whose isoelectric point is between 5.8 and 8.5.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.6, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a mealtime insulin.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.6, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5 and a gastrointestinal hormone, as defined above.
  • the invention also relates to single-dose formulations having a pH of between 6.6 and 7.6, comprising a basal insulin whose isoelectric point is between 5.8 and 8.5, a mealtime insulin and a gastrointestinal hormone, such as than previously defined.
  • the single-dose formulations further comprise a co-polyamino acid as defined above.
  • the formulations are in the form of an injectable solution.
  • the composition according to the invention is characterized in that it is administered once a day.
  • composition according to the invention is characterized in that it is administered at least twice a day.
  • composition according to the invention is characterized in that it is administered twice a day.
  • composition according to the invention is characterized in that it further comprises a prandial insulin.
  • composition according to the invention further comprising at least one mealtime insulin is characterized in that it is administered
  • composition according to the invention further comprising at least one mealtime insulin is characterized in that it is administered at least twice a day.
  • composition according to the invention further comprising at least one prandial insulin is characterized in that it is administered
  • composition according to the invention is characterized in that it further comprises a gastrointestinal hormone.
  • composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered once a day.
  • composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered at least twice a day.
  • composition according to the invention further comprising at least one gastrointestinal hormone is characterized in that it is administered twice a day.
  • composition according to the invention is characterized in that the gastrointestinal hormone is a GLP-1 RA.
  • composition according to the invention further comprising a GLP-1 RA is characterized in that it is administered once a day.
  • composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered at least twice a day.
  • the composition according to the invention further comprising at least one GLP-1 RA is characterized in that it is administered twice a day. ".
  • the solubilization at pH between 6.0 and 8.0 of the basal insulins whose isoelectric point is between 5.8 and 8.5, by the co-polyamino acids carrying carboxylate charges and at least one radical hydrophobic according to the invention can be observed and controlled in a simple manner, with the naked eye, through a change in the appearance of the solution.
  • the Applicant has been able to verify that a basal insulin whose isoelectric point is between 5.8 and 8.5, solubilized at pH between 6.0 and 8.0 in The presence of a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical according to the invention retains its slow insulin action either alone or in combination with a mealtime insulin or a gastrointestinal hormone.
  • the Applicant has also been able to verify that a prandial insulin mixed at pH between 6.0 and 8.0 in the presence of a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical according to the invention. and a basal insulin whose isoelectric point is between 5.8 and 8.5, retains its fast insulin action.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5, and a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5. a solution of prandial insulin, and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5. a solution of GLP-1 RA, an analogue or a derivative of GLP-1 RA, and a co-polyamino acid carrying charges carboxylates and at least one hydrophobic radical according to the invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of an aqueous solution of basal insulin whose isoelectric point is between 5.8 and 8.5. a solution of prandial insulin, a solution of GLP-1 RA or an analogue or derivative of GLP-1 RA and a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to invention, in aqueous solution or in freeze-dried form. If necessary, the pH of the preparation is adjusted to pH between 6 and 8.

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EP18811570.3A 2017-12-07 2018-12-07 Injektionslösung mit einem ph-wert von 7 mit mindestens einem basalinsulin mit einem pi zwischen 5,8 und 8,5 und einer copolyaminosäure mit carboxylatladungen und hydrophoben radikalen Pending EP3723728A1 (de)

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US201762606138P 2017-12-07 2017-12-07
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PCT/EP2018/083897 WO2019110774A1 (fr) 2017-12-07 2018-12-07 Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes

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US20200179489A1 (en) * 2018-12-07 2020-06-11 Adocia Injectable solution at ph 7 comprising at least one basal insulin which pi is from 5.8 to 8.5 and a co-polyamino-acid bearing carboxylate charges and hydrophobic radicals and a limited amount of m-cresol
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EP4091625A1 (de) 2021-05-22 2022-11-23 Adocia Zusammensetzungen mit kurzwirkenden hormonen zur behandlung oder vorbeugung von fettleibigkeit und pumpen mit dieser zusammensetzung

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CA2889345A1 (fr) 2012-11-13 2014-05-22 Adocia Composes anioniques substitues constitues d'un squelette forme d'un nombre discret d'unites saccharidiques
FR3001895B1 (fr) 2013-02-12 2015-07-03 Adocia Solution injectable a ph7 comprenant au moins une insuline basale dont le point isoelectrique est compris en 5,8 et 8,5 et un compose anionique porteur de charges carboxylates et de radicaux hydrophobes
JP2016509912A (ja) 2013-03-15 2016-04-04 サノフィ−アベンティス・ドイチュラント・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 医療デバイスのための本体部材およびダイヤフラム材料
EP3102241B1 (de) 2014-02-03 2019-04-17 Eidgenössiche Technische Hochschule Zürich Kleinmolekülige arzneimittelkonjugate
BR112018075259A2 (pt) 2016-06-07 2019-03-12 Adocia composição na forma de uma solução aquosa injetável, cujo ph é de 6,0 a 8,0
FR3052071B1 (fr) 2016-06-07 2018-09-07 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon et un co-polyaminoacide
FR3052072A1 (fr) 2016-06-07 2017-12-08 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes
EP3562500B1 (de) * 2016-12-27 2023-07-19 Adocia Zusammensetzungen in form einer injizierbaren wässrigen lösung mit amylin, einem amylin-rezeptor-agonist oder einem amylin-analogon und einer copolyaminosäure
TWI813604B (zh) 2017-12-07 2023-09-01 法商阿道洽公司 包含至少一具有pi從5.8至8.5之基礎胰島素以及一帶有羧酸鹽電荷及疏水基之共聚胺基酸的可注射ph7溶液
EP3720471B1 (de) 2017-12-07 2023-11-29 Adocia Zusammensetzungen in form einer injizierbaren wässrigen lösung mit menschlichem glucagon und einer copolyaminosäure
MX2020005913A (es) 2017-12-07 2020-10-19 Adocia Solución inyectable a ph 7 que comprende al menos una insulina basal que tiene un pi de entre 5.8 y 8.5 y un copoliaminoácido con cargas de carboxilato y radicales hidrofóbicos.
US11173109B2 (en) 2017-12-07 2021-11-16 Adocia Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog and a co-polyamino acid
US10987426B2 (en) 2017-12-07 2021-04-27 Adocia Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
AU2018380901A1 (en) 2017-12-07 2020-06-11 Adocia Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog and a copolyamino acid
US20190388515A1 (en) 2017-12-07 2019-12-26 Adocia Injectable solution at ph 7 comprising at least one basal insulin the pi of which is from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals
US20200179489A1 (en) 2018-12-07 2020-06-11 Adocia Injectable solution at ph 7 comprising at least one basal insulin which pi is from 5.8 to 8.5 and a co-polyamino-acid bearing carboxylate charges and hydrophobic radicals and a limited amount of m-cresol

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WO2019110774A1 (fr) 2019-06-13
TW201938190A (zh) 2019-10-01
US11633460B2 (en) 2023-04-25
CN111836616B (zh) 2024-01-16
IL275148A (en) 2020-07-30
JP2024059693A (ja) 2024-05-01
IL275148B1 (en) 2024-10-01
KR20200106892A (ko) 2020-09-15
JP2021505605A (ja) 2021-02-18
SA520412142B1 (ar) 2024-04-29
CA3084689A1 (fr) 2019-06-13
MX2020005914A (es) 2020-10-19
MA51127A (fr) 2021-03-17
PH12020550803A1 (en) 2021-05-17
CN111836616A (zh) 2020-10-27
US20190275115A1 (en) 2019-09-12
BR112020011486A2 (pt) 2020-11-17

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