WO2017211918A1 - Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacidegreffe en bout de chaine - Google Patents
Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacidegreffe en bout de chaine Download PDFInfo
- Publication number
- WO2017211918A1 WO2017211918A1 PCT/EP2017/063888 EP2017063888W WO2017211918A1 WO 2017211918 A1 WO2017211918 A1 WO 2017211918A1 EP 2017063888 W EP2017063888 W EP 2017063888W WO 2017211918 A1 WO2017211918 A1 WO 2017211918A1
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- WO
- WIPO (PCT)
- Prior art keywords
- formula
- radical
- hydrophobic
- polyamino acid
- chosen
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 453
- 239000002253 acid Substances 0.000 title claims abstract description 425
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- YSDQQAXHVYUZIW-QCIJIYAXSA-N Liraglutide Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)NCC(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](C)C(=O)N[C@@H](CCCCNC(=O)CC[C@H](NC(=O)CCCCCCCCCCCCCCC)C(O)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=C(O)C=C1 YSDQQAXHVYUZIW-QCIJIYAXSA-N 0.000 claims description 9
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- 125000003118 aryl group Chemical group 0.000 claims description 6
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 claims description 6
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- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 6
- 125000004430 oxygen atom Chemical group O* 0.000 claims description 6
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- 125000002091 cationic group Chemical group 0.000 claims description 5
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- 125000002704 decyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 claims description 4
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- 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
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
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.
- XE IS 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 envisaged in particular 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.
- these peptides whose primary sequence has been modified with respect to the peptide of human origin may present a safety risk for patients.
- hydrophilic surfactants include hydrophilic surfactants:
- GB1202607 (NOVO NORDISK) describes the use of anionic or cationic detergents.
- US6384016 (NOVO NORDISK) and US2011097386 (BIODEL) use lysophospholipids (or lysolecithins).
- 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.
- 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 rather modest performance in terms of chemical stability, that is to say that the composition comprises at least 75% of the initial concentration after 3-7 days at 37 ° C. In addition, it should be noted that to date, to the knowledge of the applicant, no pharmaceutical formulation comprising human glucagon in the form of aqueous solution is tested in clinical study.
- 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:
- - GpR is a radical of formulas II or ⁇ : O
- GpA is a radical of formulas III or ⁇
- GpC is a radical of formula IV:
- - a is an integer equal to 0 or 1;
- b is an integer equal to 0 or 1;
- p is an integer equal to 1 or 2 and
- - c is an integer equal to 0 or 1, and if c is equal to 0 then d is equal to 1 or 2;
- d is an integer equal to 0, 1 or 2;
- r is an integer equal to 0 or 1
- the hydrophobic radical of formula I is bonded to the co-polyamino acid via a covalent bond between a carbonyl of the hydrophobic radical and a nitrogen atom in the N-terminal position of the co-polyamino acid, thus forming an amide function resulting from the reaction of an amino function at the N-terminal position of the precursor of the co-polyamino acid and an acid function carried by the precursor of the hydrophobic radical, and o if r is equal to 1, then the hydrophobic radical of formula I is bound to the polyamino acid: "Via a covalent bond between a nitrogen atom of the hydrophobic group and a carbonyl co-polyamino acid, thus forming an outlet amide from the reaction of an amine functional group of the precursor of the hydrophobic group and an acidic functional group carried by the precursor of the co-polyamino acid or
- R is a radical chosen from the group consisting of:
- GpR is a radical of formula II of 2 to 12 carbon atoms or if GpR is a radical of formula ⁇ of 1 to 11 carbon atoms;
- a divalent alkyl radical linear or branched, comprising if GpR is a radical of formula II of 2 to 11 carbon atoms or if GpR is a radical of formula ⁇ of 1 to 11 carbon atoms, said alkyl radical carrying one or more -CONH2 functions, and
- an unsubstituted ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms;
- A is a linear or branched alkyl radical comprising from 1 to 6 carbon atoms
- B is a linear or branched alkyl radical, optionally comprising an aromatic nucleus comprising from 1 to 9 carbon atoms;
- Cx is a linear or branched monovalent alkyl radical, in which x indicates the number of carbon atoms and:
- x is between 9 and 15 (9 ⁇ x ⁇ 15), the ratio i between the number of hydrophobic radicals and the number of glutamic or aspartic units being between 0 ⁇ i ⁇ 0 , 5;
- the degree of DP polymerization in glutamic or aspartic units is between 5 and 250;
- GpR is a radical of formula II:
- the composition is characterized in that the pH is between 6.6 and 7.8.
- the composition is characterized in that the pH is between 7.0 and 7.8.
- the composition is characterized in that the pH is between 6.8 and 7.4.
- the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which if p is equal to 1 and if x is between 15 and 16 (15 ⁇ x ⁇ 16), then r
- the composition is characterized in that the said hydrophobic radicals are chosen from the hydrophobic radicals of formula I in which, if p is equal to 1, then x is between 17 and 25 (17 ⁇ x ⁇ 25 ).
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 4 carbon atoms .
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 2 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ⁇ .
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ⁇ wherein R is a divalent linear alkyl radical having from 1 to 11 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ⁇ in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms .
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).
- the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms and carrying one or more amide functions (-CONH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ⁇ or II, in which R is a divalent linear alkyl radical, comprising from 2 to to 5 carbon atoms and bearing one or more amide functions (-CONH2).
- the hydrophobic radical is a radical of formula V in which GpR is a radical of formula ⁇ or II, in which R is a divalent linear alkyl radical, comprising from 2 to to 5 carbon atoms and bearing one or more amide functions (-CONH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or in which R is a radical chosen from the group consisting of radicals. represented by the formulas below:
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a radical of formula XI.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or IV, in which R is a radical of formula X2.
- the composition is characterized in that the radical R is linked to the co-polyamino acid via an amide function carried by the carbon in the delta or epsilon position (or in position 4 or 5) with respect to the amide function (- COIMH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is an ether radical.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or IV, in which R is an ether radical comprising from 4 to 6 atoms. of carbon.
- the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising 6 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or in which R is an ether radical represented by the formula
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a polyether radical.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which GpR is a radical of formula II or IV, 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 V in which GpR is a radical of formula II or ⁇ , in which R is a polyether radical chosen from the group consisting of radicals
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a radical of formula X3.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or IV, in which R is a radical of formula X4.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or ⁇ , in which R is a radical of formula X5.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II or IV, in which R is a radical of formula X6.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical chosen from the group consisting of the radicals represented by the formulas x5 and X6 below:
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical of formula X5.
- the composition is characterized in that the hydrophobic radical of formula V in which GpR is a radical of formula II in which R is a polyether radical of formula X6.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical is of formula IVa.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to formulas IVd, IVe and IVf below:
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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 linear alkyl radicals.
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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 branched alkyl radicals.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 11 and 14 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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:
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is selected from the group consisting of radicals in which Cx is selected from the group consisting of alkyl radicals of between 15 and 16 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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:
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 17 and 25 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 17 and 18 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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 alkyl radicals represented by the formulas below:
- the composition is characterized in that the hydrophobic radical is a radical of formula V in which the GpC radical of formula IV is chosen from the group consisting of radicals in which Cx is chosen from the group consisting of by alkyl radicals comprising between 18 and 25 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula V 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 alkyl radicals represented by the formulas below:
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 12 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent alkyl radical comprising from 2 to 6 carbon atoms .
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 6 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is an alkyl radical comprising from 2 to 4 carbon atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising from 2 to 4 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II in which R is a divalent linear alkyl radical comprising 2 carbon atoms. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ .
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ in which R is a divalent linear alkyl radical comprising from 1 to 11 carbon atoms. carbon.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula ⁇ in which R is a divalent alkyl radical comprising from 1 to 6 carbon atoms .
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or ⁇ , in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms, and bearing one or more amide functions (-CONH2).
- the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or ⁇ , in which R is a divalent alkyl radical, comprising from 2 to 5 carbon atoms, and bearing one or more amide functions (-CONH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is a divalent linear alkyl radical, comprising from 2 to to 5 carbon atoms and bearing one or more amide functions (-CONH2).
- the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is a divalent linear alkyl radical, comprising from 2 to to 5 carbon atoms and bearing one or more amide functions (-CONH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV in which R is a radical chosen from the group consisting of
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the amine function of the GpR radical involved in the formation of the amide function which binds said GpR radical to the co-polyamino acid is carried by a carbon in position delta or epsilon (or in position 4 or 5) with respect to the amide function (-CONH2).
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or ⁇ , in which R is an unsubstituted linear ether or polyether radical comprising from 4 to 14 carbon atoms and from 1 to 5 oxygen atoms.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is an ether radical.
- the composition is characterized in that the ether radical R is a radical comprising from 4 to 6 carbon atoms.
- the composition is characterized in that the ether radical is ⁇ *.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV, in which R is a polyether radical.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or ⁇ , 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 is a radical of formula VI in which GpR is a radical of formula II or IV in which R is a linear polyether radical chosen from the group
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV in which R is a linear polyether radical of formula X3.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or IV in which R is a linear polyether radical of formula X4. In one embodiment, the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is a linear polyether radical of formula X5.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which GpR is a radical of formula II or in which R is a linear polyether radical of formula X6.
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is chosen from the group consisting of the radicals of formulas IIIa, IIIb and IIIc hereof. after represented
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula of formula IIIb below is represented:
- the composition according to the invention is characterized in that the hydrophobic radical is a radical of formula VI in which the GpA radical of formula III is a radical of formula IIIc.
- 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 the radicals of formulas IVa, IVb and IVc below. after represented:
- the composition is characterized in that the hydrophobic radical is a radical of formula VI in which the GpC radical is of formula IVa.
- 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 of formulas IVa, IVb or IVc in which b is equal to 0, respectively corresponding to formulas IVd, IVe and IVf below:
- 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 linear alkyl radicals comprising between 9 and 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 branched alkyl radicals comprising between 9 and 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 alkyl radicals comprising 9 or 10 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 alkyl radicals comprising between 11 and 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 alkyl radicals comprising between 11 and 13 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:
- 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 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:
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the following co-polyamino acids of formula VII: ## STR2 ##
- D is, independently, either -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit),
- X represents an H or a cationic entity selected from the group consisting of metal cations
- n + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n + m ⁇ 250.
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the following co-polyamino acids of formula VII: ## STR2 ##
- D is, independently, either -CH2- (aspartic unit) or -CH2-CH2- (glutamic unit),
- At least one of R 1 or R 2 is a hydrophobic radical as defined above,
- X represents an H or a cationic entity selected from the group comprising metal cations
- ⁇ N + m represents the degree of DP polymerization of the co-polyamino acid, that is to say the average number of monomeric units per co-polyamino acid chain and 5 ⁇ n + m ⁇ 250.
- 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 formula VII in which at least one of the R1 or R 2 is a hydrophobic radical of formula I, V or VI.
- 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 formula VII in which at least one of the R 1 or Ri is a hydrophobic radical of formula VI.
- 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 formula VII in which R 1 is a hydrophobic radical of formula VI.
- 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 formula VII in which R 1 is a hydrophobic radical of formula VI and R2 is a radical radical -NR'R ", R 'and R" being as defined above.
- 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 VII.
- 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 formula VII in which R2 is a hydrophobic radical of formula I, V or VI.
- 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 formula VII in which R2 is a hydrophobic radical of formula VI.
- 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 formula VII in which R 2 is a hydrophobic radical.
- R1 is a radical radical -NR'R ", R 'and R" being as defined above.
- 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 formula VII in which R 2 is a hydrophobic radical.
- 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 formula VII in which R 2 is a hydrophobic radical.
- 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 formula VII in which R 1 and R 2 are a hydrophobic radical of formula I, V or VI.
- 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 formula VII in which R 1 and R 2 are a hydrophobic radical of formula VI.
- 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 formula VII in which R 1 and R 2 are a hydrophobic radical of formula VI, and Hy is a radical of formula VI, wherein r-1.
- 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 VII
- 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 formula VII below: formula VII in which,
- D represents, independently, either a -CH 2 - (aspartic unit) or a -CH 2 -CH 2 - (glutamic unit) group,
- R 'and R identical or different being selected from the group consisting of H, linear or branched or cyclic C2 to C10 alkyls, benzyl and said R' and R "alkyls may together form one or more saturated, unsaturated and / or aromatic carbon rings and / or may contain heteroatoms selected from the group consisting of O, N and S;
- At least one of R 1 or R 2 is a hydrophobic radical as defined above,
- X represents a cationic entity selected from the group comprising alkaline cations
- N> 1 and 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 co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical of formula I may also be called "co-polyamino acid" in the present description.
- 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 formula VII in which n> 1 and at least one of R1 or R2 is a hydrophobic radical of formula I, V or VI.
- 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 formula VII in which n> 1 and RI is a hydrophobic radical of formula I, V or VI.
- 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 formula VII in which n> 1 and R2 is a hydrophobic radical of formula I, V or VI.
- defined co-polyamino acid refers to a co-polyamino acid bearing carboxylate charges and at least one hydrophobic radical, a co-polyamino acid of formula VUb.
- R 1 and R 2 are as previously defined and at least one of R 1 and R 2 is a hydrophobic radical of formula I, V or VI.
- 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 formula VIIb in which at least one of the Ri or R2 is a hydrophobic radical of formula VI.
- 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 formula VIIb in which Ri is a hydrophobic radical of formula VI.
- 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 formula VIIb in which Ri is a hydrophobic radical of formula VI and R2 is a radical -NR'R ", R 'and R" being as defined above.
- 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 formula Vllb in which Ri is a hydrophobic radical of formula VI and R 2 is a radical -NR'R ", R 'and R" being as defined above.
- 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 formula Vllb in which R 2 is a hydrophobic radical. of formula I, V or VI.
- 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 formula VIIb in which R2 is a hydrophobic radical of formula VI.
- 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 formula VII in which R2 is a hydrophobic radical of Formula VI and R1 is a radical selected from the group consisting of H, C2-C10 linear acyl group, C3-C10 branched acyl group, benzyl, terminal amino acid unit and pyroglutamate.
- 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 formula VIIb in which R2 and Hy are radicals.
- 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 formula VII in which R 1 and R 2 are radicals. hydrophobes of formula I, V or VI.
- 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 formula VII in which R 1 and 2 are radicals. hydrophobic compounds of formula VI.
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which R2 is a hydrophobic radical, in particular with n>
- R 1 is a radical selected from the group consisting of C 2 -C 10 linear acyl group, C 3 -C 10 branched acyl group, benzyl, terminal amino acid unit and pyroglutamate.
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from among the co-polyamino acids of formula VII in which R2 is a hydrophobic radical, in particular with n> 1, or VIIb in which R1 is a radical chosen from the group consisting of a linear acyl group of C2 to C10 or a branched acyl group in C3 to GB.
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of R1 or R2 is a radical. hydrophobic, especially with n> 1, and at or Vllb in which the group D is a group -CH2- (aspartic unit).
- the composition is characterized in that the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is chosen from the co-polyamino acids of formula VII in which at least one of the at least one of the Ri or R2 is a hydrophobic radical, especially with n> 1, or V11b in which the D group is a -CH2-CH2- (glutamic unit) group.
- the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.007 and 0.3.
- the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.3.
- the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.3.
- the composition is characterized in that the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.02 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio 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 formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.03 and 0.3. In one embodiment, the composition is characterized in that the radical hydrophobic corresponds to formula VI and the ratio between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.05 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI and the ratio 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 VI and the ratio 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 formula VI and the ratio 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 formula VI in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.3.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 9 and 10 carbon atoms and the ratio i 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 formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.05 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.03 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio i 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 VI in which the radical Cx comprises between 11 and 12 carbon atoms and the ratio of i between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.02 and 0.08.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number Giutamic or aspartic units are between 0.03 and 0.15.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.01 and 0.1.
- the composition is characterized in that the hydrophobic radical corresponds to formula VI in which the radical Cx comprises between 13 and 15 carbon atoms and the ratio i between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.01 and 0.06.
- the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.007 and 0, 3.
- the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.01 and 0.3.
- the composition is characterized in that the hydrophobic radical corresponds to formula V and the ratio i between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.05 and 0.3.
- the composition is characterized in that the hydrophobic radical corresponds to the formula V and the ratio i between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0, 1 and 0.3.
- the composition is characterized in that the hydrophobic radical corresponds to the formula V and the ratio between the number of hydrophobic radicals and the number of giutamic or aspartic units is between 0.015 and 0, 2.
- the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i between the number of hydrophobic radicals and the number gutamic or aspartic units is between 0.1 and 0.3. In one embodiment, the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 11 and 14 carbon atoms and the ratio i 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 formula V in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.04 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to the formula V in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.06 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 15 and 16 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.04 and 0.15.
- the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.2.
- the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio i between the number of hydrophobic radicals and the number glutamic or aspartic units is between 0.02 and 0.15.
- the composition is characterized in that the hydrophobic radical corresponds to formula V in which the radical Cx comprises between 17 and 18 carbon atoms and the ratio i 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 formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i 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 formula V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio i 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 V in which the radical Cx comprises between 19 and 25 carbon atoms and the ratio of i between the number of hydrophobic radicals and the number of glutamic or aspartic units is between 0.01 and 0.05.
- composition according to the invention is characterized in that n + m is between 10 and 250.
- the composition according to the invention is characterized in that n + m is between 10 and 200.
- the composition according to the invention is characterized in that n + m is between 10 and 100.
- the composition according to the invention is characterized in that n + m is between 10 and 50.
- composition according to the invention is characterized in that n + m is between 15 and 150.
- composition according to the invention is characterized in that n + m is between 15 and 100.
- composition according to the invention is characterized in that n + m is between 15 and 80.
- composition according to the invention is characterized in that n + m is between 15 and 65.
- composition according to the invention is characterized in that n + m is between 20 and 60.
- composition according to the invention is characterized in that n + m is between 20 and 50.
- composition according to the invention is characterized in that n + m is between 20 and 40.
- 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 precursors of said hydrophobic radicals of formula, V and VI ': FORMULA,.
- GpR, GpA, GpC, r, a, p have the definitions given above.
- 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 / ml 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 the 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. 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.
- "Injectable aqueous solution” is understood to mean water-based solutions which satisfy the conditions of EP and US pharmacopoeia and which are sufficiently liquid to be injected.
- co-polyamino acid consisting of glutamic or aspartic units non-cyclic linear sequences of glutamic acid or aspartic acid units linked together by peptide bonds, said sequences having a C terminal part, corresponding to the carboxylic acid of one end, and an N-terminal portion, corresponding to the amine of the other end of the sequence.
- alkyl radical is meant a linear or branched carbon chain which does not comprise a heteroatom.
- the co-polyamino acid is a random co-polyamino acid or block.
- the co-polyamino acid is a random co-polyamino acid in the sequence of glutamic and / or aspartic units.
- the * indicate the sites of attachment of the hydrophobic radicals to the co-polyamino acid.
- the radicals Hy are attached to the co-polyamino acid via amide functions.
- the radicals Hy, GpR, GpA, GpC, and D are each independently identical or different from one monomeric unit to another.
- 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 the co-polyamino acids may further comprise monomeric units.
- GpR has formula II in which R is NH 2
- GpC corresponds to the formula IVd in which x 15 and Cx is
- GpR is of formula II wherein R is -CH2-CH2-, GpA is IIIb,
- the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or
- the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or
- GpR is of formula II wherein R is -CH2-CH2-, GpA is formula
- the co-polyamino acid bearing carboxylate charges and hydrophobic radicals is a co-polyamino acid of formula VII or
- 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 a derivative thereof. of aspartic acid N-carboxyanhydride using as a complex initiator organometallic composition 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 ammonia or a primary amine as initiator as described in patent FR 2,801,226 (Touraud, F. et al.) and references cited therein.
- the composition according to the invention is characterized in that the 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 step of hydrolysis of ester functions may consist of hydrolysis in an acidic medium or hydrolysis in a basic medium or may be carried out by hydrogenation.
- this step of hydrolysis of ester groups is a hydrolysis in acidic medium.
- this step of hydrolysis of ester groups is carried out by hydrogenation.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic depolymerization of a polyamino acid of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by chemical depolymerization of a polyamino acid of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by enzymatic and chemical depolymerization of a polyamino acid of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a polyamino acid of higher molecular weight selected from the group consisting of polyglutamate. of sodium and sodium polyaspartate.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyglutamate of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is derived from a polyamino acid obtained by depolymerization of a sodium polyaspartate of higher molecular weight.
- the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group onto a poly-L-glutamic acid or poly-L-aspartic acid using amide bond forming processes well known to those skilled in the art.
- the composition according to the invention is characterized in that the co-polyamino acid is obtained by grafting a hydrophobic group 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 an acid poly-L-glutamic acid or poly-L-aspartic acid as described. in FR 2,840,614 (Chan, YP et al.).
- 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. In one embodiment, 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 carrying carboxylate charges and hydrophobic radicals is at most 0.5 mg / ml.
- the weight ratio co-polyamino acid carrying carboxylate charges and hydrophobic radicals glucagon is between 1.5 and 25.
- the weight ratio co-polyamino acid carrying 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 carrying carboxylate charges and hydrophobic radicals on glucagon is between 2 and 10.
- the weight ratio co-polyamino acid bearing carboxylate charges and hydrophobic radicals on glucagon is between 2 and 7.
- Human glucagon is used at dosages that vary according to the applications.
- 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 approximately 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 may 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. In one embodiment, 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.
- 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. In one embodiment, 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.
- Human glucagon is a highly conserved polypeptide comprising a single chain of 29 amino acid residues having the following sequence H-His-Ser-GIn-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 composition further comprises a nicotinic compound or a derivative thereof.
- the composition comprises nicotinamide.
- the concentration of nicotinamide ranges from 10 to 160 mM.
- 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 100 mM.
- the composition further comprises a polyanionic compound.
- the polyanionic compound is chosen 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 selected from the group consisting of polyphosphoric acids and their salts of Na + , K + , Ca 2+ or Mg 2+ .
- the polyphosphoric acid is triphosphate and its salts of Na + , K ⁇ Ca 2+ or Mg 2+ .
- 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. [000384] In one embodiment, the polyanionic compound concentration is between 1 and 20 mM.
- the polyanionic compound concentration is between 2 and 15 mM.
- the concentration of polyanionic compound is between 3 and 12 mM.
- the concentration of polyanionic compound is 10 mM.
- 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. In one embodiment, 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. In one embodiment, 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 salts of Na + , K + , Ca 2+ or Mg 2+ 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 Na + , K + , Ca 2+ or Mg 2+ salts is 10 mM.
- the concentration of citric acid and its Na + , K + , Ca 2+ or Mg 2+ salts is 5 mM.
- the concentration of citric acid and its Na + , K + , Ca 2+ or Mg + salts is 10 mM for glucagon concentrations of between 0.5 mg / ml and 3 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 / 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 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. 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 of the human Glucagon receptor-Like Peptide-1 (Glucagon like peptide-1 receptor agonist) Glucagon like) and the GIP (Glucose-dependent insulinotropic peptide), oxyntomodulin (a derivative of human proglucagon), YY peptide, amylin, cholecystokinin, pancreatic polypeptide (PP), ghrelin and enterostatin, their analogs or derivatives and / or their pharmaceutically acceptable salts.
- GLP-1 RA Glucagon like peptide-1 receptor agonist
- GIP Glucose-dependent insulinotropic peptide
- oxyntomodulin a derivative of human proglucagon
- YY peptide amylin
- cholecystokinin pancreatic polypeptide
- enterostatin their analogs or derivatives and / or their pharmaceutically acceptable salts
- 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 glycoliraglutide or Victoza®
- STEMOFI lixisenatide or Lyxumia®
- GSK albiglutide or Tanzeum®
- ELI LILLY & CO dulaglutide
- their analogues or derivatives and their pharmaceutically acceptable salts acceptable selected from the group consisting of exenatide or Byetta® (ASTRA-ZENECA) , lirag
- the gastrointestinal hormone is pramlintide or Symlin® (ASTRA-ZENECA).
- the gastrointestinal hormone is exenatide or Byetta® its analogues or derivatives and their pharmaceutically acceptable salts.
- the gastrointestinal hormone is liraglutide or Victoza® its analogues or derivatives and their pharmaceutically acceptable salts.
- the gastrointestinal hormone is lixisenatide or Lyxumia® its analogues or derivatives and their pharmaceutically acceptable salts.
- the gastrointestinal hormone is albiglutide or Tanzeum® analogs or derivatives thereof and pharmaceutically acceptable salts thereof.
- the gastrointestinal hormone is dulaglutide or Trulicity® its analogues or derivatives and their pharmaceutically acceptable salts.
- the gastrointestinal hormone is pramlintide or Symlin®, its analogues 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.
- 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.
- compositions according to the invention are produced by mixing human glucagon solutions obtained by reconstituting 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.
- GLP-1 RA solutions Glucagon like peptide-1 receptor agonist
- compositions according to the invention further comprise buffers.
- compositions according to the invention comprise buffers at concentrations of between 0 and 100 mM.
- compositions according to the invention comprise buffers at concentrations of between 15 and 50 mM.
- compositions according to the invention comprise a buffer selected from the group consisting of a phosphate buffer, the
- Tris trishydroxymethylaminomethane
- sodium citrate 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 ⁇ . [000434] In one embodiment, the concentration of zinc salt is between 100 and 2000 ⁇ .
- the concentration of zinc salt is between 200 and 1500 ⁇ .
- the concentration of zinc salt is between 200 and 1000 ⁇ .
- 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 also 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 chosen from the group consisting of sodium chloride, mannitol, sucrose, sobitol and glycerol.
- compositions according to the invention may furthermore comprise all the excipients which are compatible with pharmacopoeia and compatible with human glucagon and the gastrointestinal hormones, including GLP-1 RA, used at use levels.
- the invention also relates to a pharmaceutical formulation according to the invention, characterized in that it is obtained by drying and / or lyophilization.
- the modes of administration envisaged are intravenous, subcutaneous, intradermal or intramuscular.
- transdermal, oral, nasal, vaginal, ocular, oral, and pulmonary routes of administration are also contemplated.
- the invention also relates to single-dose formulations with a pH of between 6.6 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 albigiutide.
- the gastrointestinal hormone is dulaglutide.
- the Applicant has been able to verify that human glucagon in the presence of a co-polyamino acid carrying carboxylate charges and at least one hydrophobic radical according to the invention retains its action. either alone or in combination with a gastrointestinal hormone.
- 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. In one embodiment, 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 to excipients such as glycerol, 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.
- hydrophobic radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
- Molecule A1 product obtained by the reaction between palmitoyl chloride and L-proline.
- the opalescent reaction medium is then cooled to 0 ° C.
- the precipitate obtained is filtered on sintered and then washed with water (5 x 50 mL) until filtrates of physiological pH between 6.0 and 8.0 are obtained, and then dried in an oven at 50.degree. empty overnight.
- the product is purified by recrystallization from diisopropyl ether. A white solid is obtained.
- Molecule A2 product obtained by reaction between the Al molecule and Boc-ethylenediamine.
- N-diisopropylethylamine DIPEA
- HOBt 1-hydroxybenzotriazole
- EDC N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide
- Example AA2 molecule AA2
- Molecule A3 15-methylhexadecan-1-ol.
- magnesium (9.46 g, 389 mmol) in chips.
- the magnesium is covered with anhydrous THF (40 mL) and a few drops of 1-bromo-3-methylbutane are added at room temperature to initiate the reaction. After the observation of an exotherm and a slight turbidity of the medium, the rest of 1-bromo-3-methylbutane (53.87 g, 357 mmol) is added dropwise over 90 min while the temperature of the medium remains unchanged. stable between 50 and 60 ° C. The reaction medium is then heated at 70 ° C. for 2 hours.
- Molecule A4 15-methylhexadecanoic acid.
- aqueous phase is extracted with dichloromethane and the combined organic phases are dried over Na 2 SC 3, filtered and concentrated in vacuo. After purification by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid), a white solid is obtained.
- Molecule. A5 product obtained by reaction between the A4 molecule and L-proline.
- the medium is treated with an aqueous solution of 1N HCl to pH 1.
- the aqueous phase is extracted with dichloromethane (2 ⁇ 125 mL).
- the combined organic phases are washed with an aqueous solution of 1N HCl (2 x 100 ml), water (100 ml) and then a saturated aqueous solution of NaCl (100 ml).
- the organic phase is filtered, concentrated under vacuum and the residue is purified by chromatography on silica gel (cyclohexane, ethyl acetate, acetic acid) Yield: 9.2 g (72%)
- Molecule A6 product obtained by reaction between the molecule A5 and Boc-ethylenediamine.
- Molecule A7 product obtained by the reaction between the Al molecule and the Boc-tri (ethylene glycol) diamine.
- Molecule A8 product obtained by the reaction between the Al molecule and the Boc-1-amino-4,7,10-trioxa-13-tridecane amine.
- A9 molecule product obtained by reaction between the Al molecule and the methyl ester of the V-Boc-L-lysine.
- Molecule A10 product obtained by treatment of the molecule A9 with ammonia.
- Molecule Garlic product obtained by the reaction between stearoyl chloride and L-proline.
- Molecule A12 product obtained by reaction between the molecule A11 and Boc-tri (ethylene glycol) diamine.
- Molecule A1 3 product obtained by reaction between arachidic acid and L-proline.
- Molecule A14 product obtained by the reaction between the molecule A13 and Boc-1-amino
- Molecule A15 product obtained by the reaction between L-leucine and palmitoyl chloride.
- Molecule A16 product obtained by the reaction between the molecule A15 and the methyl ester of L-proline
- Molecule Al 7 product obtained by the saponification of the methyl ester of the molecule A16.
- Molecule A18 product obtained by the reaction between Boc-ethylenediamine and the molecule A17.
- Example AA9 molecule AA9
- Molecule A19 product obtained by the reaction between lauric acid and L-phenylalanine.
- Molecule A20 product obtained by the reaction between the molecule A19 and the hydrochloride salt of the methyl ester of L-proline.
- Molecule A21 product obtained by saponification of the molecule A20.
- AAIO example AAIO molecule
- Molecule A23 product obtained by the reaction between nipecotic acid and arachidic acid.
- Molecule A24 product obtained by the reaction between the molecule A23 and the Boc-1-amino-4,7,10-trioxa-13-tridecane amine.
- Molecule A26 product obtained by the reaction between myristoyl chloride and L-proline (1646-22-CNI)
- Molecule A27 product obtained by the reaction between the molecule A26 and Boc-ethylenediamine
- reaction mixture was then washed with saturated aqueous NH4Cl (50 mL), saturated aqueous NaHCO (50 mL) then saturated aqueous NaCl solution (50 mL), dried over Na2S0 4, filtered and concentrated under pressure scaled down. A white solid is obtained after recrystallization in methanol.
- Resin AA14-1 product obtained by the reaction between 4,7,10-trioxa-1,3-tridecanediamine and 2-CI-trityl chloride resin.
- the resin is filtered, washed successively with dichloromethane (3 x 50 mL), DMF (2 x 50 mL), dichloromethane (2 x 50 mL), isopropanol (1 x 50 mL) and dichloromethane (3 x 50 mL). x 50 mL).
- AA14-2 resin product obtained by reaction between AA14-1 resin and Fmoc-glycine.
- AA14-3 resin product obtained by reaction between the AA14-2 resin and a 80:20 DMF / piperidine mixture.
- the AA14-2 resin is treated with a 80:20 DMF / piperidine mixture (50 mL). After 30 minutes stirring at room temperature, the resin is filtered, washed successively with DMF (3 ⁇ 50 mL), isopropanol (1 ⁇ 50 mL) and dichloromethane (3 ⁇ 50 mL).
- AA14-4 resin product obtained by reaction between AA14-3 resin and Fmoc-proline.
- AA14-5 resin product obtained by reaction between the AA14-4 resin and a 80:20 DMF / piperidine mixture.
- the AA14-5 resin is obtained.
- AA14-6 resin product obtained by reaction between AA14-5 resin and palmitic acid.
- AA14-6 resin is obtained.
- Molecule AA14 (1843-04-CBU)
- the AA14-6 resin is treated with a 1: 1 TFA / dichloromethane mixture (50 mL). After stirring for 30 minutes at room temperature, the resin is filtered and washed with dichloromethane (3 ⁇ 50 mL). The solvents are evaporated under vacuum. Two co-evaporations are then carried out on the residue with dichloromethane (50 ml) and then diisopropyl ether (50 ml).
- Table 1 list of co-polyamino acids synthesized according to the invention. Part AB: synthesis of co-polyamino acids
- Example AB14 Co-polyamino acid AB14 - sodium poly-L-glutamate modified at one of its ends by the molecule AA1 and having a number-average molecular weight (Mn) of 3400 g / mol
- ⁇ -benzyl-L-glutamate N-carboxyanhydride 25.59 g, 97.2 mmol
- anhydrous DMF 140 mL
- the mixture is stirred under argon until complete solubilization, cooled to 4 ° C, and then the solution of AA1 molecule prepared as described above is introduced quickly.
- the mixture is stirred at 4 ° C and room temperature for 2 days and then heated at 65 ° C for 2 hours.
- the reaction mixture is then cooled to room temperature and then poured dropwise into diisopropyl ether (1.7 L) with stirring.
- the white precipitate is recovered by filtration, washed twice with diisopropyl ether (140 mL) and then dried under vacuum at 30 ° C to obtain a white solid.
- the solid is diluted in TFA (160 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (62 mL, 354 mmol) is then added dropwise at 0 ° C.
- HBr hydrobromic acid
- acetic acid 62 mL, 354 mmol
- the solution is stirred for 2 hours at room temperature and is then poured dropwise on a mixture of 1: 1 (v / v) diisopropyl ether / water and with stirring (1.9 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
- the white precipitate is recovered by filtration, washed successively with a mixture of 1: 1 (v / v) diisopropyl ether and water (280 ml) and then with water (140 ml).
- the solid obtained is solubilized in water (530 ml) in adjusting the pH to 7 by adding 10 N aqueous sodium hydroxide solution and then 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20 g / liter by adding water to obtain a final volume of 800 mL.
- the mixture is filtered through a 0.45 ⁇ m filter and then purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 ⁇ S / cm.
- the co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.0.
- the aqueous solution is filtered through 0.2 ⁇ m and stored at 4 ° C.
- the calculated average molar mass of the co-polyamino acid AB14 is 3378 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3400 g / mol.
- Example AB15 Co-polyamino acid AB15 - sodium poly-L-glutamate modified at one of its ends by the AA6 molecule and having a number-average molar mass (Mn) 4100 g / mol
- the calculated average molar mass of the co-polyamino acid AB15 is 5005 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 4100 g / mol.
- Example AB16 Co-polyamino acid AB16 - poly-L-glutamate modified at one of its ends by the molecule AA6 and having a number-average molecular weight (Mn) of 6500 g / mol
- the calculated average molar mass of the co-polyamino acid AB16 is 7725 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 6500 g / mol.
- the calculated average molar mass of the co-polyamino acid AB17 is 4500 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3500 g / mol.
- Example AB18 Co-polyamino acid AB18 - poly-L-glutamate modified at one of its ends by the AA7 molecule and having a number-average molecular weight (Mn) of 3700 g / mol
- a poly-L-glutamate sodium modified at one of its ends by the molecule AA7 is obtained by polymerization of ⁇ -methyl / V-ca rboxya hydrate glutamic acid (25.0 g, 133.6 g). mmol) using the hydrochloride salt of the AA7 molecule (2.80 g, 4.32 mmol) as initiator and by deprotecting the methyl esters using a 37% hydrochloric acid solution according to the method described in US Pat. the patent application FR-A-2 801 226.
- the calculated average molar mass of the co-polyamino acid AB18 is 3896 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3700 g / mol.
- Example AB19 Co-polyamino acid AB19 - sodium poly-L-glutamate modified at one of its ends by the AA6 molecule and having a number-average molar mass (Mn) of 10500 g / mol
- the calculated average molar mass of the co-polyamino acid AB19 is 10293 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 10500 g / mol.
- ⁇ -benzyl-L-glutamate N-carboxyanhydride (17.0 g, 64.6 mmol) is placed under vacuum for 30 min and then with anhydrous DMF (30 mL). is introduced. The mixture is stirred under argon until complete solubilization, cooled to 4 ° C, and the solution of AA6 molecule prepared as described above is introduced quickly. The mixture is stirred at 4 ° C. and room temperature for 2 days and then precipitated in diisopropyl ether (0.6 L). The precipitate is recovered by filtration, washed twice with diisopropyl ether (40 mL) and then dried to give a white solid which is dissolved in 80 mL of THF.
- the solid is diluted in TFA (65 mL), and a solution of hydrobromic acid (HBr) at 33% in acetic acid (45 mL, 257.0 mmol) is then added dropwise and at 4 ° C.
- the solution is stirred for 2 hours at room temperature and is then poured dropwise onto a mixture of 1: 1 (v / v) diisopropyl ether / water and with stirring (780 ml). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
- the white precipitate is recovered by filtration, washed successively with a mixture of 1: 1 (v / v) diisopropyl ether and water (70 ml) and then with water (70 ml).
- the solid obtained is solubilized in water (300 mL) by adjusting the pH to 7 by adding 10 N aqueous sodium hydroxide solution and then 1N aqueous sodium hydroxide solution. After solubilization, the theoretical concentration is adjusted to 20. g / L theoretical by addition of water to obtain a final volume of 440 mL. The mixture is filtered on 0.45 ⁇ filter is then purified by ultrafiltration against 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 ⁇ S / cm. The co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7. The aqueous solution is filtered on 0.2 pm and stored at 4 ° C.
- the calculated average molar mass of the co-polyamino acid AB20 is 9619 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 10400 g / mol.
- the calculated average molar mass of co-polyamino acid ⁇ 2 is 4364 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3478 g / mol.
- radicals are represented in the following table by the corresponding hydrophobic molecule before grafting on the co-polyamino acid.
- BAI example BAI molecule
- Molecule B1 product obtained by the reaction between decanoic acid and L-proline.
- Molecule B2 product obtained by the reaction between the molecule B1 and L-lysine.
- Molecule B3 product obtained by reaction between the molecule B2 and Boc-ethylenediamine.
- the organic phase is washed with water (250 ml), a saturated aqueous solution of NaHCCb (250 ml), an aqueous solution of 1 N HCl (250 ml), a saturated aqueous solution of NaCl (250 mL) and dried over Na2S0 4. After filtration and concentration under vacuum, the residue obtained is purified by chromatography on silica gel (ethyl acetate, methanol) to give a colorless oil.
- Example BA2 molecule BA2
- Molecule B4 product obtained by the reaction between lauric acid and L-proline.
- Molecule B5 product obtained by the reaction between the molecule B4 and L-lysine.
- Example BA3 molecule BA3
- Molecule B7 product obtained by the reaction between myristic acid and L-proline.
- Molecule B8 product obtained by the reaction between the molecule B7 and L-lysine
- Molecule B9 product obtained by the reaction between Boc-ethylenediamine and the molecule B8.
- Example BA4 molecule BA4
- BIP molecule product obtained by the reaction between the molecule B8 and Boc-1-amino-4,7,10-trioxa-13-tridecane.
- Molecule B11 product obtained by reaction between palmitoyl chloride and L-proline
- a white solid of molecule B11 is obtained.
- Molecule B12 product obtained by reaction between the molecule B11 and L-Lysine
- Molecule B14 product obtained by coupling between the molecule A26 and 2,3-diaminopropionic acid
- Molecule B15 product obtained by coupling between the molecule B14 and Boc-ethylenediamine
- Example BA7 B16 molecule
- BA7 molecule product obtained by the reaction between the A / - (tert "-butoxycarbonyl) -l, 6-diaminohexane and the molecule B8
- Example BB14 co-polyamino acid BBI4 - sodium poly-L-glutamate modified at one of its ends by the molecule BA2 and having a number-average molar mass (Mn) of 4020 g / mol
- ⁇ -benzyl-L-glutamate N-carboxyanhydride (18 g, 68.42 mmol) is placed under vacuum for 30 min and then anhydrous DMF (100 mL) is introduced. .
- the mixture is stirred under argon until complete solubilization, cooled to 4 ° C, and then the BA2 molecule solution prepared as described above is introduced rapidly.
- the mixture is stirred at 4 ° C and room temperature for 2 days and then heated at 65 ° C for 2 hours.
- the reaction mixture is then cooled to ambient temperature and then poured dropwise into diisopropyl ether (1.2 L) with stirring.
- the white precipitate is recovered by filtration, washed twice with diisopropyl ether (100 mL) and then dried under vacuum at 30 ° C to obtain a white solid.
- the solid is diluted in TFA (105 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (38 mL, 220 mmol) is then added dropwise at 0 ° C.
- HBr hydrobromic acid
- acetic acid 38 mL, 220 mmol
- the solution is stirred for 2 hours at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (600 ml). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
- the white precipitate is recovered by filtration, washed successively with a 1: 1 (v / v) mixture of diisopropyl ether and water (200 ml) and then with water (100 ml).
- the solid obtained is solubilized in water (450 mL) by adjusting the pH to 7 by adding 10 N aqueous sodium hydroxide solution and then 1 N aqueous sodium hydroxide solution.
- the mixture is filtered through a 0.45 ⁇ m filter. then purified by ultrafiltration against a solution of 0.9% NaCl and then water until the conductimetry of the permeate is less than 50 pS / cm.
- the co-polyamino acid solution is then concentrated to about 30 g / L theoretical and the pH is adjusted to 7.
- the aqueous solution is filtered over 0.2 ⁇ and stored at 4 ° C.
- Example BB15 co-polyamino acid BB15 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 3610 g / mol
- the calculated average molar mass of co-polyamino acid BB15 is 4390 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3610 g / mol.
- Example BB16 co-polyamino acid BB16 - sodium poly-L-glutamate modified at one of its ends by the molecule BA4 and having a number-average molar mass (Mn) of 3300 g / mol
- the calculated average molar mass of co-polyamino acid BB16 is 4399 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3300 g / mol.
- EXAMPLE BB18 Co-polyamino acid BB18 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass of 6600 g / mol
- the calculated average molar mass of co-polyamino acid BB18 is 6889 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 6600 g / mol.
- Example BB19 co-polyamino acid BB19 - poly-L-glutamate sodium modified at one of its ends by the molecule BA3 and having a number-average molecular weight (Mn) of 3400 g / mol
- the calculated average molar mass of co-polyamino acid BB19 is 4540 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 3400 g / mol.
- co-polyamino acid BB20 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2500 g / mol
- the calculated average molar mass of co-polyamino acid BB20 is 3332 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 2500 g / mol.
- co-polyamino acid BB21 - sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 1100 g / mol
- the calculated average molar mass of co-polyamino acid BB21 is 2123 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 1100 g / mol.
- co-polyamino acid BB22 - sodium poly-D-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2900 g / mol
- the calculated average molar mass of co-polyamino acid BB22 is 3936 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 2900 g / mol.
- ⁇ -benzyl-L-glutamate N-carboxyanhydride (20.0 g, 76.00 mmol) and ⁇ -benzyl-D-glutamate N- carboxyanhydride (20.0 g, 76.00 mmol) are placed under vacuum for 30 min and then anhydrous DMF (75 mL) is introduced.
- the mixture is stirred under argon until complete solubilization, cooled to 4 ° C., then a solution of molecule BA3 in the form of free amine (5.55 g, 6.91 mmol) in chloroform (14.5 ml) is introduced quickly.
- the mixture is stirred at 4 ° C and room temperature for 18 h and then heated at 65 ° C for 2 h.
- the reaction mixture is then cooled to ambient temperature and then poured dropwise into diisopropyl ether (1.2 L) with stirring.
- the white precipitate is recovered by filtration, washed three times with diisopropyl ether (80 mL) and then dried under vacuum at 30 ° C to obtain a white solid.
- the solid is diluted in TFA (152 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (106 mL, 220 mmol) is then added dropwise at 0 ° C.
- HBr hydrobromic acid
- the solution is stirred for 3 h at room temperature and then is poured dropwise onto a mixture of 1: 1 (v / v) diisopropyl ether / water and stirring (1.84 L).
- the aqueous phase is separated in a dropping funnel and the pH is adjusted to 7.2 by addition of a 10N aqueous solution of NaOH.
- water 250 ml
- the mixture is filtered through a 0.45 filter. pm and then purified by ultrafiltration against a 0.9% NaCl solution and then water until the conductimetry of the permeate is less than 50 ⁇ S / cm.
- the co-polyamino acid solution is then concentrated to approximately 25 g / l, filtered over 0.2 ⁇ and stored at 4 ° C.
- the calculated average molar mass of co-polyamino acid BB23 is 3936 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 2800 g / mol.
- Example BB24 co-polyamino acid BB24 - block copolymer of poly-D-glutamate and sodium poly-L-glutamate modified at one of its ends by the molecule BA3 and having a number-average molar mass (Mn) of 2800 g / mol
- ⁇ -benzyl-D-glutamate N-carboxyanhydride (13.5 g, 51.3 mmol) is placed under vacuum for 30 minutes and then anhydrous DMF (52 mL) is introduced. The mixture is stirred under argon until complete solubilization, cooled to 0 ° C, then a solution of molecule BA3 as free amine (3.43 g, 4.27 mmol) in chloroform (8.6 mL) is introduced quickly.
- the solid is diluted in TFA (96 mL), and a solution of 33% hydrobromic acid (HBr) in acetic acid (68 mL, 388 mmol) is then added dropwise at 0 ° C.
- the solution is stirred for 2 hours at room temperature and is then poured dropwise onto a 1: 1 (v / v) mixture of diisopropyl ether / water and with stirring (1.2 L). After stirring for 2 h, the heterogeneous mixture is allowed to stand overnight.
- the white precipitate is recovered by filtration, washed successively with a mixture of 1: 1 (v / v) diisopropyl ether and water (100 ml) and then with water (100 ml).
- the solid obtained is solubilized in water (900 mL) by adjusting the pH to 7 by adding 10 N aqueous sodium hydroxide solution and then 1N aqueous sodium hydroxide solution.
- the mixture is filtered through a 0.45 ⁇ filter. then purified by ultrafiltration against a solution of 0.9% NaCl and then water until the conductimetry of the permeate is less than 50 pS / cm.
- the co-polyamino acid solution is then concentrated to about 20 g / L theoretical and the pH is adjusted to 7.
- the aqueous solution is filtered on 0.2 ⁇ m and stored at 4 ° C.
- the calculated average molar mass of co-polyamino acid BB24 is 4541 g / mol.
- Aqueous HPLC-SEC (PEG calibrant): Mn 2800 g / mol.
Abstract
Description
Claims
Priority Applications (9)
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BR112018075250-9A BR112018075250A2 (pt) | 2016-06-07 | 2017-06-07 | composição na forma de uma solução aquosa injetável, cujo ph é de 6,0 a 8,0 |
JP2018564397A JP2019517560A (ja) | 2016-06-07 | 2017-06-07 | ヒトグルカゴン及びコポリアミノ酸を含む注射用溶液の形態の組成物 |
SG11201810939PA SG11201810939PA (en) | 2016-06-07 | 2017-06-07 | Compositions in the form of an injectable aqueous solution, comprising human glucagon and an end-grafted copolyamino acid |
CA3027238A CA3027238A1 (fr) | 2016-06-07 | 2017-06-07 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide |
CN201780047755.9A CN109562063A (zh) | 2016-06-07 | 2017-06-07 | 包含人胰高血糖素和末端接枝的共聚氨基酸的可注射水溶液形式的组合物 |
EP17728542.6A EP3463295B1 (fr) | 2016-06-07 | 2017-06-07 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacidegreffe en bout de chaine |
AU2017277590A AU2017277590A1 (en) | 2016-06-07 | 2017-06-07 | Compositions in the form of an injectable aqueous solution, comprising human glucagon and an end-grafted copolyamino acid |
KR1020197000533A KR20190026748A (ko) | 2016-06-07 | 2017-06-07 | 인간 글루카곤 및 말단-그래프트된 코폴리아미노산을 포함하는 주사가능한 수용액 형태의 조성물 |
MX2018015070A MX2018015070A (es) | 2016-06-07 | 2017-06-07 | Composiciones en forma de solucion acuosa inyectable, que comprende glucagon humano y un co-poliaminoacido injertado en el extremo. |
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FR1655221 | 2016-06-07 | ||
FR1655221A FR3052071B1 (fr) | 2016-06-07 | 2016-06-07 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon et un co-polyaminoacide |
FR1750221 | 2017-01-10 | ||
FR1750221A FR3061660B1 (fr) | 2017-01-10 | 2017-01-10 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide |
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PCT/EP2017/063887 WO2017211917A1 (fr) | 2016-06-07 | 2017-06-07 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide statistique |
PCT/EP2017/063888 WO2017211918A1 (fr) | 2016-06-07 | 2017-06-07 | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacidegreffe en bout de chaine |
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US (2) | US10485851B2 (fr) |
EP (2) | EP3463295B1 (fr) |
JP (2) | JP2019517560A (fr) |
KR (2) | KR20190025905A (fr) |
CN (2) | CN109562064A (fr) |
AU (2) | AU2017277590A1 (fr) |
BR (2) | BR112018075250A2 (fr) |
CA (2) | CA3026802A1 (fr) |
MX (2) | MX2018015069A (fr) |
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JP2021510205A (ja) * | 2018-01-24 | 2021-04-15 | グアンジョウ ジンデ バイオテック リミテッドGuangzhou Jinde Biotech., Ltd. | グルカゴン保護剤及びその応用 |
US11129877B2 (en) | 2017-12-07 | 2021-09-28 | Adocia | Compositions in the form of an injectable aqueous solution comprising amylin, an amylin agonist receptor or an amylin analogue and a co-polyamino acid |
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US11191812B2 (en) | 2017-12-07 | 2021-12-07 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid |
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FR3083089A1 (fr) * | 2018-06-29 | 2020-01-03 | 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 |
US20190275110A1 (en) * | 2017-12-07 | 2019-09-12 | Adocia | Compositions in the form of an injectale aqueous solution comprising human glucagon and a co-polyamino acid |
FR3083087A1 (fr) * | 2018-06-29 | 2020-01-03 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide |
US11633460B2 (en) | 2017-12-07 | 2023-04-25 | Adocia | Injectable solution at pH 7 comprising at least one basal insulin wherein the pI is comprised from 5.8 to 8.5 and a co-polyamino acid bearing carboxylate charges and hydrophobic radicals |
CN111727049A (zh) | 2017-12-07 | 2020-09-29 | 阿道恰公司 | Ph 7的包含至少一种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可注射溶液 |
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- 2017-06-07 CN CN201780049290.0A patent/CN109562064A/zh active Pending
- 2017-06-07 US US15/616,627 patent/US10485851B2/en not_active Expired - Fee Related
- 2017-06-07 JP JP2018564397A patent/JP2019517560A/ja active Pending
- 2017-06-07 US US15/616,542 patent/US10383918B2/en not_active Expired - Fee Related
- 2017-06-07 CA CA3026802A patent/CA3026802A1/fr not_active Abandoned
- 2017-06-07 WO PCT/EP2017/063887 patent/WO2017211917A1/fr unknown
- 2017-06-07 AU AU2017277590A patent/AU2017277590A1/en not_active Abandoned
- 2017-06-07 CA CA3027238A patent/CA3027238A1/fr not_active Abandoned
- 2017-06-07 SG SG11201810901VA patent/SG11201810901VA/en unknown
- 2017-06-07 WO PCT/EP2017/063888 patent/WO2017211918A1/fr unknown
- 2017-06-07 BR BR112018075250-9A patent/BR112018075250A2/pt not_active Application Discontinuation
- 2017-06-07 SG SG11201810939PA patent/SG11201810939PA/en unknown
- 2017-06-07 KR KR1020197000540A patent/KR20190025905A/ko unknown
- 2017-06-07 JP JP2018564218A patent/JP2019521107A/ja active Pending
- 2017-06-07 EP EP17728542.6A patent/EP3463295B1/fr active Active
- 2017-06-07 KR KR1020197000533A patent/KR20190026748A/ko unknown
- 2017-06-07 MX MX2018015069A patent/MX2018015069A/es unknown
- 2017-06-07 MX MX2018015070A patent/MX2018015070A/es unknown
- 2017-06-07 AU AU2017277589A patent/AU2017277589A1/en not_active Abandoned
- 2017-06-07 BR BR112018075259-2A patent/BR112018075259A2/pt not_active Application Discontinuation
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- 2017-06-07 EP EP17728541.8A patent/EP3463294B1/fr active Active
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US10987426B2 (en) | 2017-12-07 | 2021-04-27 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid |
WO2019110837A1 (fr) * | 2017-12-07 | 2019-06-13 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide |
WO2019115411A1 (fr) * | 2017-12-07 | 2019-06-20 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide |
US11191812B2 (en) | 2017-12-07 | 2021-12-07 | Adocia | Compositions in the form of an injectable aqueous solution comprising human glucagon and a co-polyamino acid |
US11173109B2 (en) | 2017-12-07 | 2021-11-16 | Adocia | Compositions in the form of an injectable aqueous solution comprising amylin, an amylin receptor agonist or an amylin analog and a co-polyamino acid |
US11129877B2 (en) | 2017-12-07 | 2021-09-28 | Adocia | Compositions in the form of an injectable aqueous solution comprising amylin, an amylin agonist receptor or an amylin analogue and a co-polyamino acid |
WO2019110836A1 (fr) * | 2017-12-07 | 2019-06-13 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant du glucagon humain et un co-polyaminoacide |
JP2021510205A (ja) * | 2018-01-24 | 2021-04-15 | グアンジョウ ジンデ バイオテック リミテッドGuangzhou Jinde Biotech., Ltd. | グルカゴン保護剤及びその応用 |
JP7158063B2 (ja) | 2018-01-24 | 2022-10-21 | グアンジョウ ジンデ バイオテック リミテッド | グルカゴン保護剤及びその応用 |
FR3083086A1 (fr) * | 2018-06-29 | 2020-01-03 | Adocia | Compositions sous forme d'une solution aqueuse injectable comprenant de l'amyline, un agoniste au recepteur de l'amyline ou un analogue d'amyline et un co-polyaminoacide |
FR3084584A1 (fr) * | 2018-08-03 | 2020-02-07 | Adocia | Solution injectable a ph 7 comprenant du glucagon humain et un compose amphiphile porteur de radicaux hydrophobes |
WO2020025825A1 (fr) * | 2018-08-03 | 2020-02-06 | Adocia | Solution injectable a ph 7 comprenant du glucagon humain, au moins une espece ionique et un compose amphiphile porteur de radicaux hydrophobes |
EP4091625A1 (fr) | 2021-05-22 | 2022-11-23 | Adocia | Compositions comprenant des hormones à brève durée d'action pour traiter ou prévenir l'obésité et pompes comprenant ladite composition |
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US10383918B2 (en) | 2019-08-20 |
SG11201810939PA (en) | 2019-01-30 |
MX2018015070A (es) | 2019-05-09 |
EP3463295A1 (fr) | 2019-04-10 |
US20170348395A1 (en) | 2017-12-07 |
KR20190025905A (ko) | 2019-03-12 |
WO2017211917A1 (fr) | 2017-12-14 |
EP3463295B1 (fr) | 2020-08-05 |
CN109562063A (zh) | 2019-04-02 |
SG11201810901VA (en) | 2019-01-30 |
US10485851B2 (en) | 2019-11-26 |
BR112018075250A2 (pt) | 2019-03-12 |
JP2019521107A (ja) | 2019-07-25 |
CA3026802A1 (fr) | 2017-12-14 |
MX2018015069A (es) | 2019-05-09 |
KR20190026748A (ko) | 2019-03-13 |
EP3463294A1 (fr) | 2019-04-10 |
BR112018075259A2 (pt) | 2019-03-12 |
CA3027238A1 (fr) | 2017-12-14 |
AU2017277590A1 (en) | 2019-01-24 |
AU2017277589A1 (en) | 2019-01-24 |
CN109562064A (zh) | 2019-04-02 |
JP2019517560A (ja) | 2019-06-24 |
US20170348394A1 (en) | 2017-12-07 |
EP3463294B1 (fr) | 2020-08-05 |
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