EP3731858A1 - Zusammensetzungen in form einer injizierbaren wässrigen lösung mit menschlichem glucagon und einer copolyaminosäure - Google Patents

Zusammensetzungen in form einer injizierbaren wässrigen lösung mit menschlichem glucagon und einer copolyaminosäure

Info

Publication number
EP3731858A1
EP3731858A1 EP18826204.2A EP18826204A EP3731858A1 EP 3731858 A1 EP3731858 A1 EP 3731858A1 EP 18826204 A EP18826204 A EP 18826204A EP 3731858 A1 EP3731858 A1 EP 3731858A1
Authority
EP
European Patent Office
Prior art keywords
radical
formula
molecule
hydrophobic
polyamino acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP18826204.2A
Other languages
English (en)
French (fr)
Inventor
You-Ping Chan
Romain NOËL
Alexandre Geissler
Walter ROGER
Richard Charvet
Nicolas Laurent
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Adocia SAS
Original Assignee
Adocia SAS
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Filing date
Publication date
Application filed by Adocia SAS filed Critical Adocia SAS
Publication of EP3731858A1 publication Critical patent/EP3731858A1/de
Pending legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/26—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • 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
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G69/00—Macromolecular compounds obtained by reactions forming a carboxylic amide link in the main chain of the macromolecule
    • C08G69/02—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids
    • C08G69/08—Polyamides derived from amino-carboxylic acids or from polyamines and polycarboxylic acids derived from amino-carboxylic acids
    • C08G69/10—Alpha-amino-carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2319/00—Fusion polypeptide
    • C07K2319/30—Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto

Definitions

  • compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid
  • Human glucagon is a short-acting hyperglycemic hormone which makes it possible to increase blood glucose, thereby correcting a hypoglycemic level that may result from an excess of insulin. It allows the release of glucose by stimulating hepatic glycogenolysis, and has insulin antagonistic properties (hypoglycemic). Human glucagon is normally secreted by alpha cells from Langerhans islets in the pancreas when hypoglycemia is detected.
  • Human glucagon is used for therapeutic purposes, such as the emergency treatment of severe hypoglycaemia, also called “rescue”, but also in a diagnostic context when performing medical examinations, for example to inhibit the gastrointestinal motility.
  • Other applications are also envisaged for human glucagon, in particular its use in a bi-hormonal regulation system of glycemia also called artificial pancreas and in congenital hyperinsulinism which is a rare disease characterized by very high levels of insulin.
  • human glucagon has been limited because of some of its properties that are unfavorable for developing a stable pharmaceutical product for therapeutic purposes. Indeed, human glucagon has a very low solubility at physiological pH, a high physical instability, because of its propensity to form fibrils over a wide range of pH. It is for this reason that the only commercial products based on human glucagon (Glucagen ® , NOVO NORDISK and Glucagon for injection, ELI LILLY) are lyophilized forms to be reconstituted extemporaneously.
  • human glucagon In addition to its physical instability, human glucagon undergoes various types of chemical degradation. In aqueous solution, it degrades rapidly to form several degradation products. At least 16 human glucagon degradation products have been identified by Kirsh et al. (International Journal of Pharmaceutics, 2000, 203, 115-125). The chemical degradation of this human glucagon is therefore fast and complex.
  • the formulation to be reconstituted is also not ideal, because it involves a long preparation. and complicated, for example the leaflet GlucaGen ® describes a process in 5 steps to proceed to the injection of the recommended dose. Moreover, a study by the company LOCEMIA shows that very few people (about 10% of the participants) to perform emergency reconstitution were able to deliver the correct dose. Finally, the acidic pH of human glucagon solutions can cause injection pain in the patient.
  • the company LOCEMIA has developed a freeze-dried human glucagon spray, currently tested in phase 3 clinical study, which is intended to be administered intranasally.
  • This spray is suitable for use called “rescue”, that is to say in the case of severe hypoglycemia, because it is ready for use and therefore easy to use, unlike the solutions to be reconstituted.
  • this product is not suitable for pump use or use requiring precise control of the amount of human glucagon delivered.
  • XERIS has developed a liquid formulation of human glucagon based on a polar aprotic solvent, such as DMSO, currently tested in clinical studies.
  • a polar aprotic solvent such as DMSO
  • compositions comprising an association with other peptides are contemplated including amylin or GLP-1 RA (glucagon like peptide-1 receptor agonist).
  • analogues of human glucagon are being developed by major pharmaceutical companies, such as NOVO NORDISK, SANOFI or ELI LILLY, to obtain formulations having a stability compatible with pharmaceutical use.
  • major pharmaceutical companies such as NOVO NORDISK, SANOFI or ELI LILLY
  • these peptides whose primary sequence has been modified with respect to the peptide of human origin may present a safety risk for patients.
  • US2015291680 teaches the solubilization of human glucagon at 1 mg / ml at a pH between 8.8 and 9.4 and using ferulic acid or tetrahydrocurcumin.
  • this solution has the disadvantage of leading to a stability of human glucagon quite limited in time.
  • the article by Jackson et al (Curr Diab, Rep., 2012, 12, 705-710) proposes to formulate human glucagon at basic pH (approximately 10) in order to limit the formation of fibrils.
  • this solution does not prevent rapid chemical degradation of human glucagon.
  • the application W02014096440 intends instead to place a slightly acidic pH (about 5.5) in the presence of albumin and polysorbate, to improve stability by reducing the rate of fibrillation.
  • this solution has a limited improvement in stability.
  • Most of the solutions described in the prior art making it possible to obtain a clear solution of human glucagon and to prevent the aggregation, gelling or precipitation of human glucagon involve the use of known surfactants, detergents or solubilizing agents. .
  • GB1202607 (NOVO NORDISK) describes the use of anionic or cationic detergents
  • WO2015095389 (AEGIS) describes nonionic surfactants, such as dodecyl maltoside, for improving the bioavailability of therapeutic agents, in the case of delivery by application to the mucous membranes or the epidermis, and in particular in the case of ocular delivery , nasal, oral or nasolacrimal.
  • AEGIS nonionic surfactants
  • dodecyl maltoside for improving the bioavailability of therapeutic agents, in the case of delivery by application to the mucous membranes or the epidermis, and in particular in the case of ocular delivery , nasal, oral or nasolacrimal.
  • This document describes that the presence of alkyl glycosides leads to an improvement in the absorption of human glucagon at the ocular level;
  • WO2012059764 describes cationic surfactants, and more specifically aromatic ammonium chlorides.
  • the surfactants indicated in the above documents may be too toxic or irritating for chronic use by the subcutaneous route.
  • lysophospholipids or lysolecithins
  • lysophospholipids are known to lyse red blood cells because of their hemolytic properties.
  • this can cause local tissue damage and pain at the injection site.
  • this can lead to pain and / or irritation at the insertion site of the needle.
  • WO2013101749 (LATITUDE) describes nano-emulsions of human glucagon. However, it claims quite modest performances in terms of chemical stability, i.e. the composition comprises at least 75% of the initial concentration after 3-7 days at 37 ° C.
  • Tan et al. (Diabetes, 2013, 62, 1131-138) shows that combining human glucagon with a GLP-1 RA is an attractive proposition for treating obesity and diabetes.
  • being able to formulate human glucagon stably in aqueous solution at a pH close to physiological pH of between 6.0 and 8.0 makes it possible to be in more favorable conditions in order to be able to improve the stability of the GLP-1 RAs which are sensitive to acidic or basic conditions.
  • Co-polyamino acids bearing carboxylate charges and hydrophobic radicals Hy according to the invention have excellent resistance to hydrolysis. This can in particular be viewed 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:
  • said co-polyamino acid of formula I bearing at least one hydrophobic radical -Hy, carboxylate charges and consisting of at least two chains of glutamic or aspartic units PLG bonded together by a radical or spacer Q [- * ] k linear or branched divalent at least consisting of an alkyl chain comprising one or more heteroatoms selected from the group consisting of nitrogen and oxygen atoms and / or bearing one or more heteroatoms consisting of nitrogen atoms and oxygen and / or radicals bearing one or more heteroatoms consisting of nitrogen and oxygen atoms and / or carboxyl functions,
  • radical or spacer Q [- *] k being bonded to at least two PLG glutamic or aspartic unit chains by an amide function and
  • said amide functions linking said radical or spacer Q [- *] linked to the at least two chains of glutamic or aspartic units result from the reaction between an amine function and an acid function respectively carried either by the precursor Q 'of the radical or spacer Q [- *] k either by a glutamic or aspartic unit,
  • k is 2, 3, 4, 5 or 6.
  • k 2.
  • k 3.
  • k 4.
  • k 5.
  • k 6.
  • j is 1, 2, 3, 4, 5 or 6.
  • j 1.
  • j 2.
  • j 5.
  • j 6.
  • the invention further relates to a method for preparing stable injectable compositions.
  • soluble capable of allowing to prepare a clear solution and free of particles at a concentration of less than 100 mg / l in distilled water at 25 ° C.
  • solution means a liquid composition devoid of visible particles, using the procedure according to EP 8.0 pharmacopoeia, point 2.9.20, and US ⁇ 790>.
  • compositions which after a certain storage period at a certain temperature 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 visible particles, but also colorless.
  • compositions which, after storage for a certain time and at a certain temperature, have a minimum recovery of the active ingredients and are in accordance with the specifications applicable to pharmaceutical products.
  • a conventional method for measuring the stabilities of proteins or peptides is to measure the formation of fibrils using Thioflavin T, also called ThT.
  • ThT Thioflavin T
  • This method makes it possible to measure, under temperature and agitation conditions that allow an acceleration of the phenomenon, the latency time before the formation of fibrils by measuring the increase in fluorescence.
  • the compositions according to the invention have a lag time before the formation of fibrils much higher than that of glucagon at the pH of interest.
  • aqueous injectable solution water-based solutions that meet the conditions of EP and US pharmacopoeia, and which are sufficiently liquid to be injected.
  • Co-polyamino acid consisting of glutamic or aspartic units is understood to mean non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a C-terminal part corresponding to the acid. carboxylic acid end, and an N-terminal portion, corresponding to the amine of the other end of the sequence.
  • 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.
  • compositions in the form of an aqueous solution for injection according to the invention are clear solutions.
  • the term "clear solution” means compositions which satisfy the criteria described in the US and European pharmacopoeias concerning injectable solutions.
  • the solutions are defined in the ⁇ 1151> part referring to the injection ⁇ 1> (referring to ⁇ 788> according to USP 35 and specified in ⁇ 788> according to USP 35 and in ⁇ 787>, ⁇ 788> and ⁇ 790> USP 38 (from 1 August 2014), according to USP 38).
  • injectable solutions must meet the criteria given in sections 2.9.19 and 2.9.20.
  • composition according to the invention is characterized in that Hy comprises between 15 and 100 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 30 and 70 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 40 and 60 carbon atoms.
  • composition according to the invention is characterized in that Hy comprises between 20 and 30 carbon atoms.
  • Hy comprises more than 15 carbon atoms.
  • Hy comprises more than 30 carbon atoms.
  • the composition is characterized in that the pH is between 6.0 and 8.0.
  • the composition is characterized in that the pH is between 6.6 and 7.8.
  • the composition is characterized in that the pH is between 7.0 and 7.8. In one embodiment, the composition is characterized in that the pH is between 6.8 and 7.4.
  • radical or spacer Q [- *] k is represented by a radical of formula II:
  • At least one of ui "or u 2 " is different from 0,
  • ui 'and u 2 ' are the same or different and,
  • Fc, Fc 'and Fc are 1 -NH- and 2 -CO- then no conditions.
  • the at least two PLG chains of glutamic or aspartic units being linked to Q [- *] k by an Fx or Fy function by a covalent bond to form an amide bond with a function -NH- or -CO- of PLG.
  • 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-diaminopentane. , propylene diamine, pentylene diamine.
  • 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.
  • 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. In one embodiment, the precursor of the radical of formula III is a diacid selected from the group consisting of succinic acid, glutaric acid and adipic acid.
  • t 2 and the precursor of the radical of formula III is succinic acid.
  • t 3 and the precursor of the radical of formula III is glutaric acid.
  • t 4 and the precursor of the radical of formula III is adipic acid.
  • At least one of Q ' is a radical of formula
  • the precursor of the radical of formula IV is a diamine selected from the group consisting of diethyleneglycoldiamine, triethyleneglycol diamine, 1-amino-4,9-dioxa-12-dodecanamine and amino-4,7,10-trioxa-13-tridecanamine.
  • the precursor of the radical of formula IV is triethyleneglycol diamine.
  • At least one of Q ' is a radical of formula V
  • Formula V whose precursor is selected from the group consisting of amino acids.
  • the precursor of the radical of formula V is an amino acid selected from the group consisting of lysine, ornithine, 1,3-diaminopropionic acid.
  • At least one of Q ' is a radical of formula
  • Formula V whose precursor is selected from the group consisting of triacids.
  • the precursor of the radical of formula V is a triacid selected from the group consisting of tricarballylic acid.
  • 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 V
  • 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
  • w ' ( 2 0 and the precursor of the radical of formula
  • VI is a triamine selected from the group consisting of spermidine, norspermldine, and diethylenetriamine and bis (hexamethylene) triamine.
  • w "2 0 and the precursor of the radical of formula VI is spermidine.
  • w " 2 0 and the precursor of the radical of formula
  • VI is norspermidine.
  • w "2 0 and the precursor of the radical of formula VI is diethylenetriamine.
  • w "2 1 and the precursor of the radical of formula VI is a tetramine.
  • w "2 1 and the precursor of the radical of formula VI is a tetramine selected from the group consisting of spermine and triethylenetetramine.
  • w "2 1 and the precursor of the radical of formula VI is a tetramine selected from the group consisting of spermine and triethylenetetramine.
  • the precursor of the radical or spacer Q [- *] k has 4 reactive functions, chosen from the group of amine functions and carboxylic acid functions. In one embodiment, the precursor of the radical or spacer Q [- *] k has 4 reactive functions and the precursor of the radical or spacer Q [- *] k is 1,2,3,4-butanetrathoic acid. .
  • At least one of Q ' is a radical of formula VI'
  • w " 2 0 and the precursor of the radical of formula VI 'is spermidine.
  • w " 2 0 and the precursor of the radical of formula VI 'is norspermidine.
  • w " 2 0 and the precursor of the radical of formula VI 'is diethylenetriamine.
  • w " 2 0 and the precursor of the radical of formula VI is bis (hexamethylene) triamine.
  • At least one of Q ' is a radical of formula VI'
  • w " 2 1 and the precursor of the radical of formula VI 'is a tetramine.
  • w " 2 1 and the precursor of the radical of formula
  • VI ' is a tetramine selected from the group consisting of spermine and triethylenetetramine.
  • the precursor of the radical or spacer Q [- *] k has 4 reactive functional groups, selected from the amine and carboxylic acid functional groups.
  • the precursor of the radical or spacer Q [- *] i ⁇ has 4 reactive functions and the precursor of the radical or spacer Q [- *] k is 1,2,3,4- butanetétrao ⁇ que.
  • all Fx's are linked to PLG or other Fx or Fy.
  • one or more Fx are free, that is to say are not related to the PLG, or another Fx, or a Fy.
  • an Fx is free, that is to say not related to the PLG, to another Fx, or to a Fy.
  • the FOC (s) of the -CO- type is free, it is in the form of a carboxylic acid salt.
  • the free -CO- type Fx is carried by a radical Q 'of Formula V.
  • the (s) Fx of the -NH- type is free, it is in the form of amine or ammonium.
  • the co-polyamino acid comprises one or more aspartic unit (s), that (s) can undergo structural rearrangements.
  • the composition according to the invention is characterized in that when the co-polyamino acid comprises aspartate units, then the co-polyamino acid may further comprise monomeric units of formula XXXX and / or XXXX ' :
  • a "co-polyamino acid with random grafting” is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical represented by a co-polyamino acid of formula XXXa 'and XXXb'.
  • a "co-polyamino acid with defined grafting” is a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical represented by a co-polyamino acid of formula XXXa and XXXb.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids of formulas XXXa, XXXa ', XXXb or XXXb' wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is a -CH 2 - (aspartic unit) group.
  • 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 an H or a cationic entity chosen from the group comprising metal cations
  • Ra and R'a which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of an H, a linear acyl group of C2 to Cio, a branched acyl group of Ca to Cio, a benzyl, a terminal "amino acid” unit and a pyroglutamate,
  • Ra and R'a being a hydrophobic radical -Hy
  • n + m has the same definition as given above.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying 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 are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which Ra and R'a, different are hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which Ra is a hydrophobic radical -Hy and R ' a is not a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa in which R'a is a hydrophobic radical -Hy, and R a is not a hydrophobic radical -Hy.
  • 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 :
  • Ni + nru represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a radical -Hy,
  • N2 + nri2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid having no -Hy radical
  • n '+ m' represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n '+ m' ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing 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 are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa 'in which Ra and R'a, different are hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXa 'in which Ra is a hydrophobic radical -Hy and R'a is not a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and from at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXa 'in which R'a is a hydrophobic radical -Hy, and Ra is not a hydrophobic radical -Hy.
  • composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula
  • Rb and R'b which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid” unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
  • N + m has the same definition as given above.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, identical are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb and R'b, different are hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
  • 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
  • Rb and R'b which are identical or different, are either a hydrophobic radical -Hy or a radical chosen from the group consisting of -OH, an amine group, a terminal "amino acid” unit and a pyroglutamate, at least one of Rb and R'b is a hydrophobic radical -Hy,
  • nl + m l represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid bearing a -Hy radical
  • N2 + m2 represents the number of glutamic units or aspartic units of the PLG chains of the co-polyamino acid not carrying a -Hy radical
  • n '+ m' represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n '+ m' ⁇ 250.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which Rb and R'b, identical are a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from the co-polyamino acids of formula XXXb 'in which Rb and R'b are different hydrophobic radicals -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which Rb is a hydrophobic radical -Hy and R'b is not a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical -Hy is chosen from co-polyamino acids of formula XXXb 'in which R'b is a hydrophobic radical -Hy, and Rb is not a hydrophobic radical -Hy.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formulas XXXa, XXXa ', XXXb or XXXb 'wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is a -CH2- (aspartic unit) group.
  • the composition according to the invention is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from co-polyamino acids of formulas, XXXa, XXXa, XXXb or XXXb. wherein the co-polyamino acid is selected from co-polyamino acids in which the group D is -CH2-CH2- (glutamic unit).
  • the composition according to the invention is characterized in that n + m is between 5 and 40.
  • composition according to the invention is characterized in that n + m is between 5 and 20.
  • composition according to the invention is characterized in that n + m is between 10 and 250.
  • 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.
  • 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.
  • composition is characterized in that the said hydrophobic radicals Hy are chosen from radicals of formula X as described below.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X as defined below: Formula X in which
  • GpG and GpH are chosen from the radicals of formulas XI or XI ': * - NH - G - NH - *
  • GpA is chosen from the radicals of formula VIII
  • a ' is selected from radicals of formula VIII', VIII "or VIII" '
  • 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 O or 1;
  • A, A 1, A 1 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
  • C x is a radical selected from the group consisting of a linear or branched monovalent alkyl radical, optionally comprising a cyclic part, in which x indicates the number of carbon atoms and 6 ⁇ x ⁇ 25:
  • G is a divalent linear or branched alkyl radical comprising from 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
  • R is a radical chosen from the group consisting of a 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; CONH 2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of alkali metal salt chosen from the group consisting of Na + and K + .
  • x is between 9 and 15 (9 ⁇ x ⁇ 15).
  • the GpR group bonded to PLG is chosen from GpR of formula VII ".
  • the GpR group linked to PLG is chosen from GpR of formula VII and the second GpR is chosen from GpR of formula VII.
  • Formula Xc wherein GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I, a' and I 'have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula Xc as defined below: Formula Xc in which GpR is a radical of formula VII '. Formula VU '
  • GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, let I' 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 VII. Form VII "
  • GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and I' have the definitions given above.
  • GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and I' have the definitions given above.
  • GpR, GpG, GpA, GpL, GpH, GpC, R, a, a ', g, h, I and I' have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula Xq as defined below:
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula Xr as defined below:
  • GpR, GpA, GpC, r, a 'and a have the definitions given above.
  • GpR, GpA, GpH, GpC, r and h have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below:
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which r, g, a, I, h are equal to 0, of formula Xo as defined below:
  • said at least one hydrophobic radical - Hy is chosen from radicals of formula Xs as defined below:
  • Formula Xb in which GpA is a radical of formula VIII and A is selected from radicals of formula HIV '' with s' 1, and GpA is a radical of formula VUId
  • said at least one hydrophobic radical - Hy is chosen from radicals of formula X in which
  • GpR, GpH, GpG, GpC, Al, B, Cx, G, H, R have the definitions as given previously;
  • GpR, GpG, GpA, GpH, GpC, r, g, h, and a have the definitions given above.
  • said at least one hydrophobic radical-Hy is chosen from radicals of formulas X, Xa to Xu:
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which
  • said at least one hydrophobic radical-Hy is chosen from radicals of formula X in which
  • the GpCs are directly or indirectly related to V and V and the PLG is directly or indirectly linked via- GpR to IMpi, or
  • the GpCs are directly or indirectly related to V and Npi, and the PLG is linked directly or indirectly via GpR to V; or
  • the GpCs are directly or indirectly related to V and IMpi, and the PLG is directly or indirectly linked via- GpR- to V.
  • the GpCs are directly or indirectly related to V and V and the PLG is directly or indirectly related to Npi; or
  • GpCs are directly or indirectly related to V and IV, and PLG is directly or indirectly related to IV; or
  • the GpCs are directly or indirectly related to V, V and Npi and the PLG is directly or indirectly linked via GpR to V; or the GpCs are directly or indirectly related to N "i, l ⁇ l a 2 and Np2 and the PLG is linked directly or indirectly via GpR to Npi; or
  • GpCs are directly or indirectly linked to N "i, Npi and N 2 and PLG is linked directly or indirectly via -GpR- to N a2 ; or
  • N - GpC are directly or indirectly linked to N a2 , Npi and N p2 and the PLG is directly or indirectly linked via GpR to N "i.
  • GpCs are directly or indirectly related to IM a i, IM a2 and Npi and the PLG is directly or indirectly related to I ⁇ lp2; or
  • the GpCs are directly or indirectly related to N a i, Npi and Np 2 and the PLG is directly or indirectly linked to N a 2; or
  • GpCs are directly or indirectly related to N "2, Npi and Np 2 and the PLG is directly or indirectly related to Nui.
  • a 0.
  • g is greater than or equal to 2 (g> 2).
  • h is greater than or equal to 2 (h> 2).
  • g or h is greater than or equal to 2 (g> 2) and b is equal to 0.
  • h is greater than or equal to 2 (g> 2)
  • the * indicate the sites of attachment of the hydrophobic radicals to the PLG or between the different groups GpR, GpG, GpA, GpL, GpH and GpC to form amide functions.
  • radicals -Hy are attached to the PLG via amide functions.
  • radicals -Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently identical or different from one residue to another.
  • the radicals Hy, GpR, GpG, GpA, GpL, GpH and GpC are each independently the same or different from a residue at the other.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 2 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising from 2 to 5 carbon atoms and bearing one or more amide functional groups ( -COIMH2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent linear alkyl radical comprising from 2 to 5 carbon atoms and carrying one or more amide functional groups. (-CONH2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula XI.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X2.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is linked to the polyamino acid via an amide function carried by carbon in the delta or epsilon position (or in position 4 or 5) with respect to the amide function (-CONH 2).
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear ether or unsubstituted polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 carbon atoms. oxygen atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical comprising from 4 to 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a divalent alkyl radical comprising 6 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is an ether radical represented by the formula
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a linear polyether radical comprising from 6 to 10 carbon atoms and from 2 to 3 oxygen atoms. .
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas below.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X3. [000297] In one embodiment, the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X4.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X5.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a radical of formula X6.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical chosen from the group consisting of the radicals represented by formulas x5 and X6 below. :
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical of formula X5.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which R is a polyether radical of formula X6.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula CG in which G is an alkyl radical comprising 6 carbon atoms represented by the formula Z below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpG and / or GpH radical is of formula XI wherein G is an alkyl radical having 4 carbon atoms represented by the formula Z 'below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by - (CH2) 2-CH (COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 4 carbon atoms represented by -CH ((CH2) 2COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpG and / or GpH is of formula XI in which G is an alkyl radical comprising 3 carbon atoms represented by -CH 2 -CH- (COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpG and / or GpH radical is of formula XI in which G is an alkyl radical comprising 3 carbon atoms. represented by -CH (CH 2 COOH) -.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the radical GpA is of formula VIII and in which Ai, A2 or A3 is chosen from the group consisting of radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of the radicals of formulas IXe, IXf or IXg hereinafter represented:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which the GpC radical of formula IX is chosen from the group consisting of radicals of formulas IXe, IXf or IXg in which b is equal to 0, respectively corresponding to formulas IXh, IXi, and IXj hereinafter represented:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of linear alkyl radicals.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of branched alkyl radicals.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 11 and 14 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 15 and 16 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 17 and 18 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below: ## STR5 ##
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of alkyl radicals comprising between 18 and 25 carbon atoms.
  • the composition is characterized in that the hydrophobic radical of formula X is a radical in which Cx is chosen from the group consisting of the alkyl radicals represented by the formulas below:
  • the composition is characterized in that the hydrophobic radical is a radical of formula X in which the GpC radical of formula IX is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising 14 or 15 carbon atoms.
  • the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by the radicals represented by the formulas below: [000328]
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.35.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 15.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0, 1.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.03 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.015 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X in which the Cx radical comprises between and 12 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.08.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.1.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0, 3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.015 and 0, 2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.1 and 0.35.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.2 and 0.35.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.1 and 0.2.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the Cx radical comprises between 15 and 15 carbon atoms. and 16 carbon atoms and the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.04 and 0.15.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.06.
  • the composition is characterized in that the hydrophobic radical corresponds to the formula X in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio M between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.01 and 0.05.
  • the invention also relates to said co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I and the precursors of said hydrophobic radicals.
  • co-polyamino acids bearing carboxylate charges and hydrophobic radicals of formula I are soluble in distilled water at a pH of between 6 and 8, at a temperature of 25 ° C. and at a concentration of less than 100 mg / ml. ml.
  • the invention also relates to the precursors Hy 'of said hydrophobic radicals of formula X' as defined below: Formula X 'in which
  • GpR is chosen from the radicals of formulas VII, VU 'or VU ": o;
  • GpG and GpH identical or different are chosen from the radicals of formulas XI or XI ': * - NH- G- NH- *
  • GpA is chosen from the radicals of formula VIII
  • GpC is a radical of formula IX:
  • b is an integer equal to 0 or 1;
  • c is an integer equal to 0 or 1, and if c is 0 then d is 1 or 2; d is an integer of 0, 1 or 2;
  • e is an integer equal to 0 or 1;
  • g is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • h is an integer of 0, 1, 2, 3 to 4 to 5 or 6;
  • A, A 1, A 2 and A 3, which may be identical or different, are linear or branched alkyl radicals comprising from 1 to 8 carbon atoms and optionally substituted with a radical resulting from a saturated, unsaturated or aromatic ring;
  • B is a radical selected from the group consisting of an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms or a linear or branched alkyl radical, optionally comprising an aromatic nucleus, comprising 1 to 9 carbon atoms;
  • Cx is a radical selected from the group consisting of a linear or branched monovalent alkyl radical, optionally comprising a cyclic portion, wherein x denotes the number of carbon atoms and 6 ⁇ x ⁇ 25:
  • G is a divalent linear or branched alkyl radical comprising from 1 to 8 carbon atoms, said alkyl radical carrying one or more free carboxylic acid function (s).
  • R is a radical chosen from the group consisting of a linear or branched divalent alkyl radical comprising from 1 to 12 carbon atoms, a divalent linear or branched alkyl radical comprising from 1 to 12 carbon atoms carrying one or more functions -COIMH2 or an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms:
  • the ratio M between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ M ⁇ 0.5;
  • the degree of DP polymerization in glutamic or aspartic units for the PLG chains is between 5 and 250;
  • the free carboxylic acid functions being in the form of an alkali metal salt selected from the group consisting of Na + and K + .
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by ring opening polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof of aspartic acid N-carboxyanhydride as described in Adv. Polym. Sci. 2006, 202, 1-18 (Deming, T.J.).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative chosen from the group consisting of by N-carboxyanhydride methyl glutamate (GluOMe-NCA), benzyl N-carboxyanhydride glutamate (GluOBzl-NCA) and t-butyl N-carboxyanhydride glutamate (GluOtBu-NCA).
  • GluOMe-NCA N-carboxyanhydride methyl glutamate
  • GluOBzl-NCA benzyl N-carboxyanhydride glutamate
  • GluOtBu-NCA t-butyl N-carboxyanhydride glutamate
  • the glutamic acid N-carboxyanhydride derivative is methyl N-carboxyanhydride L-glutamate (L-GluOMe-NCA).
  • the glutamic acid N-carboxyanhydride derivative is benzyl N-carboxyanhydride L-glutamate (L-GluOBzl-NCA).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or an aspartic acid N-carboxyanhydride derivative using as the initiator an organometallic complex of a transition metal as described in Nature 1997, 390, 386 -389 (Deming, TJ).
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof of aspartic acid N-carboxyanhydride using as initiator ammonia or a primary amine as described in patent FR 2,801,226 (Touraud, F. et al.) and references cited therein.
  • the initiator may be a polyamine to obtain polyamino acid comprising several PLG.
  • Said polyamines can be chosen from diamines, triamines and tetramines. The amines of these polyamines can be primary amines.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or a derivative thereof. 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 process for the synthesis of the polyamino acid obtained by polymerization of a glutamic acid N-carboxyanhydride derivative or of an N-carboxyanhydride derivative aspartic acid from which the co-polyamino acid is derived comprises a step of hydrolysis of ester functions.
  • this ester function hydrolysis step 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 acidic medium.
  • this step of hydrolysis of ester groups is carried out by hydrogenation.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight. In one embodiment, the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight selected from the group consisting of polyglutamate. of sodium and sodium polyaspartate.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.
  • the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using amide bond forming processes well known to those skilled in the art.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using the amide bond formation processes used for peptide synthesis.
  • the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid as described above. in FR 2,840,614 (Chan, YP et al.).
  • One or more free carboxylic acid function (s) of Hy may be in protected form prior to grafting to PLG via an acid protecting group, this protection is carried out for example by esterification with 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 +.
  • one or more amine function (s) may be in protected form before grafting on PLG via an amine protecting group, this protection is carried out for example by 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).
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 40 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 30 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 20 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 10 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 5 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 2.5 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 1 mg / ml.
  • the concentration of co-polyamino acid bearing carboxylate charges and hydrophobic radicals is at most 0.5 mg / ml.
  • Human glucagon is a highly conserved polypeptide comprising a single chain of 29 amino acid residues having the following sequence H-His-Ser-Gln-Gly-Thr-Phe-Thr-Ser-Asp-Tyr-Ser- Lys-Tyr-Leu-Asp-Ser-Arg-Arg-Ala-GIn-Asp-Phe-Val-GIn-Trp-Leu-Met-Asn-Thr-OH.
  • Human glucagon is available via many sources. For example, it may be human glucagon produced by Bachem via peptide synthesis, in particular under the reference 407473.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on glucagon is between 1.0 and 25.
  • the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on glucagon is between 1.5 and 25.
  • the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on glucagon is between 2 and 20.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on glucagon is between 2.5 and 15.
  • the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on glucagon is between 2 and 10.
  • the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals on glucagon is between 2 and 7.
  • the recommended dosage is 1 mg intramuscularly or intravenously (0.5 mg if the body weight is less than 25 kg). This administration is carried out with a solution of human glucagon at a concentration of 1 mg / ml.
  • the envisaged daily dose is about 0.5 mg
  • the solutions can thus comprise from 0.25 mg / ml to 5 mg / ml of human glucagon.
  • the solutions may comprise from 0.5 mg / ml to 3 mg / ml of human glucagon.
  • the envisaged daily dose is approximately 0.5 mg
  • the solutions can thus comprise from 0.25 mg / ml to 5 mg / ml of human glucagon.
  • the concentration of human glucagon is between 0.25 and 5 mg / ml.
  • the concentration of human glucagon is between 0.5 and 4 mg / ml.
  • the concentration of human glucagon is between 0.75 and 3 mg / ml.
  • the concentration of human glucagon is between 0.75 and 2.5 mg / ml.
  • the concentration of human glucagon is between 0.75 and 2 mg / ml.
  • the concentration of human glucagon is between 1 and 2 mg / ml.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 20.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 15.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 10.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 5.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 2.5.
  • the molar ratio [hydrophobic radical] / [human glucagon] is less than 1.5.
  • the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 20. In one embodiment, the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 15.
  • the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 10.
  • the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 5.
  • the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 2.5.
  • the molar ratio [co-polyamino acid carrying carboxylate charges and hydrophobic radicals Hy] / [human glucagon] is less than 1.5.
  • the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 0.5 and 15.
  • the co-polyamino acid molar ratio carrying carboxylate charges and hydrophobic radicals on glucagon is between 1 and 10.
  • the molar ratio of co-polyamino acid carrying carboxylate charges and hydrophobic radicals on glucagon is between 1 and 7.
  • the molar ratio of co-poiyamino acid carrying carboxylate charges and hydrophobic radicals on glucagon is between 1 and 5.
  • the composition further comprises a nicotinic compound or a derivative thereof.
  • the composition comprises nicotinamide.
  • the concentration of nicotinamide ranges from 10 to
  • the concentration of nicotinamide ranges from 20 to 150 mM.
  • the concentration of nicotinamide ranges from 40 to 120 mM.
  • the concentration of nicotinamide ranges from 60 to
  • the composition further comprises a polyanionic compound.
  • the polyanionic compound is selected from the group consisting of polycarboxylic acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polycarboxylic acid is selected from the group consisting of citric acid, tartaric acid, and their salts of Na + , K + , Ca 2+ or Mg 2+ .
  • the polyanionic compound is chosen from the group consisting of polyphosphoric acids and their Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polyphosphoric acid is triphosphate and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polyanionic compound is citric acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polyanionic compound is tartaric acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the polyanionic compound is triphosphoric acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the concentration of polyanionic compound is between 1 and 20 mM.
  • the concentration of polyanionic compound is between 2 and 15 mM.
  • the concentration of polyanionic compound is between 3 and 12 mM.
  • the polyanionic compound concentration is 10 mM. In one embodiment, the concentration of polyanionic compound is 5 mM.
  • the concentration of polyanionic compound is 10 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.
  • the concentration of polyanionic compound is 10 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 10 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 5 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml.
  • the concentration of polyanionic compound is 5 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml.
  • the concentration of polyanionic compound is 5 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is between 1 and 20 mM.
  • the concentration of citric acid and its Na + , K + , Ca 2+ or Mg 2+ salts is between 2 and 15 mM.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is between 3 and 12 mM.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 10 mM.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 5 mM. In one embodiment, the concentration of citric acid and its Na + , K + , Ca 2+ or Mg 2+ salts is 10 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml. mg / ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 10 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg. mg / ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 10 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml. ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 5 mM for glucagon concentrations of between 0.5 mg / ml and 3 mg / ml. mg / ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 5 mM for glucagon concentrations of between 0.5 mg / ml and 2 mg / ml. mg / ml.
  • the concentration of citric acid and its salts of Na + , K + , Ca 2+ or Mg 2+ is 5 mM for glucagon concentrations of between 1 mg / ml and 2 mg / ml. ml.
  • compositions according to the invention further comprise a gastrointestinal hormone.
  • gastrointestinal hormones the hormones selected from the group consisting of GLP-1 RA for agonists Glucagon receptor human-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin, their analogues or derivatives and / or their pharmaceutically acceptable salts.
  • GLP-1 RA for agonists Glucagon receptor human-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), peptide YY, amylin, cholecystokinin, pancreatic polypeptide (
  • the gastrointestinal hormones are analogues or derivatives of GLP-1 RA (glucagon like peptide-1 receptor agonist) selected from the group consisting of exenatide or Byetta® (ASTRA-ZENECA) , 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 acceptable.
  • GLP-1 RA glycolia-1 receptor agonist
  • the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts.
  • gastrointestinal hormone is liraglutide Victoza ® or analogue or derivative thereof and pharmaceutically acceptable salts thereof.
  • the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts.
  • gastrointestinal hormone is albiglutide Tanzeum ® or analogue or derivative thereof and pharmaceutically acceptable salts thereof.
  • gastrointestinal hormone is Dulaglutide Trulicity ® or analogue or derivative thereof and pharmaceutically acceptable salts thereof.
  • gastrointestinal hormone is pramlintide or Symlin ®, analogs or derivatives and their pharmaceutically acceptable salts.
  • analogue when 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 residues of amino acid and / or wherein one or more constituent amino acid residues have been deleted and / or wherein one or more constituent amino acid residues have been added.
  • the percentage of homology allowed for the present definition of an analogue is 50%.
  • derivative when used with reference to a peptide or a protein, a peptide or a protein or a chemically modified analogue with a substituent that is not present in the peptide or 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 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. In one embodiment, 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 pramlintide, its analogues or derivatives and their pharmaceutically acceptable salts is between 0.1 to 5 mg / ml.
  • the invention also relates to compositions which further comprise ionic species, said ionic species making it possible to improve the stability of the compositions.
  • the invention also relates to the use of ionic species selected from the group of anions, cations and / or zwitterions to improve the physicochemical stability of the compositions.
  • the ionic species comprise less than 10 carbon atoms.
  • Said ionic species are chosen from the group of anions, cations and / or zwitterions.
  • Zwitterion means a species carrying at least one positive charge and at least one negative charge on two non-adjacent atoms.
  • Said ionic species are used alone or as a mixture and preferably as a mixture.
  • the anions are chosen from organic anions.
  • the organic anions comprise less than 10 carbon atoms.
  • the organic anions are chosen from the group consisting of acetate, citrate and succinate.
  • the anions are chosen from anions of mineral origin.
  • the anions of mineral origin are chosen from the group consisting of sulphates, phosphates and halides, especially chlorides.
  • the cations are chosen from organic cations.
  • the organic cations comprise less than 10 carbon atoms.
  • the organic cations are chosen from the group consisting of ammoniums, for example 2-amino-2- (hydroxymethyl) propane-1,3-diol, where the amine is in the form of amines. ammonium.
  • the cations are chosen from cations of mineral origin.
  • the cations of mineral origin are chosen from the group consisting of zinc, in particular Zn 2+ and alkali metals, in particular IMa + and K +,
  • the zwitterions are chosen from zwitterions of organic origin.
  • the zwitterions of organic origin are chosen from amino acids.
  • the amino acids are chosen from aliphatic amino acids in the group consisting of glycine, alanine, valine, isoleucine and leucine.
  • the amino acids are chosen from cyclic amino acids in the group consisting of proline.
  • the amino acids are chosen from hydroxylated or sulfur-containing amino acids in the group consisting of cysteine, serine, threonine, and methionine.
  • the amino acids are chosen from aromatic amino acids in the group consisting of phenylalanine, tyrosine and tryptophan.
  • the amino acids are chosen from amino acids whose carboxyl function of the side chain is amidated in the group consisting of asparagine and glutamine.
  • the zwitterions of organic origin are selected from the group consisting of amino acids having an uncharged side chain.
  • the zwitterions of organic origin are chosen from the group consisting of aminodiacides or acidic amino acids.
  • aminodiacides are chosen from the group consisting of glutamic acid and aspartic acid, optionally in the form of salts.
  • the zwitterions of organic origin are chosen from the group consisting of basic or so-called "cationic" amino acids.
  • the so-called "cationic" amino acids are chosen from arginine, histidine and lysine, in particular arginine and lysine.
  • the zwitterions comprise as many negative charges as positive charges and therefore a zero overall charge at the isoelectric point and / or at a pH between 6 and 8.
  • Said ionic species are introduced into the compositions in the form of salts.
  • the introduction of these can be in solid form before dissolution in the compositions, or in the form of a solution, in particular of concentrated solution.
  • the cations of mineral origin are provided in the form of salts chosen from sodium chloride, zinc chloride, sodium phosphate, sodium sulphate, and the like.
  • anions of organic origin are provided in the form of salts selected from sodium or potassium citrate, sodium acetate.
  • amino acids are added in the form of salts selected from arginine hydrochloride, histidine hydrochloride or non-salified form such as histidine, arginine.
  • the total molar concentration of ionic species in the composition is greater than or equal to 10 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 20 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 30 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 50 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 75 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 100 mM,
  • the total molar concentration of ionic species in the composition is greater than or equal to 200 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 600 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is greater than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1200 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 1000 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 900 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 800 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 700 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 600 mM. In one embodiment, the total molar concentration of ionic species in the composition is less than or equal to 500 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 400 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 300 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 200 mM.
  • the total molar concentration of ionic species in the composition is less than or equal to 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 1000 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 900 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 800 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 600 and 700 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 400 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 500 and 600 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 500 mM. [000601] In one embodiment, the total molar concentration of ionic species in the composition is between 400 and 500 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 300 and 400 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 200 and 300 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 100 and 200 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 75 and 100 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 50 and 75 mM.
  • the total molar concentration of ionic species in the composition is between 10 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 20 and 50 mM.
  • the total molar concentration of ionic species in the composition is between 30 and 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 400 mM,
  • said ionic species are present in a concentration ranging from 5 to 300 mM.
  • said ionic species are present in a concentration ranging from 5 to 200 mM.
  • said ionic species are present in a concentration ranging from 5 to 100 mM.
  • said ionic species are present in a concentration ranging from 5 to 75 mM.
  • said ionic species are present in a concentration ranging from 5 to 50 mM.
  • said ionic species are present in a concentration ranging from 5 to 25 mM.
  • said ionic species are present in a concentration ranging from 5 to 20 mM.
  • said ionic species are present in a concentration ranging from 5 to 10 mM.
  • said ionic species are present in a concentration ranging from 10 to 400 mM.
  • said ionic species are present in a concentration ranging from 10 to 300 mM.
  • said ionic species are present in a concentration ranging from 10 to 200 mM.
  • said ionic species are present in a concentration ranging from 10 to 100 mM.
  • said ionic species are present in a concentration ranging from 10 to 75 mM.
  • said ionic species are present in a concentration ranging from 10 to 50 mM.
  • said ionic species are present in a concentration ranging from 10 to 25 mM. In one embodiment, said ionic species are present in a concentration ranging from 10 to 20 mM.
  • said ionic species are present in a concentration ranging from 20 to 300 mM.
  • said ionic species are present in a concentration ranging from 20 to 200 mM.
  • said ionic species are present in a concentration ranging from 20 to 100 mM.
  • said ionic species are present in a concentration ranging from 20 to 75 mM.
  • said ionic species are present in a concentration ranging from 20 to 50 mM.
  • said ionic species are present in a concentration ranging from 20 to 25 mM.
  • said ionic species are present in a concentration ranging from 50 to 300 mM.
  • said ionic species are present in a concentration ranging from 50 to 200 mM.
  • said ionic species are present in a concentration ranging from 50 to 100 mM.
  • said ionic species are present in a concentration ranging from 50 to 75 mM.
  • its molar concentration within the composition may be between 0.25 and 20 mM, in particular between 0.25 and 10 mM or between 0.25 and 5 mM.
  • the ionic species present is NaCl.
  • the NaCl is present in a concentration ranging from 5 to 250 mM.
  • the NaCl is present in a concentration ranging from 10 to 150 mM.
  • the NaCl is present in a concentration ranging from 20 to 100 mM.
  • the ionic species present is citric acid and / or its salts
  • the citric acid and / or its salts is present in a concentration ranging from 5 to 40 mM.
  • the citric acid and / or its salts is present in a concentration ranging from 7 to 30 mM.
  • the citric acid and / or its salts is present in a concentration ranging from 8 to 20 mM.
  • the citric acid and / or its salts is present in a concentration ranging from 10 to 15 mM.
  • the pharmaceutical composition further comprises at least one absorption promoter selected from absorption promoters, diffusion promoters or vasodilator agents, alone or in admixture.
  • Absorption promoters include, but are not limited to, surfactants, e.g., bile salts, fatty acid salts, or phospholipids; nicotinic agents, such as nicotinamides, nicotinic acids, niacin, niacinamide, vitamin B3 and their salts; inhibitors of pancreatic trypsin; magnesium salts; polyunsaturated fatty acids; phosphatidylcholine didecanoyl; aminopolycarboxylates; tolmetin; sodium caprate; salicylic acid; oleic acid; linoleic acid; eicosapentaenoic acid (EPA); docosahexaenoic acid (DHA); benzyl acid; Nitric oxide donors, for example, 3- (2-Hydroxy-1- (1-methylethyl) -2-nitrosohydrazino) -1-propanamine, N-ethyl
  • the pharmaceutical composition further comprises at least one vasodilating agent. In one embodiment, the pharmaceutical composition further comprises at least one vasodilator causing hyperpolarization by blocking calcium ion channels.
  • the vasodilator causing hyperpolarization by blocking the ion channels of calcium is adenosine, a hyperpolarizing agent derived from the endothelium, a phosphodiesterase type 5 (PDE5) inhibitor, a agent for opening potassium channels or any combination of these agents.
  • the pharmaceutical composition further comprises at least one cAMP-mediated vasodilator agent.
  • the pharmaceutical composition further comprises at least one cGMP-mediated vasodilator agent. In one embodiment, the pharmaceutical composition further comprises at least one vasodilating agent selected from the group consisting of vasodilator agents that act by causing hyperpolarization by blocking calcium ion channels, cAMP mediated vasodilator agents, and cGMP-mediated vasodilator agents.
  • the at least one vasodilator is selected from the group consisting of nitrogen monoxide donors, for example, nitroglycerin, isosorbide dinitrate, isosorbide mononitrate, amyl nitrate, and the like. erythrityl, tetranitrate, and nitroprusside); prostacyclin and its analogues, for example, epoprostenol sodium, iloprost, epoprostenol, treprostinil or selexipag; histamine, 2-methylhistamine, 4-methylhistamine; 2- (2-pyridyl) ethylamine, 2- (2-thiazolyl) ethylamine; papaverine, papaverine hydrochloride; minoxidil; dipyridamole; hydralazine; adenosine, adenosine triphosphate; uridine trisphosphate; the GPLC; L-carnitine; arginine;
  • the vasodilator agent is treprostinil.
  • the composition comprises in combination a polyanionic compound and an absorption promoter.
  • the composition comprises in combination citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ and an absorption promoter.
  • the polyanionic compound is citric acid and its Na + , K + , Ca 2+ or Mg 2+ salts.
  • the composition comprises in combination a polyanionic compound, an absorption promoter and optionally NaCl NaCl.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , nicotinamide or treprostinil and optionally NaCl. .
  • the composition comprises, in combination, citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , nicotinamide or treprostinil and NaCl, and is intended to be administered intramuscularly.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , nicotinamide, optionally NaCl, and is intended to to be administered not intra-muscular way.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , treprostinil and optionally NaCl, and is intended to be administered intramuscularly.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , nicotinamide or treprostinil and optionally NaCl, and is intended to be administered subcutaneously.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , nicotinamide and optionally NaCl, and is intended to to be administered not subcutaneously.
  • the composition comprises in combination with citric acid and / or its salts of Na + , K + , Ca 2+ or Mg 2+ , treprostinil and optionally NaCl and is intended to be not administered subcutaneously.
  • the compositions according to the invention are produced by mixing human glucagon solutions obtained by reconstitution of lyophilisate and GLP-1 RA solutions (Glucagon like peptide-1 receptor agonist) GLP-1 RA. of GLP-1 RA analog or derivative, said GLP-1 RA solutions being commercial or reconstituted from lyophilizate.
  • compositions according to the invention further comprise buffers.
  • compositions according to the invention comprise buffers at concentrations of between 0 and 100 M.
  • 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) or sodium citrate.
  • the buffer is sodium phosphate.
  • the buffer is Tris
  • the buffer is sodium citrate.
  • the composition further comprises a zinc salt, in particular zinc chloride.
  • the concentration of zinc salt is between 50 and 5000 mM.
  • the concentration of zinc salt is between 100 and 2000 mM. In one embodiment, the concentration of zinc salt is between 200 and 1500 mM.
  • the concentration of zinc salt is between 200 and 1000 mM.
  • the zinc concentration is such that the molar ratio [zinc] / [glucagon] is between 0, 1 and 2.5.
  • the zinc concentration is such that the molar ratio [zinc] / [glucagon] is between 0.2 and 2.
  • the zinc concentration is such that the molar ratio [zinc] / [glucagon] is between 0.5 and 1.5.
  • the zinc concentration is such that the [zinc] / [glucagon] molar ratio is 1.
  • 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.
  • compositions according to the invention further comprise antioxidants.
  • the antioxidants are chosen from methionine.
  • the concentration of the preservatives is between 10 and 50 mM.
  • the concentration of the preservatives is between 10 and 40 mM.
  • compositions according to the invention further comprise a surfactant.
  • the surfactant is selected from the group consisting of propylene glycol or polysorbate.
  • compositions according to the invention may further comprise additives such as tonicity agents.
  • the tonicity agents are selected from the group consisting of sodium chloride, mannitol, sucrose, sorbitol and glycerol.
  • the compositions according to the invention may furthermore comprise all excipients compatible with the pharmacopoeia and compatible with human glucagon and gastrointestinal hormones, in particular GLP-1 RAs, used at use concentrations.
  • the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
  • the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
  • the mode of administration is the subcutaneous route.
  • the mode of administration is the intramuscular route.
  • 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 6.6 and 7.8 comprising human glucagon.
  • the invention also relates to single-dose formulations at a pH of between 6.6 and 7.8 comprising human glucagon and a gastrointestinal hormone, as defined above.
  • the single-dose formulations further comprise a substituted co-polyamino acid as defined above.
  • the formulations are in the form of an injectable solution.
  • GLP-1 RA, analogue or derivative of GLP-1 RA is selected from the group consisting of 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.
  • the gastrointestinal hormone is dulaglutide.
  • the preparation of a composition according to the invention has the advantage of being possible by simple mixing of a solution of human glucagon, a solution of GLP-1 RA, an analogue or a derivative of GLP-1 RA, 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 7.
  • the mixture of human glucagon and substituted co-polyamino acid is concentrated by ultrafiltration before mixing with GLP-1 RA, an analogue or a derivative of GLP-1 RA in aqueous solution or under freeze-dried form.
  • composition of the mixture is adjusted by excipients such as glycerin, m-cresol, and polysorbate (Tween ®) by addition of concentrated solutions of these excipients in the mixture. If necessary, the pH of the preparation is adjusted to 7.
  • Figure 1 An example of a graphical determination is shown in Figure 1.
  • Molecule 1 1 Product obtained by the reaction between decanoyl chloride and L-proline.
  • the white solid obtained after crystallization in AcOEt is solubilized in DCM (400 mL), the organic phase is washed with an aqueous solution of 1N HCl (200 mL) and then a saturated aqueous solution of NaCl (200 mL), dried over Na 2 SO 4 , filtered and concentrated in vacuo.
  • a white solid of the molecule A2 is obtained after crystallization in AcOEt.
  • Molecule 2 Product obtained by the reaction between lauroyl chloride and L-proline.
  • Molecule 3 Product obtained by the reaction between Fmoc-Lys (Fmoc) -OH and the resin 2-Cl- trityl chloride.
  • Molecule 4 Product obtained by reaction between the molecule 3 and a mixture of DMF / piperidine 80: 20.
  • the molecule 3 previously washed with DMF, is treated with a mixture of DMF / piperidine 80: 20 (60 mL). After 30 minutes stirring at room temperature, the resin is filtered, washed successively with DMF (3 x 60 mL), isopropanol (1 x 60 mL) and DCM (3 x 60 mL).
  • Molecule 5 Product obtained by reaction between molecule 4 and 8- (9-Fluorenylmethyloxycarbonylamino) -3,6-dioxaoctanoic acid (Fmoc-020c-OH).
  • Molecule 6 Product obtained by reaction between the molecule 5 and a mixture of DMF / piperidine 80: 20.
  • the molecule 6 is obtained.
  • Molecule 7 Product obtained by reaction between molecule 6 and lauric acid.
  • the molecule 7 is treated with a mixture of dichloromethane / 1,1,1,3,3,3-hexafluoro-2-propanol (HFIP) 80: 20 (60 mL). After stirring for 20 minutes at room temperature, the resin is filtered and washed with dichloromethane (2 ⁇ 60 mL). The solvents are evaporated under reduced pressure. Two coevaporations are then carried out on the residue with dichloromethane (60 ml) and then diisopropyl ether (60 ml). A white solid of molecule 8 is obtained after recrystallization in acetonitrile.
  • HFIP 1,1,1,3,3,3-hexafluoro-2-propanol
  • Molecule 9 Product obtained by the reaction between molecule 8 and N-Boc ethylenediamine.
  • the organic phase is washed with a saturated aqueous solution of NF CI (2 ⁇ 10 mL), a saturated aqueous solution of NaHCO 3 (2 ⁇ 10 mL), and a saturated aqueous solution of NaCl (2 ⁇ 10 mL).
  • the organic phase is dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • a white solid of molecule 9 is obtained after purification by chromatography on silica gel (eluent: dichloromethane, methanol).
  • Molecule 10 Product obtained by hydrogenation of retinoic acid.
  • Molecule 11 Product obtained by coupling between Boc-1-amino-4,7,10-trioxa-13-tridecan amine (BocTOTA) and molecule 10.

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EP18826204.2A 2017-12-07 2018-12-07 Zusammensetzungen in form einer injizierbaren wässrigen lösung mit menschlichem glucagon und einer copolyaminosäure Pending EP3731858A1 (de)

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CN111836616B (zh) 2017-12-07 2024-01-16 阿道恰公司 包含至少一种pi在5.8与8.5之间的基础胰岛素和带有羧酸根电荷及疏水基的共聚氨基酸的ph 7为7的可注射溶液
MA51597A (fr) 2017-12-07 2020-11-25 Adocia Solution injectable a ph 7 comprenant au moins une insuline basale dont le pi est compris entre 5,8 et 8,5 et un co-polyaminoacide porteur de charges carboxylates et de radicaux hydrophobes
EP4091625A1 (de) 2021-05-22 2022-11-23 Adocia Zusammensetzungen mit kurzwirkenden hormonen zur behandlung oder vorbeugung von fettleibigkeit und pumpen mit dieser zusammensetzung
WO2022248419A2 (en) 2021-05-22 2022-12-01 Adocia Compositions comprising short-acting hormones for treating or preventing obesity and pumps comprising said composition
EP4144362A1 (de) 2021-09-06 2023-03-08 Adocia Zusammensetzungen mit kurzwirkenden hormonen zur behandlung oder vorbeugung von fettleibigkeit und pumpen mit besagter zusammensetzung

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US6384016B1 (en) 1998-03-13 2002-05-07 Novo Nordisk A/S Stabilized aqueous peptide solutions
FR2801226B1 (fr) 1999-11-23 2002-01-25 Flamel Tech Sa Suspension colloidale de particules submicroniques de vectorisation de principes actifs et son mode de preparation
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JP2015503565A (ja) 2011-12-29 2015-02-02 ラティチュード ファーマシューティカルズ インコーポレイテッドＬａｔｉｔｕｄｅ Ｐｈａｒｍａｃｅｕｔｉｃａｌｓ， Ｉｎｃ． 安定化させたグルカゴンナノエマルジョン
BR112014016889A8 (pt) * 2012-01-09 2017-07-04 Adocia composição sob a forma de uma solução aquosa injetável, sujo ph está compreendido entre 6,0 e 8,0 e, formulação de dose unitária com ph compreendido entre 7 e 7,8
WO2014096440A2 (en) 2012-12-21 2014-06-26 Novozymes Biopharma Dk A/S Composition
EP3082817A4 (de) 2013-12-18 2017-06-21 Aegis Therapeutics, LLC Zusammensetzungen zur arzneimittelverabreichung
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FR3052071B1 (fr) 2016-06-07 2018-09-07 Adocia Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon et un co-polyaminoacide
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