Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K38/00—Medicinal preparations containing peptides
  • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
  • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
  • A61K38/22—Hormones
  • A61K38/28—Insulins
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—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
  • 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
  • A61K47/42—Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • 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

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.
• ADOs oral antidiabetic drugs
• Metformin oral antidiabetic drugs
• 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.
• 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 glucose is too high, for example after a meal.
• the gastrointestinal hormones are also called satiety hormones. These 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 and
• 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 mealtime insulin before each food intake, ie approximately 2 to 3 injections per day.
• 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 most commonly used basal insulins are Levemir ® (insulin detemir from NOVO NORDISK) and Lantus ® (insulin glargine from 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 over time.
• the release profile is bell-shaped and lasts only between 12 and 16 hours. It is injected twice a day. This insulin based NPH is much less effective than modern basal insulins, 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 the albumi 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 degludec insulin sold under the name Tresiba® d . It also comprises a fatty acid side chain attached to insulin (hexadecandioyl-YL-Glu).
• Insulin glargine is an analogue of human insulin obtained by elongation of the C-terminal portion of the B chain of human insulin by two arginine residues, and by substitution of the asparagine residue A21 with a residue of glycine (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 render this insulin analog human insoluble in a physiological medium.
• the substitution of I ⁇ 21 was designed to make insulin glargine stable at acidic pH and can thus formulate it as an injectable solution at acidic pH.
• the passage of insulin glargine from an acidic pH (pH 4-4.5) at 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.
• 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 have the major disadvantage of not being sufficiently stable to 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 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:
• radical or spacer Q [- *] i being bonded to the at least two glutamic or aspartic unit chains PLG by an amide function and
• radical or spacer Q [- *] i being bonded to at least one hydrophobic radical-Hy of formula X below defined by an amide function.
• said amide functions linking said radical or spacer Q [- *] i 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 [- *] i either by a glutamic or aspartic unit.
• the amide function linking said radical or spacer Q [- *] i to at least one hydrophobic radical-Hy of formula X results from the reaction between an amine function and an acid function borne either by the precursor Q 'of the radical or spacer Q [- *] i by the precursor Hy 'of the hydrophobic radical-Hy;
• At least one hydrophobic radical -Hy is linked either to a terminal "amino acid” unit or to a carboxyl function carried by one of the PLG glutamic or aspartic unit chains.
• radical or spacer Q [- *] i being linked to the at least two chains of glutamic or aspartic units P LG by an amide function and
• radical or spacer Q [- *] i being bonded to the at least one hydrophobic radical-Hy of formula X by an amide function.
• said amide functions linking said radical or spacer Q [- *] i 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 [- *] i either by a glutamic or aspartic unit.
• the amide function linking said radical or spacer Q [- *] i to at least one hydrophobic radical-Hy of formula X results from the reaction between an amine function and an acid function borne either by the precursor Q 'of the radical or spacer Q [- *] i by the precursor Hy 'of the hydrophobic radical-Hy.
• the pH of the compositions according to the invention is between 6.0 and 8.0, preferably between 7 and 7.8, preferably between 6.6 and 7.8 or even more preferentially between 6 and 8.0. 8 and 7.6.
• Said co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -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 60 mg / ml.
• 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 injectable solution water-based solutions that meet the requirements of EP and US pharmacopoeia.
• co-polyamino acid consisting of glutamic or aspartic units non-cyclic linear chains of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a C-terminal portion. , corresponding 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 u concentration less than 60 mg / ml in distilled water at 25 ° C.
• alkyl radical means a carbon chain, linear or branched, which does not include a heteroatom.
• the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
• composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.
• radical or spacer Q [- *] i (i> 3) is represented by a radical of formula II:
• radicals Q being identical or different and chosen from the group consisting of the following radicals of formulas III to VI, to form
• At least one of ui "or U2" is different from 0.
• ui 'and U2' are the same or different and,
• Fc, Fc 'and Fc are 1 -NH- and 2 -CO- then no conditions. In one embodiment, if Fc, Fc 'and Fc "are -CO- then at least one of v, v' and v" is different from 0.
• Hy and P LG being bound to Q [- *], by a function Fx or Fy by a covalent bond to form an amide bond with a function -NH- or -CO- LG P or Hy.
• a real isation mode 1 ⁇ q ⁇ 4.
• At least one of Q ' is a radical of formula
• the precursor of the radical of formula III is a diamine chosen from the group consisting of ethylene diamine, butylenediamine, hexylenediamine, 1,3-diaminopropane and 1,5-diamine. nopentane ,.
• t 2 and the precursor of the radical of formula III is ethylene diamine.
• 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. In one embodiment, 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.
• t 2 and and the precursor of the radical of formula 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 III is aminobutanoic acid.
• 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 and the precursor of the radical of formula
• 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 chosen 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 and 2,3-diaminopropionic acid.
• At least one of Q ' is a radical of formula
• 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
• the precursor of the radical of formula V is a triamine selected from the group consisting of (2- (aminomethyl) propane-1,3-diamine).
• At least one of Q ' is a radical of formula VI
• 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 "i 0 and the precursor of the radical of formula VI is norspermidine.
• w "2 1 and the precursor of the radical of formula VI is a tetra mi ne.
• w " ⁇ 1 and the precursor of the radical of formula VI is triethylenetetramine
• the PLGs are linked to Fx with Fx -NH- or to Fy by the carbonyl function at the C-terminal position of the PLG.
• the Hy are linked to Fy by a carbonyl function of Hy carried by GpR, GpA, GpG, GpH, GpL or GpC.
• co-polyamino acid is a copolyamino acid of general formula I:
• Hy defined by the formula X is linked to Q 'via a covalent bond to Fa, Fa', Fb, Fb ', Fd, Fd' or Fy thus forming an amide bond
• Hy is linked to Q 'via a covalent linkage between Fy and a carbonyl function of Hy carried by GpR, GpA, GpG, GpH, GpC or GpL to form an amide bond.
• Q ' is a radical of formula VI.
• co-polyamino acid is a copolyamino acid of general formula I:
• Hy is defined by the formula X, bound to Q 'via a covalent bond to Fc, Fc', Fc ', Fb, Fb', Fa or Fa 'thus forming an amide bond
• Hy is bound to Q 'via a covalent linkage with a G-R-GpR, GpG, GpA, GpH, GpL or GpC-supported carbonyl function to form an amide linkage.
• Hy is bound to Q 'via a covalent linkage with an amine function of Hy carried by GpR, GpG, GpA, GpL or GpH to form an amide bond.
• the P LG chains are linked to Q 'via a covalent bond between Fc, Fc ", Fb, Fb', Fa or Fa 'and the carbonyl function at the C-terminal position of the PLG chain, thus forming an amide bond.
• the PLG chains are linked to Q 'via a covalent bond between Fc, Fc ", Fb, Fb', Fa or Fa 'and the amine function in the N-terminal position of the PLG chain, forming thus an amide bond.
• Q ' is a radical of formula V linked to one or two radicals of formula III and 2 ⁇ q ⁇ 3.
• Q ' is a radical of formula V linked to one or two radicals of formula IV and 2 ⁇ q ⁇ 3.
• the 2 PLG chains being bound to Q 'via a covalent bond with Fa, Fa', Fb, Fb 'or Fc, Fc', Fc ", thus forming an amide bond.
• the 2 Hy are defined by the formula X, bound to Q 'via a covalent bond with Fc', forming an amide bond, and the 2 PLG chains being bound to Q 'via a covalent bond with Fc ", thereby forming an amide bond.
• q 2.
• Fc is -CO- and Fa, Fa ', Fb and Fb' are -NH-.
• Fc ' is -NH- and Hy is linked to Fc' by the carbonyl function carried by GpR, GpG, GpA GpH, GpC or GpL of Hy.
• Fc "is -NH- and PLG is linked to Fc" by the carbonyl function at the C-terminal position of the PLG.
• Q is a radical formed from the radicals chosen from the radicals of formula IV or V with at least two radicals of formula V, with 2 ⁇ q ⁇ 3 and Q [-] i is a radical in which i-4.
• the 2 PLG chains being bound to Q 'via a covalent bond with Fd or Fd', thus forming an amide bond.
• Q ' are chosen from the group of radicals of formulas III, IV, V or VI with at least two radicals chosen from radicals of formula V and radicals of formula VI, with 2 ⁇ 2> q ⁇ 5 and Q [-] i is a radical in which 4 ⁇ i ⁇ 6
• co-polyamino acid is a copolyamino acid of general formula I:
• Hy defined by the formula X is linked to Q 'via a covalent bond with Fa, Fb, Fc or Fy, forming an amide bond,
• the k chains P LG being bound to Fa, Fa ', Fb, Fb', Fc ", Fd or Fd 'by a covalent bond, thus forming an amide bond.
• Hy is defined by the formula X, linked to Q 'via a covalent bond with Fc, forming an amide bond,
• Fc is ligated to a PLG chain by covalent bonding to form an amide bond.
• Fc is -N H- and is bonded to PLG by the carbonyl at the C-terminal position to form an amide bond .
• Fc is -NH- and is bonded to the Hy carbonyl carried by GpR, GpA, GpG, GpH, GpL or GpC.
• said hydrophobic radical-Hy is chosen from 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 selected from the radicals VIII
• a ' is selected from radicals of formula VIII', VIII "or VIII '"
• -GpL is chosen from the radicals of formula XII Formed the XII,
• GpC is a radical of formula IX:
• Formula IX * indicates 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;
• s' is an integer equal to 0 or 1;
• A, A 1, I and A3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms;
• B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
• Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
• - G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more function (s) free carboxylic acid.
• H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
• R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms bearing one or more -CONH2 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 P LG 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 + .
• said at least one hydrophobic radical - Hy is chosen from radicals of formula X in which
• - GpR is chosen from the radicals of formulas VII, VU 'or VU ": ;
• GpG is chosen from the radicals of formula XI or CG: * - NH - G - NH - *
• GpC is a radical of formula IX:
• GpA is a radical of formula VUIb and
• a ' is equal to 2 then a is equal to 1, and GpA is a radical of formula Villa; b is an integer equal to 0 or 1;
• - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
• d is an integer equal to 0, 1 or 2;
• e is an integer equal to 0 or 1;
• g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
• h is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
• r is an integer equal to 0 or 1
• s' is an integer equal to 0 or 1;
• - Ai is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms
• B is a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms;
• Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
• G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
• H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical bearing one or more free carboxylic acid function (s),
• R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms 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 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 polymerization DP in glutamic or aspartic units for the P LG 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 + .
• GpR is chosen from the radicals of formulas VII, VII or VII ": ;
• GpG is chosen from the radicals of formula XI or XI ':
• GpA is chosen from the radicals of formulas, Ville or VUId:
• GpC is a radical of formula IX
• Formula IX * indicates the sites of attachment of the different groups linked by amide functions
• a ' is an integer equal to 2 or 3 and
• GpA is a radical of formula Ville or VUId
• b is an integer equal to 0 or 1;
• c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
• e is an integer equal to 0 or 1;
• g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
• h is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
• r is an integer equal to 0 or 1
• s' is an integer equal to 1;
• Al, A2, A3, which are identical or different, are linear or branched alkyl radicals comprising from 1 to 6 carbon atoms;
• B is a linear or branched alkyl radical, optionally comprising an aromatic ring, comprising from 1 to 9 carbon atoms;
• Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
• the hydrophobic radical (s) Hy of formula X being linked to Q: via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q, thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor Hy ' of the hydrophobic radical, and o via a covalent bond between a nitrogen atom of the hydrophobic radical and a carbonyl carried by Q, thus forming an amide function resulting from the reaction of an amine function of the precursor Hy 'of the hydrophobic radical and a function acid carried by the precursor of the radical Q.
• G is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
• H is a branched alkyl radical of 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s),
• R is a radical chosen from the group consisting of a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions; COIMH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
• the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
• the degree of DP polymerization in glutamic or aspartic units for P LG 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 + .
• R is a radical chosen from the group consisting of:
• GpR is a radical of formula VII of 2 to 12 carbon atoms or if GpR is a radical of formula VII 'of 1 to 11 carbon atoms;
• a divalent alkyl radical linear or branched, comprising if GpR is a radical of formula VII of 2 to 11 carbon atoms or if GpR is a radical of formula VII 'of 1 to 11 carbon atoms, said alkyl radical carrying one or several functions -CONH2, and
• an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
• the * indicate the sites of attachment of the hydrophobic radicals to Q [- *] i.
• the radicals -Hy are attached to Q [- *] i via amide functions.
• the radicals Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently identical or different from one residue to another.
• r 0 and the hydrophobic radical of formula X is bonded to Q via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom carried by Q thus forming an amide function resulting from the reaction of an amine function carried by the precursor of Q and an acid function carried by the precursor Hy 'of the hydrophobic radical.
• r 1 and the hydrophobic radical of formula X is bound to Q:
• Formula Xa in which GpA is a radical of formula VIII and A 'is chosen from the radicals of formula VIII' with s' 0 and GpA is a radical of formula VIIIb
• GpR, GpG, GpA, GpL, GpH, GpC, Al, r, g, h, I and G have the definitions given above.
• Formula Xb in which GpA is a radical of formula VIII and A 'is chosen from the radicals of formula VIII' with s' 1 and GpA is a radical of formula Formula Villa Villa Formula
• GpR, GpG, GpA, GpL, GpH, GpC, Al, a ', r, g, h, I and G have the definitions given above.
• Formula Xb in which GpA is a radical of formula VIII and A is chosen from the radicals of formula VIII "with s' 1 and GpA is a radical of formula Ville City Formula
• GpR, GpG, GpA, GpL, GpH, GpC, Al, A2, r, g, h, a ', I and G have the definitions given above.
• GpR, GpG, GpA, GpL, GpH, GpC, Al, A2, A3, a ', r, 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 wherein GpR is a radical of formula VU '. Formula VU '
• said at least one hydrophobic radical - Hy is chosen from radicals of formula Xc as defined below: Formula Xc wherein GpR is a radical of formula VII. Formula VU '
• said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd as defined below:
• said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xd 'as defined below. :
• GpR, GpG, GpA, GpH, GpC, r, g, h, and a have the definitions given above.
• GpR, GpG, GpA, GpH, GpC, r, g and h have the definitions given above.
• GpR, GpG, GpA, GpC, r, a and g have the definitions given above.
• GpR, GpG, GpA, GpC, r and g have the definitions given above.
• GpR, GpA, GpC, r, a 'and a have the definitions given above.
• GpR, GpA, GpC, r and a have the definitions given above.
• GpA is a radical chosen from radicals of formula VUId and GpR, GpC, r are as defined above.
• co-polyamino acid is a copolyamino acid of general formula I:
• co-polyamino acid is a copolyamino acid of general formula I:
• Q ' are chosen from the group of radicals of formulas III, IV, V or VI with at least one radical of formula V and at least one radical of formula VI, with 2 ⁇ q ⁇ And Q [- *] i is a radical in which 4 ⁇ i ⁇ 6 and said co-polyamino acid is a copolyamino acid of general formula I:
• r 0, and GpA is chosen from radicals of formula Villa and VIIIb.
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xf, Xh, Xi, Xj, Xk, XI, Xd, Xn, Xp or Xm wherein r-1 and GpR is a radical of formula VII
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• GpR is a radical of formula VII, VII 'or VU ", wherein R is a linear radical polyether comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the GpA radical of formula Villa is chosen from the group consisting of the radicals of formulas VIIIaa and VUIab hereinafter represented:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the radical GpA of formula Villa is a radical of formula
• VUIab hereinafter represented:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,
• GpA radical of formula Ville is chosen from the group consisting of radicals in which Al and A2, which are identical or different, are chosen from linear alkyl radicals.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,
• GpA radical of formula Ville is chosen from the group consisting of radicals in which Al and A2, which are identical or different, are chosen from linear alkyl radicals comprising from 3 to 4 carbon atoms.
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,
• GpA radical of formula Ville is chosen from the group consisting of radicals in which Al and A 2 , which are identical, are chosen from linear alkyl radicals comprising 3 carbon atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg,
• radical GpA of formula Ville is chosen from the group consisting of the radicals VlIIca and VlIIcb:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the radical GpA of formula Ville is a radical of formula VlIIca.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the radical GpA of formula Ville is a radical of formula VIIIcb.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the precursor of the GpA radical of formula Ville is chosen from the group consisting of the triamines which are spermidine and norspermidine:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the precursor of the radical GpA of formula City is the spermidi ne.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xb, Xc, Xg, Xf, Xi, Xj, XI or Xp in which the precursor GpA Radical Formula City is norspermidine.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the radical GpA is selected from the group of radicals of the formula VUId in which Ai, fKi and As, which are identical or different, are chosen from linear alkyles containing from 3 to 4 carbon atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the radical GpA of formula IIG is selected from the group the group of radicals of form VUId wherein Al and Al identical are selected from linear al kyl radicals comprising 3 carbon atoms and A 2 is selected from linear al kyl radicals comprising 4 carbon atoms.
• the radical GpA of formula IIG is selected from the group the group of radicals of form VUId wherein Al and Al identical are selected from linear al kyl radicals comprising 3 carbon atoms and A 2 is selected from linear al kyl radicals comprising 4 carbon atoms.
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the radical GpA of formula VUId is a radical of formula VlIIda:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula Xm in which the precursor of the GpA radical of formula VIIId is spermine:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xd ', Xe, Xf, Xg, Xh, Xi , Xj, Xk, XI, Xn, Xp or Xm wherein the GpC radical of formula IX is selected from the group consisting of radicals of formulas IXa ', IXb' or IXe 'hereinafter shown:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xd ', Xe, Xf, Xg, Xh, Xi , Xj, Xk, XI, Xn, Xp or Xm wherein the GpC radical is of formula IXa '.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xd, Xe, Xf, Xg, Xh, Xi, Xj, Xk, XI, Xn, Xp or Xm in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXa ', IXb' or IXe 'in which b is equal to 0, corresponding respectively to formulas IXd, IXe , and IXf hereinafter represented:
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn in which wherein the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of linear alkyl radicals comprising from 11 to 25 carbon atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xc, Xe,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xc, Xe,
• the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of X, Xa, Xb, Xc, Xe, Xg,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of the radicals represented by the formulas below:
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn in which in which the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of alkyl radicals represented by the formulas below:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn in which wherein the GpC radical of formula IX is selected from the group consisting of radicals wherein Cx is selected from the group consisting of alkyl radicals of between 19 and 25 carbon atoms.
• the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn in which wherein the GpC radical of formula IX is selected from the group consisting of radicals wherein Cx is selected from the group consisting of alkyl radicals of between 19 and 25 carbon atoms.
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xe, Xg, Xh, Xj, Xk, Xn in which in which the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of alkyl radicals represented by the formulas below:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, Xi, Xj, XI, Xp in which Wherein the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of linear alkyl radicals comprising between 9 and 15 carbon atoms.
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc, Xf, Xg, XI, Xj, XI, Xp in which
• the GpC radical of formula IX is selected from the group consisting of radicals in which Cx is selected from the group consisting of the radicals represented by the formulas below:
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula X, Xa, Xb, Xc,
• co-polyamino acid comprises one or more aspartic unit (s), that (s) can undergo structural rearrangements.
• 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 a -CH2- group (aspartic unit) or a -CH2-CH2- group (glutamic unit),
• X represents a cationic entity selected from the group comprising alkaline cations
• R a and R a ' which may be identical or different, are a radical chosen from the group consisting of H, a C 2 to C 10 linear acyl group, a C 3 to C 10 branched acyl group, a benzyl group and an amino acid unit. "Terminal and a pyroglutamate,
• 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 Ra and R a ', identical or different, are selected from the group consisting of H and pyroglutamate.
• 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 represents, independently, either a -CH 2 - (aspartic unit) or a -CH 2 -CH 2 - (glutamic unit) group,
• X represents a cationic entity selected from the group comprising alkaline cations
• R a and Ra ' which may be identical or different, are a radical chosen from the group consisting of an H, a C 2 to C 10 linear acyl group, a C 3 to C 10 branched acyl group, a benzyl, an "amino acid”unit; terminal and a pyroglutamate,
• 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 + rri2 represents the number of glutamic units or aspartic units of the P LG chains of the co-polyamino acid not bearing the -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;
• composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa "below :
• D is, independently, either a -CH 2 - (aspartic unit) group or a -CH 2 -CH 2 - (glutamic unit) group,
• X represents a cationic entity selected from the group comprising alkaline cations
• Ra and Ra which may be identical or different, are at least one hydrophobic radical-Hy and a radical chosen from the group consisting of -Hy, H, a C2-C10 linear acyl group, a branched C3 acyl group, and CIO, a benzyl, a terminal "amino acid” unit and a pyroglutamate,
• 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;
• 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:
• R2 represents a radical or spacer of formula Q [- *] i as previously defined
• X represents a cationic entity selected from the group comprising alkaline cations
• R b and R b ' are a radical NR'R ", R' and R" are identical or different are selected from the group consisting of H, linear or branched or cyclic C2-IOC, benzyl and said alkyl R 'and R "may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms selected from the group consisting of O, N and S;
• 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.
• 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 :
• D independently represents either -CH 2 - (aspartic unit) or -CH 2 -CH 2 - (glutamic unit),
• X represents a cationic entity selected from the group comprising alkaline cations, Q, Hy and j have the meanings given above.
• Rb and Rb are a radical -NR'R ", R 'and R" identical or different being selected from the group consisting of H, alkyls linear or branched or cyclic C2 to CIO, benzyl and said alkyl R 'and R "may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may include heteroatoms selected from the group consisting of O, N and S;
• n l + m l represents the number of glutamic units or aspartic units of the P chains LG of the co-polyamino acid bearing a radical -Hy
• n2 + m2 represents the number of glutamic units or aspartic units of the P chains LG of the co-polyamino acid not carrying a 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 :
• D is, independently, either -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit),
• X represents a cationic entity selected from the group comprising alkaline cations, Rb and Rb, identical or different, are at least one hydrophobic radical-Hy and a radical chosen from the group consisting of a hydrophobic radical -Hy and a radical -NR'R ", R 'and R" identical or different being chosen from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and said R 'and R "alkyls may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may comprise heteroatoms selected from the group consisting of O, N and S;
• 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;
• 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
• a "co-polyamino acid with random grafting" is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXa 'and XXXb'.
• co-polyamino acid with defined grafting is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula XXXa, XXXa '", XXXb and XXXb'".
• the composition according to the invention 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, XXXa, XXXb. , XXXb 'or XXXb "wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is a group -CH2- (aspartic unit).
• the composition according to the invention 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 ', XXXa ", XXXb , XXXb 'or XXXb "wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is a group -CH 2 -CH 2 - (glutamic unit).
• the hydrophobic radical by basal insulin 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 the basal insulin at pH between 6.0 and 8.0, the basal insulin precipitation 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 composition according to the invention 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 according to the invention 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 according to the invention 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 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.
• the composition according to the invention is characterized in that n + m is between 15 and 80.
• the composition according to the invention is characterized in that n + m is between 15 and 65.
• composition according to the invention is characterized in that n + m is between 20 and 60.
• the composition according to the invention is characterized in that n + m is between 20 and 50.
• the composition according to the invention is characterized in that n + m is between 20 and 40.
• the invention also resides in a method for preparing stable injectable compositions.
• the invention also relates to the precursors of said hydrophobic radicals of formula X.
• the invention also relates to the co-polyamino acid of formula I Q [Hy] j [PLG] k
• radical or spacer Q [- *] i being linked to the at least two chains of glutamic or aspartic units P LG by an amide function and
• radical or spacer Q [- *] i being bonded to at least one hydrophobic radical - Hy of formula X hereinafter defined by an amide function.
• Said amide functions linking said radical or spacer Q [- *] i 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 [- *] i either by a glutamic or aspartic unit.
• the amide function linking said radical or spacer Q [- *] i to at least one hydrophobic radical - Hy of formula X results from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] i by the precursor Hy 'of the hydrophobic radical-Hy,
• the invention also relates to the compound of formula Ib precursor of the co-polyamino acid of formula I defined above:
• said compound of formula Ib consisting of the precursor of the linear or branched radical or spacer Q "'[- *] consisting of an alkyl chain comprising one or more heteroatoms chosen from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions said radical Q '"[- *] j bearing at least one hydrophobic radical monovalent-Hy bonded by amide bonds, and
• the invention also relates to the co-polyamino acid of formula the precursor of the co-polyamino acid of formula I defined above:
• said co-polyamino acid of formula la carrying carboxylate charges and consisting of at least two chains of glutamic or aspartic units P LG linked together by the precursor of the radical or spacer Linear or branched chain 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 locus Q "[- *] k being bonded to the at least two chains of glutamic or aspartic units P LG by an amide function and bearing after binding to the at least two chains of glutamic or aspartic units P LG at least amine or acid reactive functions, free,
• Said amide functions linking said radical or spacer Q "[- *] k to the at least two chains of glyamic 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,
• the at least one reactive functional group is not bonded to a radical Q 'or to the at least two chains of glutamic or aspartic units, they constitute carboxylic acid or amine free functions.
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization.
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a derivative of N-carboxy glutamic acid anhydride or a derivative thereof. of aspartic acid N-carboxyanhydride as described in Adv. Polym. Sci. 2006, 202, 1-18 (Deming, TJ.).
• the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative.
• the composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of methyl N-carboxyanhydride polyglutamate (GluOMe-NCA), benzyl N-carboxyanhydride polyglutamate (GluOBzl-NCA) and t-butyl polyglutamate N-carboxyanhydride (GluOtBu-NCA).
• GluOMe-NCA methyl N-carboxyanhydride polyglutamate
• GluOBzl-NCA benzyl N-carboxyanhydride polyglutamate
• GluOtBu-NCA t-butyl polyglutamate N-carboxyanhydride
• the N-carboxyanhydride derivative of glutamic acid is methyl N-carboxyanhydride poly-L-glutamate (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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative 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 PLG chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative of N-carboxyanhydride of aspartic acid 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 composition according to the invention is characterized in that the PLG chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative of Aspartic acid N-carboxyanhydride using as initiator hexamethyldisilazane 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 LG P chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof. aspartic acid N-ca rboxyanhydride, polymerization initiated by the amine functions carried by the radical or spacer Q [- *] i.
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of by N-carboxyanhydride methyl poly-glutamate (GluOMe-NCA), benzyl N-carboxyanhydride polyglutamate (GluOBzl-NCA) and t-butyl polyglutamate N-carboxanhydride (GluOtBu-NCA), initiated polymerization by the amine functions carried by the radical or spacer Q [- *] ,.
• GluOMe-NCA N-carboxyanhydride methyl poly-glutamate
• GluOBzl-NCA benzyl N-carboxyanhydride polyglutamate
• GluOtBu-NCA t-butyl polyglutamate N-carboxanhydride
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of the methyl poly-L-glutamate N-carboxyanhydride (L-GiuOMe-CA). ), polymerization initiated by the amine functions carried by the radical or spacer
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of the benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl- NCA), polymerization initiated by the amine functions carried by the radical or spacer
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof. aspartic acid N-ca rboxyanhydride, polymerization initiated by the amine functions carried by the precursor of the radical Q [- *] k [Hy] j .
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of by N-carboxyanhydride methyl poly-glutamate (GluOMe-NCA), benzyl N-carboxyanhydride polyglutamate (GluOBzl-NCA) and t-butyl polyglutamate N-carboxanhydride (GluOtBu-NCA), initiated polymerization by the amine functions carried by the precursor of the radical Q [- *] k [Hy] j.
• GluOMe-NCA N-carboxyanhydride methyl poly-glutamate
• GluOBzl-NCA benzyl N-carboxyanhydride polyglutamate
• GluOtBu-NCA t-butyl polyglutamate N-carboxanhydride
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of methyl poly-L-glutamate N-carboxyanhydride (L-GluOMe-IMCA ), polymerization initiated by the amine functions carried by the precursor of the radical Q [ - * MHy] j.
• L-GluOMe-IMCA methyl poly-L-glutamate N-carboxyanhydride
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are obtained by polymerization of the benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl- CA), polymerization initiated by the amine functions carried by the precursor of the radical Q [- * MHyjj.
• LG P chains constituting the co-polyamino acid are obtained by polymerization of the benzyl N-carboxyanhydride poly-L-glutamate (L-GluOBzl- CA), polymerization initiated by the amine functions carried by the precursor of the radical Q [- * MHyjj.
• the composition according to the invention is characterized in that the process for the synthesis of PLG chains constituting the co-polyamino acid, including the polymerization of a glutamic acid N-carboxyanhydride derivative or of an aspartic acid N-ca rboxyanhydride derivative comprises a step of hydrolyzing 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.
• 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 PLG chains constituting the co-polyamino acid are 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 PLG chains constituting the co-polyamino acid are 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 PLG chains constituting the co-polyamino acid are 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 PLG chains containing the co-polyamino acid are derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight. In one embodiment, the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight chosen from group consisting of sodium polyglutamate and sodium polyaspartate.
• the composition according to the invention is characterized in that the LG P chains constituting the co-polyamino acid are 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 LG P chains constituting the co-polyamino acid are derived from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
• composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid are derived from amide bond formation processes well known to those skilled in the art.
• the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid are derived from amide bond formation processes used for peptide synthesis.
• the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid are derived from amide bond formation processes described in patent FR 2,840,614 (Chan, YP) and al.).
• the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the P LG chains and the radical or spacer Q [- *] i and between the radical or spacer and the hydrophobic radical -Hy arise from amide bond formation processes well known to those skilled in the art.
• the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the P LG chains and the radical or spacer Q [- *] i and between the radical or spacer and the hydrophobic radical -Hy arise from amide bond formation processes used for peptide synthesis.
• the composition according to the invention is characterized in that the amide bonds present in the co-polyamino acid between the P LG chains and the radical or spacer Q [- *] i and between the radical or spacer Q [- *] i and the hydrophobic radical -Hy arise from amide bond formation processes described in patent FR 2,840,614 (Chan, YP et al).
• the units used for insulins are those recommended by pharmacopoeia whose correspondences in mg / ml are given in the table below:
• Basal insulin whose isoelectric point is between 5.8 and 8.5 insoluble insulin at pH 7 and whose duration of action is between 8 and 24 hours or more in the standard models of diabetes .
• basal insulins whose isoelectric point is between 5.8 and 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 the following patents, patent applications or publications WO 2003/053339, WO 2004/096854, US 5,656,722 and US 6,100,376, the content of which is 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 SAIMOFI.
• the basal insulin with an isoelectric point 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. In one embodiment, the 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
• compositions according to the invention comprise 200 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 250 U / mL of basal insulin whose isoelectric point is between
• 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
• 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 4.
• the mass ratio is between 0.2 and 3.
• the mass ratio is between 0.2 and 2.
• the weight ratio is between 0.2 and 1. In one embodiment, 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. In one embodiment, 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 compositions according to the invention further comprise a mealtime insulin. Prandial insulins are soluble at pH 7.
• Prandial insulin is understood to mean a so-called fast or "regular" insulin.
• fast prandial insulins are insulins which must meet the needs caused by the ingestion of proteins and carbohydrates during a meal, they must act in less than 30 minutes.
• the so-called "regular” meal insulin is human insulin.
• the prandial insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
• Human insulin is for example marketed under the brands Humulin ® (ELI LILLY) and Novolin ® (NOVO NORDISK).
• the so-called fast acting mellitus 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.
• compositions according to the invention comprise in total between 40 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. In one embodiment, 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 prandial 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 prandial 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 prandial 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 prandial 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 mealtime 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 percent 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.
• compositions according to the invention comprising a total of 40 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 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 ), lixisenatide or Lyxumia ® (SANOFI), albiglutide or Tanzeum ® (GSK) or dulaglutide or Trulicity ® (ELI LILLY & CO), their analogues or derivatives 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 ), lixisenatide or Lyxumia ® (SANOFI), albiglutide or Tanzeum ® (GSK) or dulaglutide or Trulicity ® (ELI LILLY & CO), their analogues or derivatives and their pharmaceutically acceptable
• the gastrointestinal hormone is pramlintide or Symlin® (ASTRA-ZENECA).
• gastrointestinal hormone is exenatide or Byetta ®, analogs or derivatives and their pharmaceutically acceptable salts.
• gastrointestinal hormone is liraglutide or Victoza ®, analogs or derivatives and their pharmaceutically acceptable salts.
• gastrointestinal hormone is lixisenatide or Lyxumia ®, analogs 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 it is used with reference to a peptide or a protein, a peptide or a protein, in which one or more constituent amino acid residues have been substituted by other amino acid residues and / or in which one or more constituent amino acid residues have been deleted and / or in which one or more 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 gastrointestinal hormone is in a range of 0.01 to 10 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 analogs or derivatives and their pharmaceutically acceptable salts is between 0.1 to 5 mg / ml.
• 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. [000435] In one embodiment, 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 / L 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 400 U / ml of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 400 U / m L 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 400 U / ml of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 300 U / mL of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 300 U / mL of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 300 U / ml of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 300 U / m L of basal insulin whose isoelectric point is between
• compositions according to the invention comprise 300 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 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
• 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 5.8 and 8.5 and from 0.01 to 1 mg / ml of lixisenatide.
• 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
• 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 from 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 further comprise zinc salts at a concentration of between 0 and 3000 .mu.M.
• compositions according to the invention also 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 ⁇ M.
• compositions according to the invention also comprise zinc salts at a concentration of between 50 and 600 ⁇ M.
• compositions according to the invention further comprise zinc salts at a concentration of between 100 and 500 ⁇ M.
• compositions according to the invention also 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 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 in admixture.
• 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 also 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.
• the transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
• 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.
• 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 prandial insulin.
• the invention also relates to single-dose formulations at a pH of between 7.0 and 7.8 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 pH 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 at pH between 7.0 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 pH 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 having a pH of between 7.0 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 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 having 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 with 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 having 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 prandial 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. as defined previously.
• the single-dose formulations further comprise a co-polyamino acid as defined above.
• the formulations are in the form of an injectable solution.
• the basal insulin whose isoelectric point is between 5.8 and 8.5 is insulin glargine.
• the mealtime insulin is human insulin.
• insulin is a recombinant human insulin as described in the European Pharmacopoeia and the American Pharmacopoeia.
• the prandial insulin is 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.
• GLP-1 RA analog or derivative of GLP-1 RA is selected from the group comprising exenatide (Byetta ®), liraglutide (Victoza ®), lixisenatide (Lyxumia ®), albiglutide (Tanzeum ®), dulaglutide (Trulicity ® ) or a derivative thereof.
• the gastrointestinal hormone is exenatide.
• the gastrointestinal hormone is liraglutide.
• the gastrointestinal hormone is lixisenatide.
• the gastrointestinal hormone is albiglutide. [000531] In one embodiment, the gastrointestinal hormone is dulaglutide.
• 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 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 poi nt 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 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 bearing 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.
• the mixture of basal insulin and co-polyamino acid is concentrated by ultrafiltration before mixing with the prandial insulin in aqueous solution or in freeze-dried form.
• composition of the mixture is adjusted by excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®) by addition of concentrated solutions of these excipients in the mixture.
• excipients such as glycerin, m-cresol, zinc chloride, and polysorbate (Tween ®)
• pH of the preparation is adjusted to pH between 6 and 8.
• the one or more free carboxylic acid function (s) of Hy may be in protected form before the grafting on P LG via an acid-protecting group, this protection is carried out for example by esterification with using methanol, ethanol, benzyl alcohol or t-butanol.
• the functions are deprotected, that is to say that a deprotection reaction is carried out so that the carboxylic function (s) is (are) free (s) or in the form of a cation salt.
• alkali selected from the group consisting of Na + and K +.
• the one or more amine function (s) may 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 the phenylmethoxycarbonyl group or the 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).
• Humalog® 100 IU / mL, 0.17 IU / kg
• Lantus ® 100 IU / mL, 0.50 U / kg
• composition CB3-10 (266 U / ml, 0.67 U / kg)
• hydrophobic intermediate compounds linked to the pacer are shown in Table 1 by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
• Table 1 List of hydrophobic intermediate compounds related to spacer.
• Molecule 1 Product obtained by coupling between lauric acid and L-proline
• Molecule 3 Product obtained by the reaction between spermidine and 2- (tert-butoxycarbonyloxyimino) -2-phenylacetonitrile (Boc-ON)
• Molecule 4 Product obtained by coupling between molecule 2 and molecule 3
• Molecule 5 Product obtained by the reaction between myristoyl chloride and L-proline
• the reaction mixture is stirred for 10 min at 0 ° C and then 1 h at 0 ° C to 20 ° C.
• the organic phase is separated, washed with a solution of 10% HCl (3 ⁇ 430 mL), a saturated aqueous solution of NaCl (430 mL), dried over Na 2 SO 4, filtered through cotton and then concentrated under reduced pressure.
• the residue is solubilized in heptane (315 mL) and then pentane (1.6 L) is added with mechanical stirring. A white solid is obtained after sintering and drying under reduced pressure.
• Molecule 7 Product Obtained by the Reaction Between Molecule 3 and Molecule 6 [000551] By a Method Similar to that Used for the Preparation of Molecule 4 and Applied to Molecule 3 (3.00 g, 8.68 mmol) and at molecule 6 (6.00 g, 7.89 mmol), a colorless oil of molecule 7 is obtained.
• Molecule 8 Product obtained by the reaction between norspermidine and tert-butylphenylcarbonate
• aqueous phase is washed with methyl tert-butyl ether (MTBE, 2 ⁇ 500 mL), basified to pH 12 with 10% aqueous sodium hydroxide solution, and the product is extracted with DCM (4 x 250 mL).
• MTBE methyl tert-butyl ether
• DCM dimethyl tert-butyl ether
• Molecule 9 Product obtained by the reaction between molecule 6 and molecule 8
• Molecule 10 Product obtained by the reaction between molecule 6 and [2- (2-aminoethoxy) ethoxy] acetic acid
• Molecule 11 Product Obtained by the Reaction Between Molecule 3 and Molecule [000558] By a Method Similar to That Used for the Preparation of Molecule 4 Applied to Molecule 3 (2.24 g, 6.49 mmol) and to the molecule (4.90 g, 5.41 mmol) dissolved in DMF (15 mL), a colorless oil of molecule 11 is obtained after purification by flash chromatography (eluent: DCM, methanol). Yield: 5.30 g (79%)
• Molecule 12 Product Obtained by the Reaction Between Molecule 6 and Methyl Ester of N-epsilon-tert-butyloxycarbonyl-L-Lysine (HLys (Boc) OMe)
• a solution of molecule 12 (55.8 g, 55.61 mmol) in 1: 1 THF / methanol (370 mL) is cooled to 0 ° C. and then a solution of LiOH (2.0 g, 83 g) is added. 41 mmol) in water (185 mL) is slowly added. The reaction medium is stirred for 16 h at 0 ° C and then 30 min at room temperature. The residue is concentrated under reduced pressure, taken up in DCM (500 mL) and acidified with an aqueous solution of 10% HCl to pH 1. DCM (500 mL) is added, the organic phase is separated and the aqueous phase is extracted with DCM (2 x 300 mL). The combined organic phases are washed with a saturated aqueous solution of NaCl (2 ⁇ 300 mL), dried over Na 2 SO 4, filtered and concentrated under reduced pressure. A white solid of molecule 13 is obtained after crystallization in acetone.
• Molecule 14 Product Obtained by the Reaction Between Molecule 13 and / V-Boc Ethylenediamine

Applications Claiming Priority (7)

Publications (1)

Family

ID=66750821

Family Applications (1)

Country Status (2)

Families Citing this family (2)

Family Cites Families (10)

• 2018
  • 2018-12-04 EP EP18812169.3A patent/EP3720472A1/de active Pending
  • 2018-12-04 WO PCT/EP2018/083558 patent/WO2019110625A1/fr active Search and Examination

Also Published As

Similar Documents

Legal Events